Oncology Reports

A frequent somatic mutation in the 3'UTR of GAPDH facilitates the development of ovarian cancer by creating a miR‑125b binding site

Ovarian cancer (OVCA) is one of the most common types of cancer in women worldwide. Recent studies have focused on the presence and effect of somatic mutations in patients with OVCA; however, studies on the roles of mutations located in the untranslated regions (UTR) of genes in OVCA remain limited. In the present study, a frequent somatic mutation in the glyceraldehyde 3‑phosphate dehydrogenase (GADPH) 3'UTR was identified using transcriptome sequencing of 120 pairs of OVCA tissue samples. The mutant GAPDH 3'UTR promoted tumor growth and cell motility. Furthermore, the mutation in the GAPDH 3'UTR significantly downregulated the levels of mature miR‑125b by creating a new miR‑125b binding site. Finally, STAT3 levels were increased in SKOV3 cells stably expressing the mutant GADPH 3'UTR, which is a critical target gene of miR‑125b. In conclusion, the present study demonstrated that the mutation located in GAPDH 3'UTR promoted OVCA growth and development by sponging miR‑125b and thereby affecting STAT3 expression levels.

Association of iRhom1 and iRhom2 expression with prognosis in patients with cervical cancer and possible signaling pathways

Several proteins in the iRhom family function as oncogenic regulators in certain cancers. However, the function of these proteins in cervical cancer (CC) is unknown. The relationship of iRhom1 and iRhom2 expression with the clinicopathological features and prognosis of patients with CC was investigated, and their possible molecular mechanisms were examined using in vitro experiments. The expression of iRhom1 and iRhom2 in CC samples of 83 patients was determined by immunohistochemistry (IHC), and the associations of their expression with the clinicopathological features of patients were determined. The relationship of iRhom1, iRhom2, and Ki‑67 expression with survival rates was determined using Kaplan‑Meier analysis and Cox regression analyses. HeLa cells were analyzed using MTT assays, cell cycle analysis, and apoptosis assays. The results revealed that CC tissues had higher levels of iRhom1 and iRhom2 than adjacent normal tissues. Increased expression of iRhom1, iRhom2, and K‑i67 was significantly associated with tumor stage, size, and parametrium invasion. High expression of iRhom1, iRhom2 and Ki‑67 was correlated with poor outcomes. Cancer stage and iRhom2 expression were independent prognostic indicators of CC. Knockdown of iRhom1 and iRhom2 in HeLa cells inhibited cell proliferation, promoted the G1 phase and relieved S‑phase arrest, and induced apoptosis. Genomic microarray analysis indicated that iRhom2 knockdown altered several pathways with roles in oncogenesis, including the expression of five genes in the Wnt/β‑catenin pathway. Western blotting in HeLa cells revealed that iRhom1 knockdown significantly suppressed the expression of β‑catenin, Myc, p‑EGFR and TGFBR2, and increased the expression of FAS; iRhom2 knockdown significantly suppressed the expression of β‑catenin, GSK3β, p‑EGFR and Myc. These results were consistent with the genomic microarray data. Collectively, the results indicated that iRhom1 and iRhom2 may function as oncogenes in CC and are potential therapeutic targets.

KRT7 promotes epithelial‑mesenchymal transition in ovarian cancer via the TGF‑β/Smad2/3 signaling pathway

Keratin 7 (KRT7) is a member of the keratin gene family. KRT7 is abnormally expressed in various types of cancer and promotes the malignant progression of tumors. However, the role of KRT7 in ovarian cancer remains unclear. The present study aimed to validate the role of KRT7 in ovarian cancer progression. KRT7 expression levels in patients with ovarian cancer were analyzed using data obtained from the Human Protein Atlas and The Cancer Genome Atlas databases. KRT7 mRNA and protein expression levels were upregulated in ovarian cancer tissue compared with normal tissue. KRT7 expression was associated with the grading, staging and poor prognosis of ovarian cancer. The differentially expressed genes affected by KRT7 were primarily enriched in the functions of cell migration, cell adhesion and cell growth. In vitro studies, including a CCK8 assay, were used to detect cell proliferation. In addition, wound healing and transwell assays were performed to analyze cell migration. The results demonstrated that KRT7 overexpression was associated with increased proliferation, migration and epithelial‑mesenchymal transition (EMT) of ovarian cancer cells, and the migration and EMT of ovarian cancers cells were decreased following knockdown with KRT7 small interfering RNA. In vivo, knockdown of KRT7 inhibited tumor growth of ovarian cancer. Furthermore, KRT7 regulated EMT in ovarian cancer via the TGF‑β/Smad2/3 pathway, and regulated cell‑matrix adhesion through integrin‑β1‑focal adhesion kinase signaling. These results suggest that KRT7 may be a potential molecular marker for prognosis prediction in patients with ovarian cancer.

miRNA‑199b‑3p suppresses growth and progression of ovarian cancer via the CHK1/E‑cadherin/EMT signaling pathway by targeting ZEB1

Ovarian cancer is one of the most common gynecological malignancies and its pathogenesis and progression are regulated by multiple genes. MicroRNAs (miRNAs) are endogenous non‑coding RNAs that regulate body function by altering post‑transcriptional gene expression. Previous studies have suggested that miRNAs are closely associated with the pathogenesis and progression of several malignancies, including breast cancer, hepatocellular carcinoma and glioma, among others. Therefore, miRNAs are promising novel targets for the diagnosis, treatment and determination of prognostic factors in patients with ovarian cancer. In the present study, the role of miRNA‑133b‑3p in ovarian cancer progression and its possible mechanism of action were investigated. The results demonstrated that the expression of miRNA‑199b‑3p and zinc finger E‑box binding homeobox (ZEB)1 were increased in patients with ovarian cancer. The overall survival (OS) and disease‑free survival (DFS) of patients with ovarian cancer and high miRNA‑199b‑3p expression were prolonged compared with those of patients with low miRNA‑199b‑3p expression. Additionally, the OS and DFS of patients with ovarian cancer and low ZEB1 expression were longer compared with those of patients with high ZEB1 expression. Furthermore, miRNA‑199b‑3p overexpression reduced cell proliferation and promoted apoptosis in an in vitro model of ovarian cancer. miRNA‑199b‑3p overexpression also suppressed ZEB1 and checkpoint kinase 1 expression and induced E‑cadherin expression and epithelial‑to‑mesenchymal transition in this model. Furthermore, the effects of miRNA‑199b‑3p‑mediated apoptosis and migration were attenuated by ZEB1 and E‑cadherin, respectively. The results of the present study indicated that miRNA‑199b‑3p suppressed ovarian cancer progression by targeting ZEB1, which may represent a promising therapeutic target for ovarian cancer.

FBLN5 is targeted by microRNA‑27a‑3p and suppresses tumorigenesis and progression in high‑grade serous ovarian carcinoma

High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecological malignancies; however, the precise molecular mechanisms have not been fully characterized. Fibulin‑5 (FBLN‑5) is an extracellular matrix (ECM) glycoprotein, and plays a crucial role in maintaining the stability of ECM structures, regulating cell proliferation and tumorigenesis. In the present study, the expression of FBLN‑5, as determined by western blot analysis and immunohistochemistry, was significantly increased in normal fallopian tube (FT) samples compared with that in HGSOC samples, and decreased FBLN5 expression was associated with unfavorable prognosis of HGSOC. Functional characterization revealed that FBLN5 overexpression significantly inhibited migration, invasion and proliferation abilities of ovarian cancer cells in vitro. Furthermore, micro (mi)RNA‑27a‑3p (miR‑27a‑3p) was revealed to be increased in HGSOC, and dual‑luciferase reporter assay indicated that miR‑27a‑3p was functioned as a negative regulator of FBLN5 by directly binding with its 3'‑untranslated region. Collectively, FBLN5 expression was associated with prognosis, proliferation, and metastasis in HGSOC. We hypothesized that FBLN5 was targeted by miR‑27a‑3p and may serve as a biomarker and provide a new therapeutic approach for the treatment of HGSOC.

miR‑1299/NOTCH3/TUG1 feedback loop contributes to the malignant proliferation of ovarian cancer

Recent studies have revealed the oncogenic role of notch reporter 3 (NOTCH3) in ovarian cancer (OC). However, the possible regulators and mechanisms underlying notch receptor 3 (NOTCH3)‑mediated behaviors in OC remain to be completely investigated. In the present study, we aimed to identify regulators of NOTCH3 and their interactions underlying the pathogenesis of OC. Bioinformatics analysis and luciferase reporter assay were used to identify potential regulatory miRNAs and lncRNAs of NOTCH3 in OC. Several in vivo and in vitro assays were performed to evaluate their effects on the proliferative ability mediated by NOTCH3. We identified microRNA‑1299 (miR‑1299) as a novel negative regulator of NOTCH3. miR‑1299 was downregulated in OC and was found to be considerably correlated with tumor differentiation. Upregulation of miR‑1299 inhibited cell proliferation, colony formation, and 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation, as well as induced cell cycle arrest in the G0G1 phase in OC cells. Overexpression of miR‑1299 in xenograft mouse models suppressed tumor growth in vivo. The lncRNA taurine upregulated gene 1 (TUG1), acting as a sponge of miR‑1299, was found to upregulate NOTCH3 expression and promote cell proliferation in OC through the competing endogenous RNA mechanism. In addition, TUG1 was found to be a potential downstream target of NOTCH3, forming a miR‑1299/NOTCH3/TUG1 feedback loop in the development of OC. Collectively, our findings improve the understanding of NOTCH3‑mediated regulation in OC pathogenesis and facilitate the development of miRNA‑ and lncRNA‑directed diagnostics and therapeutics against this disease.

SNAI2 enhances HPV‑negative cervical cancer cell dormancy by modulating u‑PAR expression and the activity of the ERK/p38 signaling pathway in vitro

The prognosis of patients with human papillomavirus (HPV)‑negative cervical cancer is significantly worse than that of patients with HPV‑positive cervical cancer. Understanding the mechanisms of this is crucial for preventing disease evolution. In the present study, the GV367‑snail family transcriptional repressor 2 (SNAI2) lentiviral vector was constructed and transduced into C‑33A cells. Subsequently, the proliferation of tumor cells was detected using the Cell Counting Kit (CCK)‑8 method. Flow cytometry was used to analyze the cell cycle progression of tumor cells. The glucose consumption of tumor cells was detected using an oxidase assay, and the senescence of tumor cells was detected using beta‑galactosidase staining. The gene expression and the activity of p38 and ERK1/2 were detected using reverse transcription‑quantitative PCR and western blotting, respectively. The C‑33A‑SNAI2 cell line was successfully established. Compared with HeLa and C‑33A‑Wild cells, the proliferation and percentage of G0/G1‑phase cells in the C‑33A‑SNAI2 group were decreased, as detected by the CCK‑8 assay (100±0 vs. 239.1±58.3 vs. 39.7±20.1, P<0.01) and flow cytometry (34.0±7.1% vs. 46.2±10.6% vs. 61.3±5.3%, P<0.05). Compared with the HeLa group, the glucose consumption of the C‑33A‑Wild and C‑33A‑SNAI2 groups was significantly decreased (P<0.01). The results of beta‑galactosidase staining showed that the proportion of beta‑galactosidase‑positive cells in the C‑33A‑SNAI2 group was significantly decreased compared with the C‑33A‑Wild group (P<0.01). Upregulation of SNAI2 enhanced the increase in p21 expression, and the decrease in CDK1, urokinase plasminogen activator receptor (u‑PAR) and cyclin D1 expression in C‑33A cells compared with C‑33A‑Wild cells (P<0.05). In addition, the activities of p38, ERK1/2 and the phosphorylated (p)‑ERK1/2/p‑p38 ratio were decreased in the C‑33A‑SNAI2 group compared with the C‑33A‑Wild and HeLa groups (P<0.05). In conclusion, SNAI2 enhanced HPV‑negative cervical cancer C‑33A cell dormancy, which was characterized by G0/G1 arrest, by the downregulation of u‑PAR expression, and a decrease in the activity of the p‑ERK1/2 and p‑p38MAPK signaling pathways

Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS

High ATP6V1B1 expression is associated with poor prognosis and platinum‑based chemotherapy resistance in epithelial ovarian cancer

The vacuolar ATPase H+ transporting V1 subunit B1 (ATP6V1B1) belongs to the family of ATP6Vs, which functions to transport hydrogen ions. The expression of ATP6V1B1 and associated clinicopathological features have been linked to various cancers; however, its role in epithelial ovarian cancer (EOC) has remained to be explored. The present study aimed to unveil the function, molecular mechanisms and clinical significance of ATP6V1B1 in EOC. The mRNA levels of ATP6V1 subunits A, B1 and B2 in EOC tissues were determined using data from the Gene Expression Profiling Interactive Analysis database and RNA sequencing. Protein levels of ATP6V1B1 were evaluated through immunohistochemistry staining of EOC, borderline, benign and normal epithelial tissues. The association between ATP6V1B1 expression and clinicopathological features and prognosis of patients with EOC was analyzed. Furthermore, the biological role of ATP6V1B1 in ovarian cancer cell lines was also assessed. RNA sequencing and public dataset analyses revealed elevated ATP6V1B1 mRNA levels in EOCs. High ATP6V1B1 protein levels were also observed in EOC compared with those of borderline and benign tumors and nonadjacent normal epithelial tissues. High ATP6V1B1 expression was associated with the serous cell type, advanced International Federation of Gynecology and Obstetrics stage, high/advanced tumor grade, elevated serum cancer antigen 125 levels and platinum resistance (P<0.001, P<0.001, P=0.035, P=0.029 and P=0.011, respectively). High expression levels of ATP6V1B1 were also associated with poor overall and disease‑free survival (P<0.001). Knockdown of ATP6V1B1 decreased cancer cell proliferation and colony‑forming abilities (P<0.001)

Dual inhibition of FOXM1 and its compensatory signaling pathway decreased the survival of ovarian cancer cells

The present study aimed to analyze the compensatory signaling pathways induced by forkhead domain inhibitor‑6 (FDI‑6), which is a forkhead box protein M1 (FOXM1) inhibitor, in ovarian cancer cells and evaluate the effectiveness of simultaneous inhibition of FOXM1 and the compensatory signaling pathway in decreasing the survival of ovarian cancer cells. The present study identified the proteins involved in the compensatory mechanism activated by FDI‑6 in HeyA8 ovarian cancer cells using western blot analysis and a reverse‑phase protein array. In addition, a cell viability assay was performed to determine the effects of FDI‑6 and the compensatory signaling pathway on cancer cell viability. All experiments were performed in three‑dimensional cell cultures. The present study observed that FDI‑6 stimulated the upregulation of N‑Ras, phosphoprotein kinase Cδ (p‑PKCδ) (S664) and HER3 in HeyA8 cells. Tipifarnib as an N‑Ras inhibitor, rottlerin as a p‑PKCδ (S664) inhibitor and sapitinib as a HER3 inhibitor were selected. The combination of FDI‑6 with tipifarnib attenuated the upregulation of N‑Ras induced by FDI‑6 and the combination of FDI‑6 with sapitinib also attenuated HER3 downstream signaling pathway in HeyA8 cells, as shown by on western blot analysis. Rottlerin downregulated p‑PKCδ (S664) by inhibiting the activity of a Src‑related tyrosine kinase that transfers a phosphate group to PKCδ. Compared with FDI‑6 alone, the addition of tipifarnib or rottlerin to FDI‑6 was significantly more effective in reducing the growth of HeyA8 cells. However, the combination of FDI‑6 and sapitinib did not induce a significant decrease in survival of HeyA8 cells. In conclusion, the addition of tipifarnib or rottlerin to inhibit N‑Ras or p‑PKCδ (S664), respectively, inhibited the compensatory signaling pathway response induced by FDI‑6 in HeyA8 cells. These inhibitors increased the efficacy of FDI‑6, which inhibits FOXM1, in reducing ovarian cancer cell viability.

Long non‑coding RNA BLACAT2/miR‑378a‑3p/YY1 feedback loop promotes the proliferation, migration and invasion of uterine corpus endometrial carcinoma

Uterine corpus endometrial carcinoma (UCEC) is a common gynecological malignancy with high rates of mortality and morbidity. The expression of long non‑coding RNA bladder cancer‑associated transcript 2 (BLACAT2) has been previously found to be aberrantly upregulated in UCEC. However, the regulatory consequences of this in UCEC progression remain poorly understood. In the present study, human UCEC cell lines AN3CA and HEC‑1‑A were infected with lentiviruses to overexpress BLACAT2 (Lv‑BLACAT2) or knock down BLACAT2 using short hairpin RNA (Lv‑shBLACAT2). BLACAT2 overexpression was found to promote the G1/S transition of cell cycle progression and UCEC cell proliferation. In addition, BLACAT2 overexpression was observed to facilitate UCEC cell migration and invasion. By contrast, BLACAT2 knockdown resulted in inhibitory effects in UCEC cell physiology. BLACAT2 overexpression also contributed to the activation of the MEK/ERK pathway. Subsequently, BLACAT2 was demonstrated to bind to microRNA (miR)‑378a‑3p according to dual‑luciferase assays, where it appeared to function as a sponge of miR‑378a‑3p in 293T cells. miR‑378a‑3p overexpression was found to suppress UCEC cell proliferation, invasion, and ERK activation. Lentivirus‑mediated knockdown of its target, the transcription factor Yin Yang‑1 (YY1), was observed to reverse the oncogenic effects of BLACAT2 overexpression. Furthermore, YY1 was found to bind to the promoter of BLACAT2, suggesting that YY1 can regulate BLACAT2 expression. To conclude, results from the present study suggest that BLACAT2, miR‑378a‑3p and YY1 can form a feedback loop instead of an unidirectional axis, which can in turn regulate UCEC tumorigenesis through the MEK/ERK pathway. The present study furthered the understanding of UCEC tumorigenesis and may provide novel therapeutic targets for UCEC treatment.

A small molecule STAT3 inhibitor, LLL12, enhances cisplatin‑ and paclitaxel‑mediated inhibition of cell growth and migration in human ovarian cancer cells

Ovarian cancer is one of the most lethal cancer types in American women. The platinum agent cisplatin, and/or paclitaxel, remains the first‑line chemotherapy for ovarian cancer, but the treatment success is severely limited by chemoresistance. As previously reported, persistent STAT3 signaling is associated with resistance to cisplatin and paclitaxel. To investigate whether the STAT3 small molecule inhibitor LLL12 can enhance the treatment effect of cisplatin and paclitaxel in ovarian cancer cells, A2780, SKOV3, CAOV‑3 and OVCAR5 cells were treated with LLL12, cisplatin and paclitaxel, alone or combination, and cell viability, cell migration, cell growth and protein expression levels were then evaluated. It was found that, for all four human ovarian cancer cell lines, STAT3 phosphorylation was significantly inhibited by LLL12. The combined treatment of LLL12 with paclitaxel or LLL12 with cisplatin exerted significantly greater inhibition of cell viability, cell migration and cell growth than did monotherapy. In addition, LLL12 and cisplatin in combination, or the three drugs in combination, also led to greater inhibition of cell viability and cell migration than combined cisplatin and paclitaxel treatment, a standard treatment for ovarian cancer. The present results demonstrated that the STAT3 small molecule inhibitor LLL12 is a potent inhibitor of STAT3 phosphorylation, cell viability and migration in human ovarian cancer cells. Combining LLL12 with cisplatin or paclitaxel may be a viable therapeutic approach in the treatment of patients with ovarian cancer exhibiting persistent STAT3 signaling.

Oroxylin�A exerts anticancer effects on human ovarian cancer cells via the PPARγ‑dependent reversal of the progesterone receptor membrane component 1/2 expression profile

Ovarian cancer is the most lethal gynecological cancer worldwide. To date, the therapeutic approaches available for the treatment of ovarian cancer are still very limited. The present study first demonstrated that the Chinese herb, Oroxylin A, exerts inhibitory effects on both the migratory ability and viability of ovarian cancer cells. Notably, the inhibitory effects of the drug occurred in a dose‑dependent manner. Oroxylin A only inhibited cell migration at the lower dose, whereas it induced early or late apoptosis at the middle or higher doses, respectively. Mechanistically, Oroxylin A increased peroxisome proliferator‑activated receptor gamma (PPARγ) expression and altered the expression profile of progesterone receptor membrane component (PGRMC)1/2. Notably, PPARγ was revealed to play a central role in Oroxylin A‑mediated anticancer activity. The silencing of PPARγ significantly abrogated Oroxylin A‑induced apoptotic cell death and restored the expression profile of the PGRMC1/2 family in ovarian cancer cells. Collectively, the present study revealed that Oroxylin A exerted marked anticancer effects against ovarian cancer in vitro. Thus, Oroxylin A may have potential for use as a complementary therapy in the treatment of ovarian cancer.

Hormone therapy for ovarian cancer: Emphasis on mechanisms and applications (Review)

Ovarian cancer (OC) remains the leading cause of mortality due to gynecological malignancies. Epidemiological studies have demonstrated that steroid hormones released from the hypothalamic‑pituitary‑ovarian axis can play a role in stimulating or inhibiting OC progression, with gonadotropins, estrogens and androgens promoting OC progression, while gonadotropin‑releasing hormone (GnRH) and progesterone may be protective factors in OC. Experimental studies have indicated that hormone receptors are expressed in OC cells and mediate the growth stimulatory or growth inhibitory effects of hormones on these cells. Hormone therapy agents have been evaluated in a number of clinical trials. The majority of these trials were conducted in patients with relapsed or refractory OC with average efficacy and limited side‑effects. A better understanding of the mechanisms through which hormones affect cell growth may improve the efficacy of hormone therapy. In the present review article, the role of hormones (GnRH, gonadotropins, androgens, estrogens and progestins) and their receptors in OC tumorigenesis, and hormonal therapy in OC treatment is discussed and summarized.

miR‑26a inhibits ovarian cancer cell proliferation, migration and invasion by targeting TCF12

Epithelial ovarian cancer (OC) is a common cause of death from gynecological tumors. MicroRNAs (miRNAs) may function as either oncogenes or tumor suppressors, playing crucial role not only in tumorigenesis, but also in tumor invasion and metastasis. miR‑26a and transcription factor 12 (TCF12) have been reported to be involved in carcinogenesis, but the regulatory role of miR‑26a/TCF12 in OC remains unknown. The aim of the present study was to investigate the expression profiles of TCF12 and miR‑26a in OC patients and the correlation between TCF12 and miR‑26a expression, and to demonstrate the effects of miR‑26a binding on TCF12, to further reveal the miR‑26a/TCF12 regulatory effects on the proliferation, migration, invasion and apoptosis in OC cells. In the present study, the expression of miR‑26a was found to be low, while TCF12 was highly expressed in OC patient tissues and cell lines, and low miR‑26a expression was statistically significantly correlated with high TCF12 expression. To the best of our knowledge, the present study was the first to demonstrate that TCF12 is a direct target of miR‑26a, and upregulation of miR‑26a resulted in TCF12 inhibition in OC cells. Furthermore, the proliferation, migration and invasion were inhibited and apoptosis was induced by miR‑26a upregulation in OC cells. These results indicated that miR‑26a may act as a tumor suppressor in OC, and TCF12 targeting by miR‑26a may be a new therapeutic strategy for OC.

LncRNA TTN‑AS1 promotes endometrial cancer by sponging miR‑376a‑3p

Increasing research has demonstrated that lncRNAs participate in the development of multiple cancer types. However, the role of TTN‑AS1 in endometrial cancer (EC) remains unknown. The present study aimed to explore the function of titin‑antisense RNA1 (TTN‑AS1) in EC progression and the underlying mechanisms. qRT‑PCR was performed to assess the TTN‑AS1 expression patterns in EC tissues and cell lines. Loss of function experiments were carried out to estimate the effects of TTN‑AS1 on EC cell proliferation, migration and invasion. To reveal the underlying mechanisms, informatics tools were used to predict the targets. Rescue experiments were performed to investigate the TTN‑AS1‑regulated miR‑376a‑3p/pumilio homolog 2 (PUM2) axis involved. The results of the present study revealed that TTN‑AS1 was highly expressed in both EC tissues and cell lines, and TTN‑AS1 knockdown inhibited EC cell proliferation, migration and invasion. With respect to the mechanisms, miR‑376a‑3p was revealed to be targeted by TTN‑AS1, and reversed the effects on EC development induced by TTN‑AS1. In addition, PUM2 was positively regulated by TTN‑AS1, and miR‑376a‑3p mediated the regulation between them. Furtherly, in vivo experiments confirmed the results. Collectively, TTN‑AS1 enhanced EC cell proliferation and metastasis by targeting the miR‑376a‑3p/PUM2 axis, which may shed light on EC diagnosis and treatment.

RHPN1‑AS1 promotes ovarian carcinogenesis by sponging miR‑485‑5p and releasing TPX2 mRNA

Long non‑coding RNAs (lncRNAs) play a crucial role in cancer development. However, researchers have yet to identify the underlying association between lncRNAs and ovarian cancer (OC). The aim of the present study was to examine the effect of lncRNA RHPN1‑AS1 (RHPN1‑AS1) on OC cells and tissues. Reverse transcriptase‑quantitative PCR (RT‑qPCR) was utilized to quantify RHPN1‑AS1, miR‑485‑5p, and

Role of hsa‑miR‑105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer

More than 70% of patients with epithelial ovarian cancer (EOC), one of the leading cause of gynecological cancer‑related deaths worldwide, are diagnosed at an advanced stage of the disease. Currently, the mainstay for treatment of advanced EOC is tumor debulking surgery followed by combined platinum‑ and paclitaxel (PTX)‑based chemotherapy. However, most patients eventually develop chemoresistance, which remains a major obstacle to successful treatment. Herein, by using clinical specimens and experimentally induced cell models, we found that the expression levels of hsa‑miR‑105 were significantly decreased in PTX‑resistant EOC tissues and cell lines. Follow‑up functional experiments demonstrated that repression of hsa‑miR‑105 conferred resistance to paclitaxel in EOC cells, whereas restoration of hsa‑miR‑105 expression

Progesterone induces cell apoptosis via the CACNA2D3/Ca2+/p38 MAPK pathway in endometrial cancer

Endometrial cancer (EC) is one of the most common malignant gynecological tumors in women. The main treatments for EC (surgery, chemotherapy and radiation therapy) produce significant side effects. Thus, it is urgent to identify promising therapeutic targets and prognostic markers. CACNA2D3, as a member of the calcium channel regulatory α2δ subunit family, is reported to exert a tumor suppressive effect in numerous cancers. However, the function of CACNA2D3 in EC is not well known. In the present study, CACNA2D3 was lowly expressed in EC tissues and cells. The overexpression of CACNA2D3 via lentiviral particle injection significantly blocked the tumor growth in an in vivo xenograft model. In vitro, the overexpression of CACNA2D3 markedly inhibited cell proliferation and migration, and promoted cell apoptosis and calcium influx. These data revealed that CACNA2D3 functions as a tumor suppressor in EC. It was also revealed that the addition of progesterone (P4) blocked tumor growth in Ishikawa‑injected nude mice. P4 induced the expression of CACNA2D3 in vivo and in vitro, and the silencing of CACNA2D3 affected P4‑inhibited cell proliferation and P4‑induced cell apoptosis and calcium influx. In Ishikawa cells, P4 enhanced the expression of phosphorylated (p)‑p38 MAPK and PTEN, but blocked the levels of p‑PI3K and p‑AKT. The knockdown of CACNA2D3 blocked the function of P4. These data revealed that P4 promoted cell apoptosis via the activation of the CACNA2D3/Ca2+/p38 MAPK pathway, and blocked cell proliferation via suppression of the PI3K/AKT pathway. Collectively, these findings indicated the antitumor role of CACNA2D3 in EC, and revealed the mechanism of P4 inhibition of EC progression, which provided a new target for EC therapy and new evidence for P4 in EC therapy.

Bcl2l10 induces metabolic alterations in ovarian cancer cells by regulating the TCA cycle enzymes SDHD and IDH1

Bcl2‑like‑10 (Bcl2l10) has both oncogenic and tumor suppressor functions depending on the type of cancer. It has been previously demonstrated that the suppression of Bcl2l10 in ovarian cancer SKOV3 and A2780 cells causes cell cycle arrest and enhances cell proliferation, indicating that Bcl2l10 is a tumor suppressor gene in ovarian cancer cells. The aim of the present study was to identify possible downstream target genes and investigate the underlying mechanisms of action of Bcl2l10 in ovarian cancer cells. RNA sequencing (RNA‑Seq) was performed to obtain a list of differentially expressed genes (DEGs) in Bcl2l10‑suppressed SKOV3 and A2780 cells. The RNA‑Seq data were validated by reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis, and the levels of metabolites after Bcl2l10‑knockdown were measured using colorimetric assay kits. Pathway enrichment analysis revealed that the commonly downregulated genes in SKOV3 and A2780 cells after Bcl2l10‑knockdown were significantly enriched in metabolic pathways. The analysis of the DEGs identified from RNA‑Seq and validated by RT‑qPCR revealed that succinate dehydrogenase complex subunit D (SDHD) and isocitrate dehydrogenase 1 (IDH1), which are key enzymes of the TCA cycle that regulate oncometabolite production, may be potential downstream targets of Bcl2l10. Furthermore, Bcl2l10‑knockdown induced the accumulation of succinate and isocitrate through the downregulation of SDHD and IDH1. The present study was the first to elucidate the metabolic regulatory functions of Bcl2l10 in ovarian cancer cells, and the results indicated that Bcl2l10 may serve as a potential therapeutic target in ovarian cancer.

HPV E7 affects the function of cervical cancer cells via the TAL1/lnc‑EBIC/KLHDC7B axis

High‑risk human papillomavirus (HPV)16 and 18 are the primary cause of cervical cancer (CC) and long non‑coding RNAs (lncRNAs/lncs) are often abnormally expressed in patients with CC. The authors' previous study indicated that oncogenic enhancer of zeste homolog 2 (EZH2)‑binding lncRNA in cervical cancer (lnc‑EBIC) serves a role in the tumorigenic activity of the HPV E6 protein in patients with CC. However, whether HPV E7 affects the development of CC through lnc‑EBIC, and the potential mechanisms underlying this remains unclear. Therefore, the present study investigated the effects of lnc‑EBIC and HPV E7 in cervical cancer cell lines HeLa, CaSki and C33A

DDX41 regulates the expression and alternative splicing of genes involved in tumorigenesis and immune response

DEAD‑box helicase 41 (DDX41) is an RNA helicase and accumulating evidence has suggested that DDX41 is involved in pre‑mRNA splicing during tumor development. However, the role of DDX41 in tumorigenesis remains unclear. In order to determine the function of DDX41, the human DDX41 gene was cloned and overexpressed in HeLa cells. The present study demonstrated that DDX41 overexpression inhibited proliferation and promoted apoptosis in HeLa cells. RNA‑sequencing analysis of the transcriptomes in overexpressed and normal control samples. DDX41 regulated 959 differentially expressed genes compared with control cells. Expression levels of certain oncogenes were also regulated by DDX41. DDX41 selectively regulated the alternative splicing of genes in cancer‑associated pathways including the EGFR and FGFR signaling pathways. DDX41 selectively upregulated the expression levels of five antigen processing and presentation genes (HSPA1A, HSPA1B, HSPA6, HLA‑DMB and HLA‑G) and downregulated other immune‑response genes in HeLa cells. Additionally, DDX41‑regulated oncogenes and antigen processing and presentation genes were associated with patient survival rates. Moreover, DDX41 expression was associated with immune infiltration in cervical and endocervical squamous cancer. The present findings showed that DDX41 regulated the cancer cell transcriptome at both the transcriptional and alternative splicing levels. The DDX41 regulatory network predicted the biological function of DDX41 in suppressing tumor cell growth and regulating cancer immunity, which may be important for developing anticancer therapeutics.

Exosomal miR‑663b exposed to TGF‑β1 promotes cervical cancer metastasis and epithelial‑mesenchymal transition by targeting MGAT3

Transforming growth factor (TGF)‑β1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor‑derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF‑β1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF‑β1 stimulated cervical cancer cells to secrete more miR‑663b‑containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR‑663b directly targets the 3'-untranslated regions (3'‑UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial‑mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR‑663b, causing increased expression of epithelial differentiation marker E‑cadherin and decreased expression of mesenchymal markers N‑cadherin and β‑catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify

[Expression of Concern] Adenovirus‑mediated truncated Bid overexpression induced by the Cre/LoxP system promotes the cell apoptosis of CD133 + ovarian cancer stem cells

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that a section of the western blot image for β‑actin in Fig. 1B on p. 157 had also been used for the control β‑actin blots in Fig. 3C on p. 159, despite these data having come from different sources (Fig. 1: CD133

SIRT1 and gynecological malignancies (Review)

Sirtuin 1 (SIRT1), a member of the sirtuin protein family, is a nicotinamide adenine dinucleotide (NAD

Cross‑validation of genes potentially associated with neoadjuvant chemotherapy and platinum‑based chemoresistance in epithelial ovarian carcinoma

Ovarian carcinomas have the poorest prognosis and the highest mortality among gynecological malignancies. Neoadjuvant chemotherapy (NACT) is considered as a novel therapeutic strategy and an alternative treatment for advanced epithelial ovarian cancer (AEOC). The aim of the present study was to identify the core genes related to platinum‑based NACT resistance in AEOC and to allow screening at the molecular level for the most appropriate ovarian cancer patients for NACT. We obtained three drug‑resistant microarrays GSE114206, GSE41499 and GSE33482 from the Gene Expression Omnibus (GEO) database as well as a microarray representing NACT, GSE109934. Bioinformatics analysis revealed the nature of the four potential candidate genes for using in functional enrichment analyses and interaction network construction. The potential associations and possible genetic alterations among the DEGs were summarized using the STRING database in Cytoscape and the cBioPortal visualization tool, respectively. A total of 63 genes were identified as DEGs from GSE109934 representing NACT. From the drug‑resistant GSE114206 and GSE41499 datasets, 106 DEGs containing 36 upregulated genes and 70 downregulated genes were selected, and from the drug‑resistant GSE114206 and GSE33482 datasets, 406 DEGs with 157 upregulated genes and 249 downregulated genes were selected. The 36 upregulated DEGs and the 70 downregulated genes were notably abundant in the different categories. In KEGG pathway analysis, the 157 upregulated genes and the 249 downregulated genes were concentrated in distinctive signaling pathways. Four potential genes associated with NACT and platinum‑based chemoresistance were screened, including nuclear factor of activated T‑cells, cytoplasmic 1 (NAFTc1), Kruppel‑like factor 4 (KLF4), nuclear receptor subfamily 4 group A member 3 (NR4A3) and hepatocyte growth factor (HGF). Our study showed that the mRNA expression levels of NAFTc1, NR4A3 and HGF were increased in drug‑resistant OC cell lines (all P<0.01), whereas the mRNA expression levels of KLF4 were notably lower in the SKOV3‑CDDP and HeyA8‑CDDP cell line (all P<0.01) but higher in the A2780‑CBP cell line. The NAFTc1, KLF4, NR4A3 and HGF genes may be potential therapeutic targets for NACT and platinum‑based chemoresistance factors as well as candidate biomarkers in AEOC. Determination of the expression levels of these four genes in tumor tissues before planning NACT treatment or initial surgery would be beneficial for AEOC patients.

Knockdown of SLCO4C1 inhibits cell proliferation and metastasis in endometrial cancer through inactivating the PI3K/Akt signaling pathway

Endometrial cancer (EC) is the second leading type of cancer among women, and its progression is dependent on several factors. The aim of the present study was to examine the effect of solute carrier organic anion transporter family member 4C1 (SLCO4C1) on human EC and determine the underlying molecular mechanism. A total of 57 differentially expressed genes associated with advanced stage and survival were identified in The Cancer Genome Atlas database. In addition, gene ontology analysis indicated that SLCO4C1 was highly expressed in cell differentiation and integral component of plasma membrane. High SLCO4C1 expression in EC tissues was verified by immunohistochemistry. The results demonstrated that the downregulation of SLCO4C1 could significantly suppress the viability, sphere formation, migration and invasion abilities of cells, but enhance apoptosis in EC cell lines. Furthermore, the present results demonstrated that SLCO4C1 had effects on the epithelial‑mesenchymal transition (EMT) phenotype in EC cells and regulated the expression of EMT‑related proteins. Mechanistically, the present study revealed that SLCO4C1 regulated the biological functions of EC cells by inactivating the PI3K/Akt signaling pathway. Collectively, it was demonstrated that the SLCO4C1/PI3K/Akt pathway may play an important role in EC progression and metastasis and serve as a potential biomarker and target for EC diagnosis and treatment.

The Hedgehog signaling pathway promotes chemotherapy resistance via multidrug resistance protein 1 in ovarian cancer

Various studies have revealed that the Hedgehog (Hh) signaling pathway promotes ovarian cancer invasion, migration and drug resistance. Previous studies by our group have identified a set of genes, including multidrug resistance gene 1 (MDR1), that are regulated by Hh signaling in ovarian cancer. However, the association between Hh signaling activation and MDR1 expression requires further validation. In the present study, reverse transcription‑quantitative PCR or western blot assays were used to evaluate the mRNA and protein expression levels of MDR1, Sonic Hh (Shh), glioma‑associated oncogene 2 (Gli2), Gli1 and γ‑phosphorylated H2A.X variant histone (γ‑H2AX). MTT and colony‑formation assays were performed to determine the effect of cisplatin (DDP) after inhibiting the Hh pathway in ovarian cancer cells. The results indicated that MDR1, Gli2 and Shh levels were much higher in SK‑OV‑3 cells with acquired DDP resistance than in native SK‑OV‑3 cells. ES‑2 cells with overexpression of Gli2 were capable of efficiently forming colonies in the presence of low DDP concentrations. By contrast, Gli2 knockdown in SK‑OV‑3 cells decreased the colony‑forming ability under the same concentration of DDP. As determined by MTT assays, knockdown of Gli2 or targeting of the Hh signaling pathway with either Gli‑antagonist 61 (GANT61) or cyclopamine, in combination with DDP treatment, diminished the viability of ES‑2 and SK‑OV‑3 cells, whereas Gli2 overexpression increased the viability of ES‑2 cells in the presence of DDP. Knockdown of Gli2 or targeting the Hh signaling pathway with GANT61 also increased γ‑H2AX levels but decreased the expression of MDR1 in the presence of DDP. MDR1 expression is regulated by the Hh signaling pathway and is likely a downstream transcription factor of Gli2. In conclusion, targeting the Hh signaling pathway increases the sensitivity of ovarian cancer to DDP. MDR1 is a target gene of the Hh signaling pathway and this pathway may affect chemoresistance of ovarian cancer to DDP via MDR1.

Gomisin A enhances the antitumor effect of paclitaxel by suppressing oxidative stress in ovarian cancer

Gomisin A (GA) is an effective component of

Inhibition of GP130/STAT3 and EMT by combined bazedoxifene and paclitaxel treatment in ovarian cancer

The interleukin 6 (IL‑6)/glycoprotein 130 (GP130)/signal transducer and activator of transcription 3 (STAT3) signalling pathway, with GP130 as an intermediate membrane receptor, is involved in the survival, metastasis, and resistance of ovarian cancer. Bazedoxifene, an FDA‑approved drug, is an inhibitor of GP130 and a selective estrogen modulator (SERM). We studied the mechanism of the combination therapy of bazedoxifene and paclitaxel in inhibiting the IL‑6‑mediated GP130/STAT3 signaling pathway in ovarian cancer. Surface plasmon resonance (SPR) was used to assess the binding of bazedoxifene to GP130. Migration, invasion, and apoptosis of ovarian cancer cells were assessed using bazedoxifene and paclitaxel. In addition, we determined the effects of bazedoxifene and paclitaxel alone or in combination on the GP130/STAT3 pathway and epithelial‑mesenchymal transition (EMT). The results revealed that the combination of bazedoxifene and paclitaxel suppressed cell viability, migration, and invasion in the ovarian cancer cells. In addition, the combination treatment increased apoptosis. Furthermore, bazedoxifene combined with paclitaxel inhibited the growth of ovarian cancer cells in a xenograft tumour model. This combination reduced STAT3 phosphorylation and suppressed gene expression and EMT. In conclusion, inhibition of GP130/STAT3 signalling and EMT via a combination of bazedoxifene and paclitaxel could be used as a therapeutic strategy by which to overcome ovarian cancer.

Ursolic acid: A natural pentacyclic triterpenoid with clinical promise in gynecological and breast cancers (Review)

Gynecological and breast cancers pose significant challenges to women's health worldwide. Despite notable advancements in diagnosis and treatment, they remain leading causes of cancer‑related mortality. Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid widely found in plants, has garnered considerable attention due to its diverse pharmacological activities. It has been demonstrated that UA exhibits a range of biological effects, including antitumor, anti‑inflammatory, and antioxidant properties, with particularly promising therapeutic potential in breast and gynecological cancers. UA exerts its anticancer effects by modulating multiple signaling pathways, such as PI3K/AKT, NF‑κB, and Wnt/β‑catenin, thereby effectively inhibiting tumor cell proliferation, inducing apoptosis, reversing chemoresistance, and suppressing cancer stem cell characteristics. When combined with chemotherapeutic agents such as cisplatin and doxorubicin, UA not only enhances antitumor efficacy but also mitigates the adverse effects associated with chemotherapy. The present review summarizes the recent research progress and underlying mechanisms of UA in the treatment of gynecological and breast cancers, aiming to provide valuable insights for researchers and clinicians in the field.

Role and mechanism of FLNa and UCP2 in the development of cervical cancer

Recent studies have reported that filamin A (FLNa) and uncoupling protein 2 (UCP2) are highly expressed in various types of cancer, but little is currently known about their roles in cervical cancer (CC). In the present study, immunohistochemical staining of paraffin sections of cervical tissues was performed in order to compare the differential expression of FLNa, UCP2, p16 and Ki67 between CC and high‑grade intraepithelial neoplasia (HSIL). UCP2 and FLNa were knocked down in CC cell lines to investigate the effects on cell proliferation, cell cycle arrest, apoptosis, migration and invasion. In addition, the present study investigated the expression of cell‑associated proteins [extracellular signal‑regulated kinase (ERK), phosphorylated (p) ERK, protein kinase B (AKT), p‑AKT and B‑cell lymphoma‑2 (Bcl‑2)] and the mRNA levels of cellular proteins such as Ras, matrix metalloproteinase (MMP)‑2 and MMP‑9. FLNa and UCP2 expression levels were significantly higher in CC tissues than in HSIL tissues, with no significant differential expression of p16 or Ki67. UCP2 expression was significantly different in patients with clinical stage II or higher or lymph node metastasis compared with in other patients with cervical cancer. FLNa or UCP2 knockdown slowed or decreased SiHa and HeLa cell proliferation, migration and invasion, with no significant change in apoptosis, and downregulated the protein levels of p‑ERK1/2, and the mRNA levels of Ras, MMP‑2 and MMP‑9. UCP2 knockdown arrested the cell cycle at the G2 phase in SiHa and HeLa cells, while FLNa knockdown arrested the cell cycle at the G2 phase in HeLa cells. The results of the present study revealed that FLNa and UCP2 play roles in the development and progression of CC via the Ras/MAPK/ERK signalling pathway. FLNa and UCP2 are superior to p16 and Ki67 for early prediction of CC, indicating that FLNa and UCP2 may be used for the early diagnosis of CC. UCP2 may be used to predict the prognosis of CC.

Mechanism of hydrogen on cervical cancer suppression revealed by high‑throughput RNA sequencing

Cervical cancer is considered one of the diseases with the highest mortality among women and with limited treatment options. Hydrogen (H

Kindlin‑2 suppresses cervical cancer cell migration through AKT/mTOR‑mediated autophagy induction

Kindlin‑2 plays a carcinogenic or tumor‑suppressor role in various tumors. However, its role in cervical cancer remains unclear. In the present study, kindlin‑2 expression was first analyzed using public expression data and clinical specimens. It was revealed that kindlin‑2 was downregulated in cervical cancer tissues, and low expression of kindlin‑2 was associated with poor disease‑free survival. In addition, kindlin‑2 was overexpressed and knocked down in two cell lines to study its effect in cervical cancer cells. The results revealed that kindlin‑2 promoted cell autophagy and inactivated AKT/mTOR signaling. Rescue experiments indicated that the regulation of autophagy by kindlin‑2 was dependent on the AKT/mTOR signaling pathway. Furthermore, it was revealed that kindlin‑2 inhibited cell migration, and autophagy was required for this process. Collectively, these findings revealed the role and mechanism of kindlin‑2 in the autophagy and migration of cervical cancer cells.

Filamin B extensively regulates transcription and alternative splicing, and is associated with apoptosis in HeLa cells

Post‑transcriptional mechanisms are an important approach in the treatment of cancer, and may also be hijacked by tumor cells to help adapt to the local microenvironment. Filamin B (FLNB), an actin‑binding protein that provides crucial scaffolds for cell motility and signaling, has also been identified as an RNA‑binding protein. Recent studies demonstrated that FLNB might play an important role, not only in skeletal development, but also in regulating tumorigenesis; however, the effects of dysregulated expression of FLNB at the molecular level are not clear. In the present study, RNA‑sequencing was performed to analyze changes in overall transcriptional and alternative splicing between the knocked‑down FLNB and the control in HeLa cells. Decreased FLNB levels resulted in significantly lower apoptosis compared with control cells. FLNB knockdown extensively regulated the expression of genes in cell apoptosis, tumorigenesis, metastases, transmembrane transport and cartilage development. Moreover, FLNB regulated alternative splicing of a large number of genes involved in 'cell death' and the 'apoptotic process'. Some genes and alternative splicing related to skeletal development were enriched and regulated by FLNB. Reverse transcription‑quantitative‑PCR identified FLNB‑regulated transcription and alternative splicing of genes, such as NLR family apoptosis inhibitory protein, interleukin 23 subunit α, metastasis associated lung adenocarcinoma transcript 1, phosphofurin acidic cluster sorting protein 2, bone morphogenetic protein 7, matrix metallopeptidase 13, collagen type II α 1 chain, fibroblast growth factor receptor 2 and vitamin D receptor. The present study is the first study, to the best of the authors' knowledge, to provide transcriptome‑wide analysis of differential gene expression and alternative splicing upon FLNB silencing. The present results suggested that FLNB may play an important regulatory role in cervical cancer cell apoptosis via regulation of transcription and alternative splicing, which provide insight for the current understanding of the mechanisms of FLNB‑mediated gene regulation.

MicroRNA‑126‑3p suppresses HeLa cell proliferation, migration and invasion, and increases apoptosis via the PI3K/PDK1/AKT pathway

We previously reported that relative to normal cervical mucus, microRNA 126‑3p (miR‑126‑3p) is present in significantly greater amounts in the cervical mucus of patients with overt cervical cancer or precursor lesions. Here, we investigated the effects of enforced miR‑126‑3p expression in the cervical cancer cell line, HeLa, on proliferation, migration, invasion, apoptosis and protein expression. We transfected HeLa cells with miR‑126‑3p miRNA and found that proliferation, migration and invasion by cell counting, wound healing, cell migration and invasion assay were significantly reduced in these cells relative to those transfected with a negative control mimic. The levels of phosphoinositide 3 kinase (PI3K), phosphorylated 3‑phosphoinositide‑dependent protein kinase‑1 (p‑PDK1) and p‑AKT proteins were lower in the miR‑126‑3p‑transfected cells. Phosphorylated 70S6K (p‑p70S6K), phosphorylated glycogen synthase kinase 3β (p‑GSK3β), phosphorylated S6K (p‑S6K), cyclin D1, phosphorylated p21‑activated kinase 1 (p‑PAK1), Rho associated coiled‑coil containing protein kinase 1 (ROCK1), myotonic dystrophy‑related CDC42‑binding kinases α (MRCKα) and phospholipase C γ1 (p‑PLCγ1) were also downregulated. This suggests that downstream effectors of the PI3K/PDK1/AKT pathway are targets for inhibition by miR‑126‑3p. In contrast, apoptotic‑related proteins including the BCL‑2‑associated agonist of cell death (Bad), B‑cell lymphoma‑extra‑large (Bcl‑xL) and BCL‑2‑associated X (Bax), were all upregulated by miR‑126‑3p, resulting in increased caspase 3/7 activity and apoptosis. Thus, enforced expression of miR‑126‑3p inhibited cell migration and invasion and also induced apoptosis by regulating the PI3K/PDK1/AKT pathway in HeLa cells. Hence, high levels of miR‑126‑3p may inhibit cervical carcinogenesis, and targeting the PI3K/PDK1/AKT pathway via miR‑126‑3p could represent a new approach for treating patients with cervical cancer.

The long noncoding RNA FTH1P3 promotes the proliferation and metastasis of cervical cancer through microRNA‑145

Emerging evidence has revealed that long noncoding RNAs (lncRNAs) play crucial roles in the development and progression of tumors. The present study aimed to examine the roles and illustrate the underlying mechanisms of lncRNA ferritin heavy chain 1 pseudogene 3 (FTH1P3) in cervical cancer. The expression of lncRNA FTH1P3 and microRNA‑145 (miRNA‑145 or miR‑145) in human cervical cancer samples and cervical cancer cell lines was detected by qRT‑PCR (reverse transcription‑quantitative polymerase chain reaction). FTH1P3 overexpression, siRNA plasmid, hsa‑miR‑145 mimic or hsa‑miR‑145 inhibitor were transfected. The target of FTH1P3 was predicted by bioinformatics analysis and validated by luciferase assay. Statistical significance analysis was performed by SPSS software. The results revealed that FTH1P3 was significantly upregulated in cervical cancer tissues compared with normal tissues. Increased expression of FTH1P3 was revealed in human cervical cancer cell lines compared with cervical normal epithelial cells. Downregulation of FTH1P3 inhibited cell proliferation, invasion and migration, and promoted apoptosis in cervical cancer cells. miR‑145 was predicted and validated as a direct target of FTH1P3. Moreover, FTH1P3 siRNA partially attenuated the effects of the miR‑145 inhibitor on cell viability and mobility in cervical cancer cells. The present results demonstrated that lncRNA FTH1P3 functioned as a promoting factor in cervical cancer by targeting miR‑145.

Biological implications of decoding the extracellular matrix of vulva cancer

The present review aimed to elucidate the roles of extracellular matrix (ECM) components in the progression of vulvar squamous cell carcinoma (VSCC) and explore potential therapeutic avenues for this type of malignancy. This exploration holds promise for identifying precise molecular targets within the ECM milieu, thus facilitating the development of innovative therapeutic modalities tailored to disrupt these interactions and ultimately improve patient outcomes in VSCC. The dysregulated ECM serves as a potent driver of SCC tumor progression, orchestrating key processes such as angiogenesis, inflammation and stromal cell behavior. Yet, the exploration of ECM role in VSCC is still in its early stages. Recent research highlights the critical role of ECM organization and expression within the tumor microenvironment (TME) in influencing key aspects of VSCC, including tumor staging, grading, metastasis, invasion and patient survival. Cancer‑associated fibroblasts play a pivotal role in this dynamic by engaging in reciprocal interactions with VSCC cells, leading to significant ECM alterations and creating an immune‑suppressive TME. This hinders antitumor immunity and fosters therapeutic resistance in VSCC treatment. The dysregulated ECM in VSCC drives tumor progression, metastasis and affects patient survival. Targeting ECM, along with emerging therapies such as immune checkpoint blockade, offers promise for improved VSCC treatment outcomes.

ABT‑737 increases cisplatin sensitivity through the ROS‑ASK1‑JNK MAPK signaling axis in human ovarian cancer cisplatin‑resistant A2780/DDP cells

Ovarian cancer is a gynecological malignant tumor with the highest mortality rate, and chemotherapy resistance seriously affects patient therapeutic outcomes. It has been shown that the high expression of anti‑apoptotic proteins Bcl‑2 and Bcl‑xL is closely related to ovarian cancer chemotherapy resistance. Therefore, reducing Bcl‑2 and Bcl‑xL expression levels may be essential for reversing drug resistance in ovarian cancer. ABT‑737 is a BH3‑only protein mimetic, which can effectively inhibit the expression of the anti‑apoptotic proteins Bcl‑xL and Bcl‑2. Although it has been shown that ABT‑737 can increase the sensitivity of ovarian cancer cells to cisplatin, the specific molecular mechanism remains unclear and requires further investigation. In the present study, the results revealed that ABT‑737 can significantly increase the activation levels of JNK and ASK1 induced by cisplatin in A2780/DDP cells, which are cisplatin‑resistant ovarian cancer cells. Inhibition of the JNK and ASK1 pathway could significantly reduce cisplatin cytotoxicity increased by ABT‑737 in A2780/DDP cells, while inhibiting the ASK1 pathway could reduce JNK activation. In addition, it was further determined that ABT‑737 could increase reactive oxygen species (ROS) levels in A2780/DDP cells induced by cisplatin. Furthermore, the inhibition of ROS could significantly reduce JNK and ASK1 activation and ABT‑737‑mediated increased cisplatin cytotoxicity in A2780/DDP cells. Overall, the current data identified that activation of the ROS‑ASK1‑JNK signaling axis plays an essential role in the ability of ABT‑737 to increase cisplatin sensitivity in A2780/DDP cells. Therefore, upregulation the ROS‑ASK1‑JNK signaling axis is a potentially novel molecular mechanism by which ABT‑737 can enhance cisplatin sensitivity of ovarian cancer cells. In addition, the present research can also provide new therapeutic strategies and new therapeutic targets for patients with cisplatin‑resistant ovarian cancer with high Bcl‑2/Bcl‑xL expression patterns.

U2AF1 in various neoplastic diseases and relevant targeted therapies for malignant cancers with complex mutations (Review)

POLQ promotes tumor progression and immunosuppression via ATM‑P53 signaling in endometrial cancer

Endometrial cancer (EC) is a one of the most prevalent gynecological malignancies worldwide; however, the molecular mechanisms driving its progression remain insufficiently understood. In the present study, DNA polymerase θ (POLQ), which is implicated in multiple types of cancer, was comprehensively investigated in EC using data from The Cancer Genome Atlas and TNMplot datasets, with further validation in an independent patient cohort. POLQ expression was markedly upregulated in EC tissues and was associated with reduced 15‑year overall survival. Increased POLQ levels were also associated with higher Ki67 proliferation indices, distinct patterns of T‑cell infiltration and enhanced programmed death‑ligand 1 (PD‑L1) expression. Gene Set Enrichment Analysis revealed that POLQ expression was associated with pathways involved in cell proliferation, cell cycle regulation and DNA damage repair. Mechanistic studies based on POLQ knockdown in EC cells were conducted

Mechanistic insights into the roles of astragalosides and Astragalus polysaccharides in gynecological and breast cancers (Review)

PFKFB4 promotes endometrial cancer by regulating glycolysis through SRC‑3 phosphorylation

The present study aimed to investigate the role of 6‑phosphofructo‑2‑kinase/fructose‑2,6‑biphosphatase 4 (PFKFB4) in endometrial cancer cells and to explore its potential molecular mechanisms. PFKFB4 expression in endometrial cancer tissues was detected by immunohistochemistry. Cell Counting Kit‑8, Transwell assays and flow cytometry were used to detect cell proliferation, invasion and apoptosis in endometrial cancer cells after PFKFB4 knockdown. An enzyme‑linked immunosorbent assay was used to detect the glucose and lactic acid contents. Western blotting was performed to detect the levels of glycolysis‑related enzymes, steroid receptor coactivator‑3 (SRC‑3), and phosphorylated SRC‑3.

MS4322 is a selective protein arginine methyltransferase 5 degrader with antitumor effects in cervical cancer cells

Drug therapy serves a key role in the treatment of cervical cancer, which is one of the most common types of solid tumor in female patients. Therefore, it is important to seek more effective and less toxic therapies. Protein arginine methyltransferase 5 (PRMT5) is a key oncogenic target in cervical cancer, providing a rational basis for the development of targeted therapeutic agents. MS4322 is a highly selective proteolysis targeting chimera degrader specifically targeting PRMT5. Therefore, the present study aimed to investigate the therapeutic potential of MS4322 against cervical cancer and the underlying molecular mechanisms. The effects of MS4322 on human cervical HeLa cells were investigated by Cell Counting Kit‑8, clone formation, wound healing and Transwell assay, flow cytometry, immunofluorescence staining, immunohistochemistry and small interfering RNA assay. PRMT5 expression was upregulated in cervical cancer tissue, and functional analyses confirmed that PRMT5 promoted the proliferation of cervical cancer cells. MS4322 significantly decreased PRMT5 mRNA expression, as well as the proliferation, migration, invasion and clone formation ability of HeLa cells, leading to cell cycle arrest in G0/G1 phase and inducing apoptosis. Mechanistically, MS4322 downregulated the expression of PRMT5, β‑catenin, Wnt‑3a, and c‑myc, while upregulating GSK‑3β, thereby inactivating the Wnt/β‑catenin pathway. These findings indicated that MS4322 exerted anti‑tumor effects via regulating the PRMT5/Wnt/β‑catenin pathway and may serve as a promising candidate agent for cervical cancer treatment.

Circular RNAs in endometrial carcinoma (Review)

As one of the leading causes of death in women in Western developed countries, endometrial carcinoma (EC) is a common gynecological malignant tumor that seriously threatens women's health. In recent years, a trend has emerged of EC being manifested in younger women, and its overall incidence is gradually rising. Circular RNAs (circRNAs) are novel endogenous transcripts that have limited ability to encode proteins due to their covalent closed‑loop structure, which differs from that of other types of RNA. A growing body of evidence has demonstrated that circRNAs fulfill an important role in lung cancer, gastric cancer, breast cancer, EC and other malignant tumor types, and they can affect the occurrence and development of these malignancies through a variety of pathways, further demonstrating the potential of circRNAs as molecular biomarkers for the diagnosis, treatment and prognosis of malignant tumors. The purpose of the present review is to summarize the current understanding of the biogenesis and effects of circRNAs, and to discuss the expression, function and underlying mechanism of circRNAs in EC in order to identify potential novel biomarkers.

Interferon‑stimulated gene 15 promotes progression of endometrial carcinoma and weakens antitumor immune response

Endometrial carcinoma (EC) is one of the most common gynecological cancers with a poor prognosis. Therefore, clarifying the details of the molecular mechanisms is of great importance for EC diagnosis and clinical management. Interferon‑stimulated gene 15 (ISG15) plays an important role in the development of various cancers. However, its role in EC remains unclear. High ISG15 expression was observed in EC, which was associated with poor clinical outcomes and pathological stage of patients with EC, thus representing a promising marker for EC progression. Further exploratory analysis revealed that the elevated ISG15 levels in EC were driven by aberrant DNA methylation, independent of copy number variation and specific transcription factor aberrations. Accordingly, knockdown of ISG15 by small interfering RNA attenuated the malignant cellular phenotype of EC cell lines, including proliferation and colony formation

Long non‑coding RNA LINC01224 promotes cell proliferation and inhibits apoptosis by regulating AKT3 expression via targeting miR‑485‑5p in endometrial carcinoma

Endometrial carcinoma (EC) is the most common cancer in women worldwide, yet little is known about the underlying molecular basis of EC development. LINC01224, a novel long non‑coding (lnc)RNA, was recently identified as an oncogene in various types of cancer. However, the function and underlying mechanism of LINC01224 in EC is still unclear. A total of 50 pairs of tumor and adjacent normal tissue from patients with EC, three EC cell lines and one human normal endometrial stromal cell (ESC) line were subjected to reverse transcription‑quantitative PCR assay to evaluate the expression levels of LINC01224. Cell Counting Kit‑8, colony formation and flow cytometry assays were used to assess cell proliferation and apoptosis. Western blotting was used to measure expression levels of apoptosis‑ and proliferation‑associated proteins and AKT3 protein. A xenograft model of HEC1A cells was established to validate the

Identification of early stage recurrence endometrial cancer biomarkers using bioinformatics tools

Endometrial cancer (EC) is the sixth most common cancer in women worldwide. Early diagnosis is critical in recurrent EC management. The present study aimed to identify biomarkers of EC early recurrence using a workflow that combined text and data mining databases (DisGeNET, Gene Expression Omnibus), a prioritization algorithm to select a set of putative candidates (ToppGene), protein‑protein interaction network analyses (Search Tool for the Retrieval of Interacting Genes, cytoHubba), association analysis of selected genes with clinicopathological parameters, and survival analysis (Kaplan‑Meier and Cox proportional hazard ratio analyses) using a The Cancer Genome Atlas cohort. A total of 10 genes were identified, among which the targeting protein for Xklp2 (TPX2) was the most promising independent prognostic biomarker in stage I EC. TPX2 expression (mRNA and protein) was higher (P50% compared with <50%; P<0.01), and in intermediate‑high recurrence risk tumors compared with low‑risk tumors (P<0.05). Further validation studies in larger and independent EC cohorts will contribute to confirm the prognostic value of TPX2.

Circular RNAs: Novel biomarkers for cervical, ovarian and endometrial cancer (Review)

Cervical, ovarian and endometrial cancer are the three most common types of malignant tumor and the leading causes of cancer‑associated death in women. Tumor debulking surgery followed by platinum and paclitaxel chemotherapy is the current treatment regime of choice. However, as a result of late diagnosis and chemoresistance, the survival rates of patients with advanced gynecological cancers remains unsatisfactory. Circular RNAs (circRNAs) are stable noncoding RNAs that are present in a wide variety of tissue and cell types. With the enhancement of RNA sequencing methods, increasing numbers of circRNAs have been identified, and their functions are gradually being revealed. In recent years, circRNAs have received increasing attention for their regulatory roles in cervical, ovarian and endometrial cancer. The aim of the present review was to summarize the possible mechanisms of recently identified circRNAs; we hypothesize that a novel diagnostic and therapeutic biomarker may be identified to prolong the survival time of patients with gynecological malignancies.

Targeting CDK9: A novel biomarker in�the�treatment of endometrial cancer

Endometrial cancer is one of the three major malignant tumors of the female reproductive system. Although cyclin‑dependent kinase 9 (CDK9) has a definitive pathogenic role in various types of cancer, little is known concerning its function in endometrial cancer. Our study was conducted to evaluate the expression and therapeutic potential of CDK9 in endometrial cancer. CDK9 expression was determined by immunohistochemistry in endometrial cancer tissues constructed with paired primary, metastatic, and recurrent tumor tissues from 32 endometrial cancer patients. Small interfering RNA (siRNA) and inhibitors of CDK9 were used to evaluate the effect of CDK9 inhibition on the anti‑apoptotic activity and proliferation in endometrial cancer cells. Colony formation assay and wound‑healing assays were adopted to assess clonal formation and migratory capacity. The results of the immunohistochemistry demonstrated that CDK9 was highly expressed in the human endometrial cancer cell lines; moreover, it was elevated in metastatic and recurrent endometrial tumor tissue compared when compared with that in patient‑matched primary endometrial tumor tissue. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with the inhibitor suppressed cell proliferation and promoted apoptosis in endometrial cancer. In conclusion, our results provide evidence that CDK9 may be a potential prognostic biomarker and a promising therapeutic target for the treatment of endometrial cancer in the future.

MicroRNA‑21‑5p promotes epithelial to mesenchymal transition by targeting SRY‑box 17 in endometrial cancer

MicroRNA (miRNA/miR)‑21‑5p has been proposed as an oncogenic miRNA in human tumors; however, the exact role of miR‑21‑5p has not been fully determined in endometrial cancer. SRY‑box 17 (SOX17) is associated with endometrial cancer development and progression; however, the regulatory mechanisms underlying SOX17 expression in endometrial cancer remain unclear. In the present study, tumor samples were collected from 160 postmenopausal women with endometrial cancer. All tumor samples were examined for miR‑21‑5p expression by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The results demonstrated that miR‑21‑5p expression was associated with shorter overall survival. In addition, overexpression of miR‑21‑5p promoted epithelial to mesenchymal transition (EMT), whereas silencing miR‑21‑5p reversed EMT in endometrial cancer cell lines. Using RT‑qPCR and western blotting, it was revealed that overexpressing miR‑21‑5p significantly inhibited SOX17 protein expression in endometrial cancer cell lines. Furthermore, as determined by luciferase reporter assay, ectopic expression of miR‑21‑5p inhibited the activity of the SOX17 mRNA 3'‑untranslated region (3'UTR), whereas silencing miR‑21‑5p promoted the activity of the SOX17 mRNA 3'UTR in endometrial cancer cell lines. Overexpression of SOX17 promoted mesenchymal to epithelial transition, whereas silencing SOX17 induced EMT in endometrial cancer cell lines. In addition, tumor SOX17 expression was associated with better overall survival. Therefore, it may be concluded that miR‑21‑5p promotes EMT by targeting SOX17 in human endometrial cancer.

BMI‑1 promotes invasion and metastasis in endometrial adenocarcinoma and is a poor prognostic factor

Endometrial adenocarcinoma is one of the most common types of gynecological malignancies and its incidence and mortality rates are increasing. Due to tumor recurrence and metastasis, the overall five‑year survival rate of patients with endometrial adenocarcinoma is shortened. The aim of the present was to investigate the role of the polycomb group protein B‑lymphoma Mo‑MLV insertion region 1 (BMI‑1) in the invasion, metastasis and the epithelial‑mesenchymal transition (EMT) of endometrial adenocarcinoma cells, as well its effects on the prognosis of patients with endometrial adenocarcinoma. Immunohistochemistry was used to examine the expression profile of BMI‑1 in normal and endometrial adenocarcinoma tissues. Western blotting was used to examine the expression levels of BMI‑1 and EMT markers. Kaplan‑Meier plots and a Cox proportional hazards model were used to assess the overall survival. MTT cell viability assays were used to detect the proliferation of endometrial cancer cells. Transwell assays were used to examine cell migration and invasion. Small interfering RNA was used to downregulate BMI‑1 expression levels, to study its effect on EMT. Immunohistochemical and clinicopathological analyses showed that BMI‑1 expression was increased in endometrial adenocarcinoma tissue compared with the normal endometrial tissue (P<0.05). The increased expression levels of BMI‑1 were closely associated with stage, myometrial invasion and lymph node metastasis (P<0.05). Kaplan‑Meier plots and a Cox proportional hazards model showed that increased BMI‑1 expression was associated with a less favorable prognosis [P=0.040, hazards ratio (HR)=1.596] and was associated with late‑stage adenocarcinoma (P=0.006, HR=1.670). Myometrial invasion (P=0.006, HR=1.509) and lymph node metastasis (P=0.004, HR=1.703) were determined to predict a less favorable prognosis. Downregulation of BMI‑1 reduced migration and invasion in endometrial cancer cells in vivo. It was also found that downregulation of BMI‑1 increased the expression levels of the epithelial markers E‑cadherin and keratin, and decreased the expression levels of the mesenchymal markers N‑cadherin, vimentin and the downstream transcription factor, Slug. In conclusion, BMI‑1 expression was correlated with tumor invasion and metastasis, contributing to deep myometrial invasion and lymph node metastasis, and was a poor prognostic factor for endometrial adenocarcinoma.

eIF4E‑related miR‑320a and miR‑340‑5p inhibit endometrial carcinoma cell metastatic capability by preventing TGF‑β1‑induced epithelial‑mesenchymal transition

Endometrial cancer (EC) is a common form of cancer in women. Metastasis is the main cause of EC treatment failure. Eukaryotic translation initiation factor 4E (eIF4E) is an oncogene that is overexpressed in a variety of malignancies and their distant metastases. The present study analyzed microarray data from the Oncomine database and revealed that high eIF4E expression was associated with poor prognosis and high pathological grade of EC. The expression of eIF4E was higher in EC tissues compared with in adjacent normal tissues. In addition, microRNA (miR)‑320a and miR‑340‑5p expression levels were downregulated in EC tissues compared with those in adjacent normal tissues, which suggested that these microRNAs may serve as EC tumor suppressor genes. miR‑320a and miR‑340‑5p could bind to the 3'‑UTR of eIF4E mRNA, thus downregulating the expression of eIF4E and phosphorylated (p)‑eIF4E in EC cells. Overexpression of miR‑320a or miR‑340‑5p effectively suppressed HEC‑1A cell migration and invasion. The downregulation of eIF4E and p‑eIF4E following miR‑320a or miR‑340‑5p transfection reduced the invasiveness and metastatic capability of EC cells in a manner associated with decreased expression of matrix metallopeptidase (MMP)‑3 and MMP‑9. In addition, one of the effects of transforming growth factor β1 (TGF‑β1), which is to induce the phosphorylation of eIF4E, was suppressed by miR‑320a and miR‑340‑5p overexpression. These two microRNAs also attenuated the features of TGF‑β1‑induced epithelial‑mesenchymal transition (EMT). In conclusion, the results of the present study demonstrated that eIF4E was upregulated in EC, whereas miR‑320a and miR‑340‑5p were downregulated in EC compared with adjacent normal tissues. In vitro, miR‑320a and miR‑340‑5p inhibited the migratory capability of EC cells by downregulating MMP‑3 and MMP‑9 and prevented TGF‑β1‑induced EMT through p‑eIF4E.

Osteopontin‑c isoform inhibition modulates ovarian cancer cell cisplatin resistance, viability and plasticity

Osteopontin (OPN) is upregulated in several types of tumor and has been associated with chemoresistance. However, the contribution of OPN splicing isoforms (OPN‑SIs) to chemoresistance requires further investigation. The present study aimed to evaluate the expression patterns of each tested OPN‑SI in cisplatin (CDDP)‑resistant ovarian carcinoma cell lines, focusing on the role of the OPN‑c isoform (OPNc) in drug resistance. ACRP ovarian cancer cells resistant to CDDP, as well as their parental cell line A2780, were used. Analyses of the transcriptional expression of OPN‑SIs, epithelial‑mesenchymal transition (EMT) markers and EMT‑related cytokines were performed using reverse transcription‑quantitative PCR. OPNc was silenced in ACRP cells using anti‑OPNc DNA oligomers and stably overexpressed by transfecting A2780 cells with a mammalian expression vector containing the full length OPNc cDNA. Functional assays were performed to determine cell proliferation, viability and colony formation. The results demonstrated that among the three tested OPN‑SIs, OPNc was the most upregulated transcript in the ACRP cells compared with the parental A2780 cells. In addition, the expression levels of P‑glycoprotein multidrug transporter were upregulated in CDDP‑resistant ACRP cells compared with those in A2780 cells. OPNc knockdown sensitized ACRP cells to CDDP treatment and downregulated P‑gp expression levels compared with those in the negative control group. Additionally, silencing of OPNc impaired cell proliferative and colony formation abilities, as well as reversed the expression levels of EMT markers and EMT‑related cytokines compared with those in the negative control cells. Notably, although stable OPNc overexpression resulted in increased A2780 cell proliferation, it notably increased CDDP sensitivity compared with that in the cells transfected with a control vector. These results suggested that OPNc silencing may represent a putative approach to sensitize resistant ovarian cancer cells to chemotherapeutic agents.

Adipocytes induce the resistance of ovarian cancer to carboplatin through ANGPTL4

The resistance of cancer cells to carboplatin restricts their efficacy in the clinical setting, and a solution to reverse the resistance is urgently required for the treatment of ovarian cancer. An increasing number of studies have found associations between obesity and the incidence, and mortality rates of female cancer. However, the association between adipocytes and the resistance of ovarian cancer has rarely been reported. Based on this, the present study first revealed the inductive effect of adipocytes on the resistance of ovarian cancer to carboplatin using in vivo and in vitro experiments. Subsequently, it was identified that the angiopoietin‑like 4 (ANGPTL4) secreted by adipocytes played a vital role in the resistance of ovarian cancer using bioinformatics analysis, cellular and molecular biological experiments, as well as forward and backward validation. The glycosylated ANGPTL4 protein could bind with integrin α5β1 on the surface of ovarian cancer cells; following which, it could activate the c‑myc/NF‑κB pathway and stimulate the expression of the antiapoptotic protein Bcl‑xL, as well as the ABC transporter family members ABCB1, ABCC1 and ABCG2. Thus, inducing the resistance of ovarian cancer to carboplatin. In conclusion, targeting the adipocyte‑derived ANGPTL4 combined with the application of carboplatin contributes to the clinical treatment for ovarian cancer.

[Expression of Concern] Promoter methylation of death‑associated protein kinase and its role in irradiation response in cervical cancer

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that the blots showing β‑actin mRNA expression in Fig. 1 on p. 1341 appeared to be similar to the β‑actin mRNA blots shown in Fig. 3 on p. 1342, albeit with some horizontal and vertical resizing. The authors were contacted by the Editorial Office to offer an explanation for this apparent anomaly in the presentation of the data in this paper; however, up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Oncology Reports 19: 1339‑1345, 2008; DOI: 10.3892/or.19.5.1339].

EIF3B‑METTL3 complex promotes cell proliferation, invasion and EGFR/AKT signaling in cervical cancer

Eukaryotic translation initiation factor 3B (EIF3B), a translation initiation factor, has been identified to directly interact with methyltransferase‑like (METTL) family members to regulate translation and oncogenic transformation in various types of cancers. However, the interaction mechanism of EIF3B with METTL3 has not yet been reported in cervical cancer (CC). The present study further investigated the interaction between EIF3B and METTL3, as well as their regulatory effect on the malignant behaviors of CC cells. EIF3B overexpression plasmid (oeEIF3B) or small interfering RNA (siRNA; siEIF3B) and negative controls (oeNC and siNC) were transfected into HeLa and SiHa cells. In addition, METTL3 siRNA (siMETTL3) and siNC were transfected along with oeEIF3B or oeNC into HeLa and SiHa cells. Co‑immunoprecipitation was performed to determine the interaction between EIF3B and METTL3. EIF3B expression was found to be elevated in CC cell lines (C‑33A, HeLa, SiHa and CaSki) compared with the control cell line. oeEIF3B accelerated the proliferation and invasion and attenuated the apoptosis of both HeLa and SiHa cells, while siEIF3B exerted an opposite effect. In addition, oeEIF3B activated the EGFR/AKT signaling pathway, whereas siEIF3B suppressed it. Of note, EIF3B and METTL3 formed a complex, according to co‑immunoprecipitation assay; moreover, EIF3B and METTL3 could not regulate the expression of each other. Regardless of the presence or absence of oeEIF3B, siMETTL3 suppressed cell proliferation and invasion, and inhibited EGFR/AKT signaling, while promoting the apoptosis of HeLa and SiHa cells. More importantly, oeEIF3B lost its effect on these cellular functions following the addition of siMETTL3, suggesting that the EIF3B‑METTL3 complex, but not EIF3B alone, plays a cancer‑promoting role in CC. On the whole, the present study demonstrates that the EIF3B‑METTL3 complex induces cell proliferation and invasion, and activates EGFR/AKT signaling in CC.

Histone modifications in cervical cancer: Epigenetic mechanisms, functions and clinical implications (Review)

Cervical cancer (CC) poses a substantial global health challenge and it ranks as the fourth most prevalent malignancy among women worldwide. Management strategies include surgical intervention, radiotherapy, chemotherapy and emerging systemic treatments. Although advancements in immunotherapy and targeted therapies have been achieved, the aggressive metastatic nature of the disease, coupled with immune evasion and drug resistance, continues to limit overall survival rates. Therefore, there remains an urgent need to identify novel treatment modalities and more effective therapeutic agents. As fundamental regulators of epigenetic modifications, histone alterations serve a critical role in controlling gene expression, DNA repair mechanisms and cellular differentiation. These modifications include acetylation, methylation, phosphorylation, ubiquitination, ADP‑ribosylation and glycosylation, as well as the more recently identified lactylation and palmitoylation. By restructuring chromatin and facilitating interactions among histones, DNA and regulatory proteins, these modifications exert a substantial influence on cellular functions. Aberrant histone modifications contribute to tumorigenesis, tumor heterogeneity and resistance to conventional anticancer therapies, making them a key focus of oncological research. In recent years, therapeutic strategies targeting histone modifications have gained increasing attention in the treatment of CC. Among these epigenetic alterations, histone acetylation and deacetylation have been extensively studied, with numerous histone deacetylase inhibitors showing promise in preclinical studies. The present review explores the patterns of histone modifications in CC, emphasizing their molecular roles in tumor progression, metastasis and therapeutic resistance. Additionally, histone modification‑driven therapeutic targets are examined, laying the groundwork for future precision medicine approaches in CC treatment.

IFITM1 as a modulator of surfaceome dynamics and aggressive phenotype in cervical cancer cells

Interferon‑induced transmembrane proteins (IFITMs) are frequently overexpressed in cancer cells, including cervical carcinoma cells, and play a role in the progression of various cancer types. However, their mechanisms of action remain incompletely understood. In the present study, by employing a combination of surface membrane protein isolation and quantitative mass spectrometry, it was comprehensively described how the IFITM1 protein influences the composition of the cervical cancer cell surfaceome. Additionally, the effects of interferon‑γ on protein expression and cell surface exposure were evaluated in the presence and absence of IFITM1. The IFITM1‑regulated membrane and membrane‑associated proteins identified are involved mainly in processes such as endocytosis and lysosomal transport, cell‑cell and cell‑extracellular matrix adhesion, antigen presentation and the immune response. To complement the proteomic data, gene expression was analyzed using reverse transcription‑quantitative PCR to distinguish whether the observed changes in protein levels were attributable to transcriptional regulation or differential protein dynamics. Furthermore, the proteomic and gene expression data are supported by functional studies demonstrating the impact of the IFITM1 and IFITM3 proteins on the adhesive, migratory and invasive capabilities of cervical cancer cells, as well as their interactions with immune cells.

ZBTB7A promotes malignant phenotypes in ovarian cancer through transcriptional activation of CRLF1

Ovarian cancer (OV) remains the most lethal gynecological malignancy, owing to late‑stage diagnosis, high metastatic potential and limited therapeutic efficacy. Although the transcription factor zinc finger and BTB domain‑containing 7A (ZBTB7A) has been implicated in several types of cancer, its role in OV has not yet been systematically characterized. The present study comprehensively investigated the expression pattern, prognostic relevance, functional role and downstream mechanisms of ZBTB7A in OV progression. Multi‑cohort transcriptomic analyses across independent public datasets revealed consistent upregulation of ZBTB7A in OV tissues, and high expression predicted a significantly poor prognosis. Single‑cell RNA sequencing demonstrated that ZBTB7A‑high tumor cells were enriched in proliferative, migratory and epithelial‑mesenchymal transition‑related programs, accompanied by activation of oncogenic pathways such as Wnt/β‑catenin and Hippo‑YAP. Functional assays using overexpression and RNA interference demonstrated that ZBTB7A enhanced malignant phenotypes, including increased cell proliferation, DNA synthesis, clonogenic survival and migration. Further analyses identified cytokine receptor‑like factor 1 (CRLF1) as a key downstream effector of ZBTB7A. ZBTB7A overexpression elevated CRLF1 transcription, whereas CRLF1 knockdown abrogated ZBTB7A‑induced proliferation and migration, defining a functional ZBTB7A/CRLF1 oncogenic axis. Collectively, these findings establish ZBTB7A as an important transcriptional driver of OV aggressiveness and highlight the ZBTB7A/CRLF1 regulatory pathway as a potential prognostic biomarker and therapeutic target.

2‑D08 mediates notable anticancer effects through multiple cellular pathways in uterine leiomyosarcoma cells

2',3',4'‑trihydroxyflavone (2‑D08), a SUMO E2 inhibitor, has several biological functions, including anticancer activity, but its effects on uterine leiomyosarcoma (Ut‑LMS) are unknown. The anticancer activity of 2‑D08 was explored in an

STAT4, a potential predictor of prognosis, promotes CD8 T‑cell infiltration in ovarian serous carcinoma by inducing CCL5 secretion

Ovarian serous carcinoma (OC) is a common cause of mortality among gynecological malignancies. Although tumor‑infiltrating CD8 T cells are associated with a favorable prognosis of OC, the underlying mechanisms are not clearly understood. The present study identified the key genes and potential molecular mechanisms associated with CD8 T‑cell infiltration in OC. The score of CD8 T cells in The Cancer Genome Atlas dataset (376 samples from patients with OC) was estimated using the quanTIseq and MCP‑counter algorithms. Thereafter, a protein‑protein interaction network of differentially expressed genes was constructed and the hub genes were identified using cytoHubba in Cytoscape. The results revealed that signal transducer and activator of transcription 4 (

Expression of Ferredoxin1 in cisplatin‑resistant ovarian cancer cells confers their resistance against ferroptosis induced by cisplatin

Ovarian cancer (OC) is a refractory cancer that shows recurrence due to the acquisition of resistance to anticancer drugs, including cisplatin. However, the molecular mechanism underlying the acquisition of cisplatin resistance by cancer cells remains largely unknown. In the present study, two sets of ovarian endometrioid carcinoma cell lines were used: The parental A2780 cell line, the OVK18 cell line, and their derived cisplatin‑resistant cells. It was found that cisplatin could induce ferroptosis in these parental cells by enhancing mitochondrial membrane potential and lipid peroxidation as assessed by flow cytometric analysis, and that expression of Ferredoxin1 (Fdx1), an iron‑sulfur protein localized to the mitochondria, could be upregulated in cisplatin‑resistant cells in the absence of cisplatin. Intriguingly, it was shown that the siRNA‑mediated depletion of Fdx1 in cisplatin‑resistant cells resulted in enhanced ferroptosis by increasing the mitochondrial membrane potential and lipid peroxidation induced by cisplatin. By examining Fdx1 expression with immunohistochemical analysis in clinical specimens from patients with OC, higher expression of Fdx1 was detected in cisplatin‑resistant specimens than in cisplatin‑sensitive specimens. Collectively, these results indicated that Fdx1 may be a novel and suitable diagnostic/prognostic marker and therapeutic molecular target for the treatment of cisplatin‑resistant OC.

Paclitaxel induces pyroptosis by inhibiting the volume‑sensitive chloride channel leucine‑rich repeat‑containing 8a in ovarian cancer cells

Pyroptosis is a newly identified form of cell death, morphologically characterized by excessive cell swelling. In the present study, paclitaxel (PTX) combined with platinum were used as first‑line chemotherapy, against ovarian cancer cells by inducing multiple types of cell death. However, it remains unclear whether PTX can induce pyroptosis in ovarian cancer cells. It was recently reported that PTX inhibited chloride channels, an inhibition known to cause cell swelling. In the present study, it was first verified that pyroptosis‑like cell death, as well as cleaved‑caspase‑3 and cleaved‑gasdermin E (GSDME) were induced by PTX in A2780 ovarian cancer cells. PTX inhibited the background‑ and hypotonicity‑activated chloride currents, promoted intracellular chloride ion accumulation, those manifestations are similar to those of the classic volume‑regulatory anion channel (VRAC) blocker, 4‑(2‑butyl‑6,7‑dichloro‑2‑cy-clopentyl‑indan‑1‑on5‑yl) oxobutyric acid (DCPIB). Of note, both DCPIB and the downregulation of VRAC constituent protein leucine‑rich repeat‑containing 8a themselves could not induce persisted cell swelling and pyroptosis‑like phenotypes. However, they could enhance the effects of PTX in inducing pyroptosis‑like phenotypes, such as marked cell swelling, cell membrane rupture and excessive activation of caspase‑3 and GSDME N‑terminal fragment, which ultimately caused marked pyroptosis in A2780 cells. These findings revealed a potential mechanism of PTX and offered new insights into the effects of a synergistical combination of PTX and VRACs blockers in ovarian cancer chemotherapy.

HOXA‑AS3 induces tumor progression through the epithelial‑mesenchymal transition pathway in epithelial ovarian cancer

HOXA cluster antisense RNA 3 (HOXA‑AS3) is considered to be involved in several malignancies, however, its biological function in the progression of epithelial ovarian cancer (EOC) remains unclear. The present study compared the expression of HOXA‑AS3 in ovarian cancer and normal ovarian tissues and analyzed the association between the expression of HOXA‑AS3 and the survival outcomes of patients with ovarian cancer. RNA interference was used to suppress HOXA‑AS3 expression in ovarian cancer cell lines in order to demonstrate the function of HOXA‑AS3 in ovarian cancer progression. The associations between HOXA‑AS3 and epithelial‑mesenchymal transition (EMT) markers were explored to verify the mechanism of action of HOXA‑AS3 in ovarian cancer. The results of the present study revealed that ovarian cancer tissues exhibited higher HOXA‑AS3 expression than normal ovarian tissues. Clinical data indicated that HOXA‑AS3 was a significant predictor of progression‑free survival and overall survival. Patients with high HOXA‑AS3 expression had a poorer prognosis than patients with low HOXA‑AS3 expression.

Analysis of the expression and mechanism of follistatin‑like protein 1 in cervical cancer

The abnormal expression of follistatin‑like protein 1 (FSTL1) in various tumors is a crucial regulator of the biological process of tumorigenesis. Nonetheless, the regulatory role of FSTL1 in cervical cancer is yet to be elucidated. Hence, the present study aimed to explore the expression, function, and molecular mechanism of FSTL1 in cervical cancer. The expression of FSTL1 in normal and cervical cancer tissues was examined using quantitative reverse transcription‑polymerase chain reaction and immunohistochemistry assays. The effects of abnormal expression of FSTL1 on cervical cancer cells were assessed using colony formation, MTT, wound‑healing, Transwell, apoptosis, and nude mouse tumorigenicity assays. FSTL1‑related molecular mechanisms were screened using gene chip analysis. Western blotting analysis was used to verify the regulatory mechanisms of FSTL1 in cervical cancer. The results indicated that the expression of FSTL1 was downregulated in cervical cancer tissues and that its downregulation was associated with tumor differentiation, pathologic type, and infiltration depth. Moreover, FSTL1 inhibited the proliferation, migration, and invasion of cervical cancer cells as well as xenograft tumor growth and promoted cell apoptosis. In addition, the findings of gene chip analysis suggested that the differentially expressed genes of FSTL1 were predominantly enriched in multiple signaling pathways, of which the insulin‑like growth factor (IGF)‑1 signaling pathway was significantly activated. Western blotting suggested the involvement of FSTL1 in the regulation of the IGF‑1R/PI3K/AKT/BCL‑2 signaling pathway. These data establish the downregulation of FSTL1 in cervical cancer tissues. FSTL1 inhibited the proliferation, migration, and invasion of cervical cancer cells and promoted their apoptosis. Furthermore, xenograft tumor growth in nude mice was inhibited. FSTL1 may be involved in the regulation of the IGF‑1R/PI3K/AKT/BCL‑2 signaling pathway in cervical cancer. Therefore, FSTL1 may be employed as a novel biomarker to determine the extent of disease progression in patients with cervical cancer.

miR‑27a‑3p upregulation by p65 facilitates cervical tumorigenesis by increasing TAB3 expression and is involved in the positive feedback loop of NF‑κB signaling

An altered microRNA (miRNA/miR)‑27a‑3p expression has been identified in cervical cancer, while the exact regulatory mechanisms responsible for the dysregulation of miR‑27a‑3p remain to be fully elucidated. In the present study, a NF‑κB/p65 binding site was identified upstream of the miR‑23a/27a/24‑2 cluster and p65 binding enhanced the transcription of pri‑miR‑23a/27a/24‑2, as well as the expression levels of mature miRNAs, including miR‑27a‑3p in HeLa cells. Mechanistically, using bioinformatics analyses and experimental validation, TGF‑β activated kinase 1 binding protein 3 (TAB3) was identified as a direct target of miR‑27a‑3p. By binding to the 3'UTR of TAB3, miR‑27a‑3p significantly enhanced TAB3 expression. Functionally, it was found that the overexpression of miR‑27a‑3p and TAB3 promoted the malignant potential of cervical cancer cells, as evaluated using cell growth, migration and invasion assays, and specific cell marker determinations in the epithelial mesenchymal transition progression, and vice versa. Further rescue experiments revealed that the enhanced malignant effects induced by miR‑27a‑3p were mediated via its upregulation of TAB3 expression. Moreover, miR‑27a‑3p and TAB3 also activated the NF‑κB signaling pathway and formed a positive feedback regulatory loop composing of p65/miR‑27a‑3p/TAB3/NF‑κB. On the whole, the findings presented herein may provide novel insight into the underlying cervical tumorigenesis and novel biomarker identification for clinical applications.

[Corrigendum] Triptolide inhibits JAK2/STAT3 signaling and induces lethal autophagy through ROS generation in cisplatin‑resistant SKOV3/DDP ovarian cancer cells

Following the publication of the above article, the authors contacted the Editorial Office to explain that they had made inadvertent errors in compiling a couple of the figures in the above paper; first, regarding the immunohistochemical images shown in Fig. 2D on p. 5, the data panel shown correctly for the 'LC3/TPL+DDP' experiment contained an overlapping section with the 'LC3/TPL' data panel in the same figure part (the latter of which had been incorporated into this figure incorrectly). Secondly, the β‑actin bands correctly shown in Fig. 3D on p. 6 had incorrectly been included to represent the JAK2 western blot data in Fig. 4F on p. 7. However, the authors were able to re‑examine their original data, and realized how these errors had occurred. The revised and corrected versions of Figs. 2 and 4, now showing the correct data for the 'LC3/TPL' experiment in Fig. 2D and the JAK2 western blot data in Fig. 4F, are shown on the next two pages. Note that the errors made with the assembly of the data in these figures did not affect the overall conclusions reported in the paper. The authors apologize to the Editor of

Polyphyllin VII induces mitochondrial apoptosis by regulating the PP2A/AKT/DRP1 signaling axis in human ovarian cancer

Ovarian cancer is a gynecological malignancy with high mortality. Adjuvant therapy such as chemoradiotherapy inevitably leads to side effects and drug resistance. In recent years, traditional Chinese medicine has been widely studied for its safety, effectiveness, and unique pharmacological effects. Polyphyllin VII is an important component of Rhizoma paridis saponins, and has cytotoxic effects on many types of cancer cells. The aim of the present study was to evaluate the anti‑tumor activity of polyphyllin VII in human ovarian cancer cells. Recent studies found that polyphyllin VII induces mitochondrial pathway apoptosis by increasing mitochondrial division, but the specific mechanism was unclear. The results of this study revealed that polyphyllin VII could effectively induce mitochondrial dysfunction, including increased mitochondrial division and reactive oxygen species (ROS) production. Notably, the mitochondrial location of dynamin‑related protein 1 (DRP1) plays an important role in its function. In addition, polyphyllin VII enhanced the mitochondrial localization of DRP1 which is mediated by increased protein phosphatase 2A (PP2A) activity, and decreased AKT activity. A specific PP2A inhibitor, LB100, attenuated mitochondrial division and apoptosis in cells caused by polyphyllin VII, confirming the function of the PP2A/AKT pathway in polyphyllin VII treatment. Additionally, xenotransplantation experiments have also confirmed the anti‑tumor effect of polyphyllin VII in vivo. Therefore, interference of the mitochondrial translocation of DRP1 through PP2A/AKT pathway may be an attractive and effective therapeutic approach by polyphyllin VII in ovarian cancer. This may provide new strategies for polyphyllin VII in the clinical treatment of ovarian cancer.

MicroRNA-134-3p inhibits ovarian cancer progression by targeting flap structure-specific endonuclease 1 in vitro

Ovarian cancer (OC) is one of the most lethal gynecological malignancies in the world. The aim of the present study was to examine the role of microRNA (miR)-134-3p in OC. Reverse transcription-quantitative PCR was used to measure the expression levels of miR-134-3p. Cell Counting Kit-8, TUNEL, flow cytometric and colony formation assays were performed to examine the effects of miR-134-3p on OC cell proliferation. Moreover, wound healing and Transwell assays were performed to examine the effects on migration and invasion. In addition, western blot analyses were used to assess protein expression. Finally, the target genes of miR-134-3p were analyzed by bioinformatics analysis and dual-luciferase reporter assay. The results revealed that miR-134-3p expression was low in OC cells compared with in normal ovarian cells. The overexpression of miR-134-3p decreased cell viability, facilitated cell apoptosis, inhibited cell proliferation and arrested the cell cycle in SKOV-3 and OVCAR-3 cells. Furthermore, transfection using a miR-134-3p mimic inhibited the migration and invasion of SKOV-3 and OVCAR-3 cells, and decreased the protein expression levels of cyclooxygenase-2, matrix metalloproteinase (MMP)2 and MMP9. Bioinformatics analysis indicated that one of the potential target genes of miR-134-3p was flap structure-specific endonuclease 1 (FEN1), which was confirmed by dual-luciferase reporter assay. Moreover, overexpression of miR-134-3p decreased the expression levels of FEN1 in SKOV-3 and OVCAR-3 cells. Additionally, overexpression of FEN1 reversed the effects of the miR-134-3p mimic on the proliferation, migration and invasion of SKOV-3 and OVCAR-3 cells. Overall, the findings of the present study demonstrated that miR-134-3p may inhibit OC cell proliferation, migration and invasion by directly targeting FEN1.

Long non‑coding RNA MCM3AP‑AS1 drives ovarian cancer progression via the microRNA‑143‑3p/TAK1 axis

The long non‑coding RNA (lncRNA) MCM3AP antisense 1 (MCM3AP‑AS1) has previously been shown to be a key regulator of multiple types of cancer; however whether it is important in the context of ovarian cancer (OC) is uncertain. The present study determined that MCM3AP‑AS1 expression in samples from patients with OC was significantly increased, and was associated with tumor stage, presence of lymph node metastases and poorer overall survival. The role of this lncRNA was investigated in vitro, and it was observed that knockdown of MCM3AP‑AS1 impaired OC cell proliferation, migration and colony formation. Similarly, it disrupted tumor growth in vivo. The present study further determined that MCM3AP‑AS1 was able to directly interact with microRNA (miRNA or miR)‑143‑3p as a competing endogenous (ce)RNA for this miRNA, thereby regulating the expression of transforming growth factor‑β‑activated kinase 1 (TAK1), a known target of miR‑143‑3p in OC. Consistent with this, inhibition of miR‑143‑3p was sufficient to partially reverse the effects of MCM3AP‑AS1‑knockdown, which inhibited the proliferation, migration and invasion of OC cells. Together, these results indicate that MCM3AP‑AS1 serves as an oncogenic lncRNA in OC by binding to miR‑143‑3p and thereby promoting TAK1 expression, and suggest that this lncRNA may be a possible target for therapy in OC.

PTEN/AKT/mTOR signaling mediates anticancer effects of epigallocatechin‑3‑gallate in ovarian cancer

Epigallocatechin‑3‑gallate (EGCG), a polyphenol present in green tea, exhibits anticancer effects in various types of cancer. A number of studies have focused on the effects of EGCG on lung cancer, but not ovarian cancer. Previous reports have implicated that EGCG suppressed ovarian cancer cell proliferation and induced apoptosis, but its potential anticancer mechanisms and signaling pathways remain unclear. Thus, it is necessary to determine the anti‑ovarian cancer effects of EGCG and explore the underlying mechanisms. In the present study, EGCG exerted stronger proliferation inhibition on SKOV3 cells compared with A549 cells and induced apoptosis in SKOV3 cells, as well as upregulated PTEN expression and downregulated the expression of phosphoinositide‑dependent kinase‑1 (PDK1), phosphor (p)‑AKT and p‑mTOR. These effects were reversed by the PTEN inhibitor VO‑Ohpic trihydrate. The results of the mouse xenograft experiment demonstrated that 50 mg/kg EGCG exhibited increased tumor growth inhibition compared with 5 mg/kg paclitaxel. In addition, PTEN expression was upregulated, whereas the expression levels of PDK1, p‑AKT and p‑mTOR were downregulated in the EGCG treatment group compared with those in untreated mice in vivo. In conclusion, the results of the present study provided a new underlying mechanism of the effect of EGCG on ovarian cancer and may lead to the development of EGCG as a candidate drug for ovarian cancer therapy.

Identification of an energy metabolism‑related gene signature in ovarian cancer prognosis

Changes in energy metabolism may be potential biomarkers and therapeutic targets for cancer as they frequently occur within cancer cells. However, basic cancer research has failed to reach a consistent conclusion on the function(s) of mitochondria in energy metabolism. The significance of energy metabolism in the prognosis of ovarian cancer remains unclear; thus, there remains an urgent need to systematically analyze the characteristics and clinical value of energy metabolism in ovarian cancer. Based on gene expression patterns, the present study aimed to analyze energy metabolism‑associated characteristics to evaluate the prognosis of patients with ovarian cancer. A total of 39 energy metabolism‑related genes significantly associated with prognosis were obtained, and three molecular subtypes were identified by nonnegative matrix factorization clustering, among which the C1 subtype was associated with poor clinical outcomes of ovarian cancer. The immune response was enhanced in the tumor microenvironment. A total of 888 differentially expressed genes were identified in C1 compared with the other subtypes, and the results of the pathway enrichment analysis demonstrated that they were enriched in the 'PI3K‑Akt signaling pathway', 'cAMP signaling pathway', 'ECM‑receptor interaction' and other pathways associated with the development and progression of tumors. Finally, eight characteristic genes (tolloid‑like 1 gene, type XVI collagen, prostaglandin F2α, cartilage intermediate layer protein 2, kinesin family member 26b, interferon inducible protein 27, growth arrest‑specific gene 1 and chemokine receptor 7) were obtained through LASSO feature selection; and a number of them have been demonstrated to be associated with ovarian cancer progression. In addition, Cox regression analysis was performed to establish an 8‑gene signature, which was determined to be an independent prognostic factor for patients with ovarian cancer and could stratify sample risk in the training, test and external validation datasets (P0.8). Gene Set Enrichment Analysis results revealed that the 8‑gene signature was involved in important biological processes and pathways of ovarian cancer. In conclusion, the present study established an 8‑gene signature associated with metabolic genes, which may provide new insights into the effects of energy metabolism on ovarian cancer. The 8‑gene signature may serve as an independent prognostic factor for ovarian cancer patients.

Molecular mechanisms of platinum‑based chemotherapy resistance in ovarian cancer (Review)

Cisplatin is one of the most effective chemotherapy drugs for ovarian cancer, but resistance is common. The initial response to platinum‑based chemotherapy is as high as 80%, but in most advanced patients, final relapse and death are caused by acquired drug resistance. The development of resistance to therapy in ovarian cancer is a significant hindrance to therapeutic efficacy. The resistance of ovarian cancer cells to chemotherapeutic mechanisms is rather complex and includes multidrug resistance, DNA damage repair, cell metabolism, oxidative stress, cell cycle regulation, cancer stem cells, immunity, apoptotic pathways, autophagy and abnormal signaling pathways. The present review provided an update of recent developments in our understanding of the mechanisms of ovarian cancer platinum‑based chemotherapy resistance, discussed current and emerging approaches for targeting these patients and presented challenges associated with these approaches, with a focus on development and overcoming resistance.

RHPN1‑AS1 promotes ovarian carcinogenesis by sponging miR‑6884‑5p thus releasing TOP2A mRNA

Ovarian cancer, a severe lethal gynecological malignancy, is characterized by both high morbidity and mortality. Long noncoding RNAs (lncRNAs) have recently caused extensive concern due to their regulatory function in various human tumors. There are a mounting number of lncRNAs that are in extreme need of research, serving as biomarkers for diagnosis and therapy for ovarian cancer. In the present study, RT‑qPCR was employed to detect how Rhophilin Rho GTPase binding protein 1 antisense RNA1 (RHPN1‑AS1), miR‑6884‑5p and DNA topoisomerase IIα (TOP2A) are expressed in ovarian cancer tissues or cell lines. BrdU, MTT, colony formation and cell adhesion assays, caspase‑3 activity, flow cytometry and wound healing assay were employed to assess cell proliferation, viability, colony number, adhesion, apoptosis and migration in ovarian cancer, respectively. RHPN1‑AS1 was determined to be enriched in ovarian cancer tissues and cell lines. Silencing of RHPN1‑AS1 was reported to increase cell apoptosis and impair cell proliferation, viability, colony number, adhesion and migration

Ultrasound‑targeted microbubble destruction‑mediated overexpression of Sirtuin 3 inhibits the progression of ovarian cancer

Ultrasound‑targeted microbubble destruction (UTMD) has recently been developed as a promising noninvasive tool for organ‑ and tissue‑specific gene or drug delivery. The aim of the present study was to explore the role of UTMD‑mediated Sirtuin 3 (SIRT3) overexpression in the malignant behaviors of human ovarian cancer (HOC) cells. Reverse transcription‑quantitative PCR was performed to detect

Hypochlorous acid selectively promotes toxicity and the expression of danger signals in human abdominal cancer cells

Tumors of the abdominal cavity, such as colorectal, pancreatic and ovarian cancer, frequently metastasize into the peritoneum. Large numbers of metastatic nodules hinder curative surgical resection, necessitating lavage with hyperthermic intraperitoneal chemotherapy (HIPEC). However, HIPEC not only causes severe side effects but also has limited therapeutic efficacy in various instances. At the same time, the age of immunotherapies such as biological agents, checkpoint‑ inhibitors or immune‑cell therapies, increasingly emphasizes the critical role of anticancer immunity in targeting malignancies. The present study investigated the ability of three types of long‑lived reactive species (oxidants) to inactivate cancer cells and potentially complement current HIPEC regimens, as well as to increase tumor cell expression of danger signals that stimulate innate immunity. The human abdominal cancer cell lines HT‑29, Panc‑01 and SK‑OV‑3 were exposed to different concentrations of hydrogen peroxide (H

Matrine inhibits ovarian cancer cell viability and promotes apoptosis by regulating the ERK/JNK signaling pathway via p38MAPK

Ovarian cancer displays the highest mortality rate among all types of gynecological cancer worldwide. The survival of patients with ovarian cancer remains poor due to poor responses to anticancer treatments. The present study aimed to investigate the therapeutic effects and potential mechanism underlying matrine in ovarian cancer tissues, ovarian cancer cells and a CAOV‑3‑derived tumor‑bearing mouse model. MTT, migration, invasion, flow cytometry, immunofluorescence and immunohistochemistry assays were performed to assess the inhibitory effects of matrine on ovarian cancer. A xenograft ovarian cancer mouse model was established and treated with matrine or PBS. The results demonstrated that compared with the control group, matrine significantly induced ovarian cancer cell apoptosis by upregulating caspase‑8 and Fas cell surface death receptor (Fas) expression levels, and downregulating Bcl‑2 and Bcl‑xl expression levels. Moreover, compared with the control group, matrine significantly inhibited ovarian cancer cell viability, migration and invasion by downregulating metastasis associated protein‑1, fibronectin, angiotensin II type 2 receptor-interacting protein 3a and H high mobility group AT‑hook 2 expression levels. Compared with the control group, matrine significantly increased p38MAPK, phosphorylated (p)ERK/ERK and pJNK/JNK expression levels in ovarian cancer cells. p38MAPK knockdown significantly downregulated p38MAPK, pERK/ERK and pJNK/JNK expression levels compared with the control group, which significantly promoted ovarian cancer cell viability, migration and invasion. In vivo experiments demonstrated that compared with the control group, matrine significantly suppressed tumor growth by markedly upregulating p38MAPK, ERK and JNK expression levels. The immunohistochemistry results demonstrated that caspase‑8 and Fas expression levels were notably increased, whereas Bcl‑2 and Bcl‑xl expression levels were obviously decreased in matrine‑treated tumors compared with PBS‑treated tumors. In conclusion, the present study demonstrated that matrine inhibited ovarian cancer cell viability, migration and invasion, but induced cell apoptosis, suggesting that matrine may serve as a promising anticancer agent for the treatment of ovarian cancer.

Triptolide inhibits JAK2/STAT3 signaling and induces lethal autophagy through ROS generation in cisplatin‑resistant SKOV3/DDP ovarian cancer cells

Advanced and recurrent ovarian cancer has a poor prognosis and is frequently resistant to numerous therapeutics; thus, safe and effective drugs are needed to combat this disease. Previous studies have demonstrated that triptolide (TPL) exhibits anticancer and sensitization effects against cisplatin (DDP)‑resistant ovarian cancer both

BCG immunotherapy inhibits cancer progression by promoting the M1 macrophage differentiation of THP‑1 cells via the Rb/E2F1 pathway in cervical carcinoma

Bacillus Calmette‑Guérin (BCG) immunotherapy increases macrophage polarization toward M1‑type macrophages. In the present study, to identify the M1/M2 marker genes in the carcinogenesis and progression of cervical cancer, the microarray datasets GSE9750 and GSE7803 were downloaded from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and the University of California Santa Cruz (UCSC) Xena browser. Survival analysis revealed that M1 markers (IL‑12) were involved in anti‑tumour progression, and M2 markers (IL‑10) were involved in the carcinogenesis and invasion of cervical cancer. The expression of M1 markers (IL‑12, inducible nitric oxide synthase and CD80) and M2 markers (IL‑10 and arginase) was examined to determine whether BCG affects the polarization of macrophages and to elucidate the underlying mechanisms. The results revealed that BCG promoted macrophage polarization towards the M1 phenotype and enhanced the transition of M2 to M1 macrophages. The results also revealed that polarized M1 macrophages induced by BCG decreased the protein expression of phosphorylated (p‑)retinoblastoma (Rb)/E2F transcription factor 1 (E2F1), inhibited the proliferation and promoted the apoptosis of HeLa cells. On the whole, these results demonstrated that BCG promoted the anti‑tumour progression of M1 macrophages and inhibited the pro‑tumour activation of M2 macrophages via the Rb/E2F1 signalling pathway in HeLa cells. This suggests the possibility of a direct translation of this combination strategy to clinical practice for the treatment of cervical cancer.

Lipidomic profiling reveals lipid regulation by a novel LSD1 inhibitor treatment

Lipid metabolic alterations are associated with cancer progression. Lysine‑specific demethylase 1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the effect of LSD1 on lipid metabolism remains unclear. In the present study, we used a LC‑MS/MS‑based lipidomics approach to investigate the impact of LSD1 on cancer cell lipid metabolism using ZY0511, a specific LSD1 inhibitor developed by our group as a specific probe. ZY0511 profoundly modified the human colorectal and cervical cancer cell lipid metabolism. A total of 256 differential metabolites were identified in HeLa cells, and 218 differential metabolites were identified in HCT116 cells, respectively. Among these lipid metabolites, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelin (SM) were downregulated by ZY0511. In contrast, ceramide (Cer) and a small portion of glycerophospholipids such as phosphatidylinositol and phosphatidylethanolamine were upregulated by ZY0511. These results revealed a disturbance in sphingolipids (SPs) and glycerophospholipids, which may be correlated with the progression of cancer. Furthermore, a marked increase in Cer and prominent decrease in SM were consistent with the upregulated expression of key enzymes in the Cer synthesis process including

FOXD3‑AS1/miR‑128‑3p/LIMK1 axis regulates cervical cancer progression

Long non‑coding RNA forkhead box D3 antisense RNA 1 (FOXD3‑AS1) functions as an oncogenic regulator in several types of cancer, including breast cancer, glioma and cervical cancer. However, the effects and mechanisms underlying FOXD3‑AS1 in cervical cancer (CC) are not completely understood. The present study aimed to investigate the biological functions and potential molecular mechanisms underlying FOXD3‑AS1 in CC progression. Reverse transcription‑quantitative PCR was performed to detect FOXD3‑AS1, microRNA (miR)‑128‑3p and LIM domain kinase 1 (LIMK1) expression levels in CC tissues and cells. Immunohistochemical staining and western blotting were conducted to assess LIMK1 protein expression levels in CC tissues and cells, respectively. Cell Counting Kit‑8 and BrdU assays were used to determine the role of FOXD3‑AS1 in regulating cell proliferation. CC cell migration and invasion were assessed by performing Transwell assays. Dual‑luciferase reporter assays were conducted to verify the binding between miR‑128‑3p and FOXD3‑AS1. FOXD3‑AS1 expression was significantly increased in CC tissues and cell lines compared with adjacent healthy tissues and normal cervical epithelial cells, respectively. High FOXD3‑AS1 expression was significantly associated with poor differentiation of tumor tissues, increased tumor size and positive lymph node metastasis. FOXD3‑AS1 overexpression significantly increased CC cell proliferation, migration and invasion compared with the negative control (NC) group, whereas FOXD3‑AS1 knockdown resulted in the opposite effects compared with the small interfering RNA‑NC group. Moreover, the results demonstrated that FOXD3‑AS1 targeted and negatively regulated miR‑128‑3p, which indirectly upregulated LIMK1 expression. Therefore, the present study demonstrated that FOXD3‑AS1 upregulated LIMK1 expression via competitively sponging miR‑128‑3p in CC cells, promoting CC progression.

PLAU is associated with cell migration and invasion and is regulated by transcription factor YY1 in cervical cancer

Cervical cancer, one of the most common malignancies, has a poor survival rate. The identification of more biomarkers for cervical cancer diagnosis and therapy is urgently needed. Plasminogen activator urokinase (PLAU) exerts multiple biological effects in various physiological and pathological processes; however the role of PLAU in cervical cancer progression is not fully understood. In the present study, the involvement and transcriptional regulation of PLAU in cervical cancer were explored. The expression of PLAU in cervical cancer was first analyzed, and PLAU was found to be overexpressed.

High expression of PDIA4 promotes malignant cell behavior and predicts reduced survival in cervical cancer

The protein disulfide isomerase (PDI) gene family plays important roles in the maintenance of several cellular functions. Previous studies have showed that protein disulfide isomerase family A member 4 (PDIA4) is aberrantly expressed in several types of cancer, and correlates with prognosis of patients. However, the role of PDIA4 in cervical cancer remains unclear. In the present study, the expression pattern of PDIA4 from both public database and immunohistochemical analysis in cervical samples was analyzed. Cell Counting Kit‑8 and Transwell assays were performed to determine the effect of PDIA4 on cervical cancer cell proliferation and migration. Gene set enrichment analysis (GSEA) was used to provide the associated enriched pathways of PDIA4 in regulating cervical tumorigenesis. It was observed that mRNA expression and protein level of PDIA4 were upregulated in cervical cancer tissues. High expression of PDIA4 was significantly associated with poor overall survival (P=0.0095) and relapse‑free survival (P=0.0019) in The Cancer Genome Atlas cohort. Knockdown of PDIA4 inhibited cervical cancer cell proliferation and migration. Moreover, PDIA4 affected the expression of proliferation‑related molecules (cyclin D1 and PCNA) and migration‑related molecules (E‑cadherin and Vimentin). Additionally, GSEA revealed that PDIA4 was significantly associated with gene signatures involving glycan biosynthesis, glycosaminoglycan degradation and protein export. In conclusion, the present findings highlighted the importance of PDIA4 in cervical oncogenesis, and suggested that targeting PDIA4 may be a potential therapeutic application for cervical cancer.

Synergistic effects of thalidomide and cisplatin are mediated via the PI3K/AKT and JAK1/STAT3 signaling pathways in cervical cancer

Thalidomide (THD) has been found to synergize with cisplatin (DDP) in certain types of cancers; however, their combined use in the treatment of cervical cancer has not been reported to date, at least to the best of our knowledge. Thus, the present study aimed to explore the synergistic effects of THD and DDP and determine their regulatory effects on the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT) and Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) pathways in cervical cancer. For this purpose, 0‑160 µM THD and 0‑64 µM DDP monotherapy or in combination were used to treat the HeLa and SiHa cervical cancer cell lines. This was followed by the calculation of the combination index (CI) and 160 µM THD and 16 µM DDP were then used to treat the cells. Relative cell viability and apoptosis, as well as the mRNA and protein levels of PI3K, AKT, JAK1 and STAT3 were evaluated. The results revealed that THD and DDP monotherapy suppressed the viability of the HeLa and SiHa cells in a concentration‑dependent manner. Moreover, THD and DDP treatment exerted a more prominent suppressive effect on the relative viability of HeLa and SiHa cells compared with DDP monotherapy at several concentration settings; further CI calculation revealed that the optimal synergistic concentrations were 160 µM for THD and 16 µM for DDP. Subsequently, combined treatment with THD and DDP suppressed relative cell viability, whereas it promoted cell apoptosis compared with THD or DPP monotherapy; it also inhibited the PI3K/AKT and JAK1/STAT3 signaling pathways compared with DPP or THD monotherapy in both HeLa and SiHa cells. On the whole, the present study demonstrated that THD synergizes with DDP to exert suppressive effects on cervical cancer cell lines. This synergistic action also inactivated the PI3K/AKT and JAK1/STAT3 pathways. Thus, these findings suggest that the combined use of THD and DPP may have potential for use in the treatment of cervical cancer.

Inhibition of LDHA suppresses cell proliferation and increases mitochondrial apoptosis via the JNK signaling pathway in cervical cancer cells

The Warburg effect or aerobic glycolysis is a hallmark of cancer. Lactate dehydrogenase (LDH), which catalyzes conversion of pyruvate into lactate, serves a critical role during Warburg effect. LDH A chain (LDHA), a member of the LDH family, is upregulated in multiple types of cancer and serves a vital role in tumor growth and progression. However, its expression and function in cervical cancer has not been characterized. The present study evaluated LDHA expression in The Cancer Genome Atlas database and found that LDHA was upregulated in cervical cancer compared with normal tissue. To clarify the role of LDHA in cervical cancer HeLa and SiHa cells, lentiviral shRNA was used to stably knockdown LDHA and oxamate, a small‑molecule inhibitor of LDHA, was used to inhibit the activity of LDHA. Glucose uptake assay, lactate production measurement and ATP detection assay demonstrated LDHA inhibition notably decreased glucose consumption, lactate production and ATP levels in both HeLa and SiHa cells. Furthermore, the effect of LDHA inhibition on cell proliferation, cell cycle and apoptosis was investigated by MTT, BrdU incorporation, colony formation assay, flow cytometry and western blotting; LDHA knockdown or oxamate treatment led to decreased cell proliferation and increased apoptosis. Inhibition of LDHA induced G2/M cell cycle arrest and activated the mitochondrial apoptosis pathway. Mechanistically, the JNK signaling pathway was key for LDHA inhibition‑mediated cell cycle arrest and apoptosis. Collectively, these results indicated that LDHA was involved in cervical cancer pathogenesis and may be a promising therapeutic target for treatment.

[Expression of Concern] CDKN3 is an independent prognostic factor and promotes ovarian carcinoma cell proliferation in ovarian cancer

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the cell invasion assay data shown in the three panels of Fig. 6A appeared to contain overlapping sections at different orientations (all three panels), even though the data were apparently meant to show the results of experiments performed under different conditions. The authors were contacted by the Editorial Office to offer an explanation for this apparent anomaly in the presentation of the data in this paper; however, up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Oncology Reports 31: 1825‑1831, 2014; DOI: 10.3892/or.2014.3045].

[Expression of Concern] Lysine demethylase 2A promotes the progression of ovarian cancer by regulating the PI3K pathway and reversing epithelial‑mesenchymal transition

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that one of the colony‑formation assay images shown in Fig. 2D for the SKOV3 experiments was strikingly similar to the 'SKOV3/0 µM LY294002' image shown in Fig. 5E, if one of the dishes were to be rotated 90°. Upon performing an independent analysis of the data in this paper in the Editorial Office, it also came to light that the data shown for the MMP9 blot (A2780 cell line) in Fig. 4E was strikingly similar to the p‑mTOR blot (again for the A2780 cell line) in Fig. 5B, suggesting that one of these figures had been assembled incorrectly. The authors were contacted by the Editorial Office to offer an explanation for these apparent anomalies in the presentation of the data in this paper; however, up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Oncology Reports 41: 917‑927, 2019; DOI: 10.3892/or.2018.6888].

Monotherapy and combination therapy using antibody‑drug conjugates for platinum‑resistant ovarian cancer

Platinum‑resistant ovarian cancer (PROC) is a significant clinical challenge due to the limited number of treatment options and poor outcomes. Moreover, cytotoxic drugs have an unsatisfactory therapeutic efficacy, high toxicity and side effects. An antibody‑drug conjugate (ADC) is a novel cancer therapeutic strategy that combines an antibody, a linker and a payload. ADCs precisely target the tumor cells by binding to the antigen on the surface of tumor cells, thus accurately delivering the cytotoxic drugs and minimizing systemic toxicity. The approval of mirvetuximab soravtansine by the US Food and Drug Administration for treating folate receptor alpha‑positive, platinum‑resistant epithelial ovarian cancer has promoted studies on the use of ADCs in ovarian cancer. A phase III clinical trial showed that mirvetuximab soravtansine achieved an objective remission rate of 42.3% in platinum‑resistant, FRα‑positive ovarian cancer, compared with 15.9% using chemotherapy, demonstrating its immense potential for ADC development. The present review summarizes the research progress on the use of ADCs in PROC as a monotherapy and combination therapy and considers the future development direction of ADCs in PROC.

KLC3 activates PI3K/AKT signaling and promotes ovarian cancer cell proliferation and migration through COL3A1

Ovarian cancer (OC) is a prevalent malignancy; however, the role of kinesin light chain 3 (KLC3) in OC remains unclear. The present study conducted a comprehensive investigation of KLC3 using bioinformatics analysis, as well as

Overexpression of FOS enhances the malignant potential of eutopic endometrial stromal cells in patients with endometriosis‑associated ovarian cancer

Endometrial cysts of the ovary (EMC) may develop into endometriosis (EM)‑associated ovarian cancer over time (EAOC), but the pathogenesis of this disease has not been determined. In the present study, RNA sequencing was used to identify a feasible biomarker, and the molecular function of this biomarker in eutopic endometrial cells from EAOC and EMC patients was evaluated to explore the potential mechanism related to EAOC and orthotopic endometrial tissue. RNA sequencing was performed on 5 EAOC and 4 EMC tissue samples, and differential expression analysis was performed. To identify biomarkers, differentially expressed genes were subjected to protein‑protein interaction network design, Gene Ontology pathway enrichment, and Gene Set Enrichment Analysis pathway enrichment. The expression of

Circadian as a prognostic factor for radiation responses in patients with cervical cancer: A nested case‑control study

The radiation response of cervical cancer is thought to be enhanced by the levels of melatonin due to its roles in the circadian cycle and cancer growth. In the present study, the roles of circadian rhythms and melatonin levels as prognostic factors for predicting the radiation response in patients with cervical cancer were examined. In this nested case‑control study, patients with good and poor responses to radiotherapy were assessed in terms of the time‑of‑day radiation treatment was administered and further influencing factors. The radiation time was determined, as the subjects were either irradiated in the morning (06.00‑10.00 am) or afternoon (04.00‑06.00 pm). Data on tumour size and other biological parameters were collected and analysed by binary logistic regression. Among the 56 patients examined, most subjects had good radiation responses. Most patients were 50 kg, no pain prior to radiation, low erythrocyte sedimentation rates, normal intravenous urography results, moderate or good differentiation on pathology and histo‑pathologically non‑keratinised cells. According to the multivariate analysis, the irradiation time as a surrogate of the circadian cycle (morning vs. afternoon), the initial haemoglobin (Hb) level and the clinical tumour size were significant predictors of the radiation response. The circadian cycle, tumour size and Hb levels may affect the radiation response in patients with cervical cancer. In addition, the morning group had better 5‑year overall survival, but it was not significant, possibly due to the small cohort size. Further research is required to identify more relevant prognostic factors using different radiotherapy techniques [National Clinical Trial (NCT) no. NCT05511740, registration date, 08/20/2022].

Advances in artificial intelligence for the diagnosis and treatment of ovarian cancer (Review)

Artificial intelligence (AI) has emerged as a crucial technique for extracting high‑throughput information from various sources, including medical images, pathological images, and genomics, transcriptomics, proteomics and metabolomics data. AI has been widely used in the field of diagnosis, for the differentiation of benign and malignant ovarian cancer (OC), and for prognostic assessment, with favorable results. Notably, AI‑based radiomics has proven to be a non‑invasive, convenient and economical approach, making it an essential asset in a gynecological setting. The present study reviews the application of AI in the diagnosis, differentiation and prognostic assessment of OC. It is suggested that AI‑based multi‑omics studies have the potential to improve the diagnostic and prognostic predictive ability in patients with OC, thereby facilitating the realization of precision medicine.

Enhancing the therapeutic efficacy of NK cells in the treatment of ovarian cancer (Review)

Ovarian cancer is a prevalent gynecological malignancy associated with a high mortality rate and a low 5‑year survival rate. Typically, >70% of patients present with an advanced stage of the disease, resulting in a high number of ovarian cancer‑associated deaths worldwide. Over the past decade, adoptive cellular immunotherapy has been investigated in clinical trials, and the results have led to the increased use in cancer treatment. Natural killer (NK) cells are cytotoxic lymphoid cells that recognize and lyse transformed cells, thereby impeding tumor growth. Thus, NK cells exhibit potential as a form of immunotherapy in the treatment of cancer. However, some patients with ovarian cancer treated with NK cells have experienced unsatisfactory outcomes. Therefore, further optimization of NK cells is required to increase the number of patients achieving long‑term remission. In the present review article, studies focusing on improving NK cell function were systematically summarized, and innovative strategies that augment the anticancer properties of NK cells were proposed.

Tumor microenvironment manipulates chemoresistance in ovarian cancer (Review)

Ovarian cancer (OC) is the leading cause of mortality among the various types of gynecological cancer, and >75% of the cases are diagnosed at a late stage. Although platinum‑based chemotherapy is able to help the majority of patients to achieve remission, the disease frequently recurs and acquires chemoresistance, resulting in high mortality rates. The complexity of OC therapy is not solely governed by the intrinsic characteristics of the OC cells (OCCs) themselves, but is also largely dependent on the dynamic communication between OCCs and various components of their surrounding microenvironment. The present review attempts to describe the mutual interplay between OCCs and their surrounding microenvironment. Tumor‑associated macrophages (TAMs) and cancer‑associated fibroblasts (CAFs) are the most abundant stromal cell types in OC. Soluble factors derived from CAFs steadily nourish both the OCCs and TAMs, facilitating their proliferation and immune evasion. ATP binding cassette transporters facilitate the extrusion of cytotoxic molecules, eventually promoting cell survival and multidrug resistance. Extracellular vesicles fulfill their role as genetic exchange vectors, transferring cargo from the donor cells to the recipient cells and propagating oncogenic signaling. A greater understanding of the vital roles of the tumor microenvironment will allow researchers to be open to the prospect of developing therapeutic approaches for combating OC chemoresistance.

Erb‑B2 Receptor Tyrosine Kinase 2 is negatively regulated by the p53‑responsive microRNA‑3184‑5p in cervical cancer cells

The oncogenic role of Erb‑B2 Receptor Tyrosine Kinase 2 (ERBB2) has been identified in several types of cancer, but less is known on its function and mechanism of action in cervical cancer cells. The present study employed a multipronged approach to investigate the role of ERBB2 in cervical cancer. ERBB2 and microRNA (miR)‑3184‑5p expression was assessed in patient‑derived cervical cancer biopsy tissues, revealing that higher levels of ERBB2 and lower levels of miR‑3184‑5p were associated with clinicopathological indicators of cervical cancer progression. Furthermore, ERBB2 stimulated proliferation, migration and sphere‑formation of cervical cancer cells in vitro. This effect was mediated by enhanced phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α activity. Additionally, it was revealed that miR‑3184‑5p directly suppressed ERBB2 in cervical cancer cells. The p53 activator Mithramycin A stimulated p53 and miR‑3184‑5p expression, thereby lowering the levels of ERBB2 and attenuating proliferation, migration and sphere‑formation of cervical cancer cells. In conclusion, the findings of the present study suggested ERBB2 as an oncogenic protein that may promote invasiveness in cervical cancer cells. Treatment of cervical cancer cells with the p53 activator Mithramycin A restored the levels of the endogenous ERBB2 inhibitor miR‑3184‑5p and may represent a novel treatment strategy for cervical cancer.

Molecular alterations and clinical relevance in cervical carcinoma and precursors (Review)

Cervical cancer is one of the most common types of cancer and the fourth leading cause of cancer‑related deaths in women. The occurrence and development of cervical cancer is a multifactorial and multilevel process, which usually occurs alongside a continuous high‑risk human papillomavirus infection. With further developments in molecular biology and the advancement of sequencing technology, the role of biomarkers in cervical diseases has been gradually recognized. Therefore, it remains a priority to identify key molecular markers that can be used for the screening and triaging of the lesions. In recent years, numerous studies have been conducted in order to identify important markers for cervical diseases. The present review aimed to summarize the molecular alterations and clinical relevance of chromosomal alterations, DNA polymorphisms, the DNA methylation status, histone modifications, and alterations in microRNA and protein expression levels. Accumulating evidence suggests that molecular alterations may reflect the degree and the prognosis of the disease. Although significant progress has been made in the field of cervical cancer research, further samples and experiments are still required to identify crucial molecules.

Effect of claudin 1 on cell proliferation, migration and apoptosis in human cervical squamous cell carcinoma

Claudin 1 is a member of the claudin protein family that serves an important role in tight junctions. Increased or decreased expression levels of claudin 1 are found in several diseases, including breast cancer and viral infections. However, the function of claudin 1 in cervical cancer remains controversial. The aim of the present study was to investigate the biological functions of claudin 1 in different human cervical cancer cell lines. First, SiHa and ME‑180 cells with stable claudin 1 overexpression or knockdown were established using lentiviral transduction, and the mRNA and protein levels were measured via reverse transcription‑quantitative PCR and western blot analysis. Subsequently, cell proliferation, colony formation and migration experiments were performed in vitro using standard protocols, demonstrating that claudin 1 was able to inhibit cell proliferation and migration in both SiHa and ME‑180 cells. Furthermore, cell cycle and apoptosis were detected via flow cytometry and western blotting, and the results revealed that claudin 1 inhibited cell cycle progression and promoted apoptosis. To further verify whether claudin 1 was involved in tumor growth in vivo, xenograft tumors were established in athymic mice via injecting SiHa cells overexpressing claudin 1, which was found to decrease tumor growth in vivo. Furthermore, the association between claudin 1 expression and prognosis was analyzed in different types of cancer in The Cancer Genome Atlas. Overall, the findings of the present study revealed that claudin 1 may serve an antitumor role in cervical squamous cell carcinoma and may be of value as a potential therapeutic target.

Ropivacaine inhibits cervical cancer cell growth via suppression of the miR‑96/MEG2/pSTAT3 axis

Ropivacaine, one of the most commonly used local anesthetics in clinical practice, has shown potent antitumor activity in multiple types of cancer cells. However, its effect on cervical cancer cell growth remains unknown. In the present study, it was found that ropivacaine inhibited cervical cancer cell growth by suppressing cell cycle progression and promoting cell apoptosis, as determined by CCK‑8 assay, cell cycle and apoptosis analyses. Western blot analysis and luciferase assay demonstrated that ropivacaine abrogated the phosphorylation and transcriptional activation of signal transducer and activator of transcription 3 (STAT3), and that STAT‑3C overexpression reversed the inhibition of cervical cancer cell viability mediated by ropivacaine. Furthermore, our results revealed that the increased expression of maternally expressed gene 2 (MEG2) caused by ropivacaine led to STAT3 dephosphorylation. Finally, we found that ropivacaine upregulated MEG2 by decreasing the expression of microRNA‑96 (miR‑96). Taken together, our results describe a novel mechanism for the anticancer activity of ropivacaine and suggest ropivacaine as a potential therapeutic agent for cervical cancer patients.

The effects of the Wnt/β‑catenin signaling pathway on apoptosis in HeLa cells induced by carbon ion irradiation

The molecular mechanisms underlying the biological effects of carbon ions are unclear. The aim of this study was to explore the Wnt/β‑catenin pathway in regulating carbon ion (12C6+) radiation‑induced cellular toxicity. HLY78 is a Wnt‑specific small molecular modulator, whose effects on 12C6+ radiation‑induced damage are mostly unknown. HLY78, in combination with 12C6+ radiation was investigated on HeLa cell viability, cell cycle progression, DNA damage, and the expression of apoptotic and Wnt‑related proteins. 12C6+ radiation suppressed cell viability in a time‑dependent manner, whereas the addition of HLY78 to cells significantly reduced this stress. Moreover, after irradiation with 12C6+, HeLa cells exhibited increased cell apoptosis, G2/M phase arrest, and a number of γ‑H2AX foci. However, Wnt signaling activation alleviated these effects. Furthermore, when compared with the radiation alone group, supplementation with HLY78 markedly increased the expression of anti‑apoptotic and Wnt‑related proteins, and significantly decreased the expression of apoptotic proteins. The present results indicated that activation of the Wnt/β‑catenin signaling pathway by HLY78 reduced 12C6+ radiation‑induced HeLa cell dysfunction, suggesting that the Wnt/β‑catenin signaling pathway plays an important role in regulating 12C6+ radiation‑induced cellular toxicity in HeLa cells.

Accuracy of MRI for diagnosing pelvic and para‑aortic lymph node metastasis in cervical cancer

The current study aimed to evaluate the accuracy of diffusion‑weighted imaging and morphological aspects at 3 Tesla (T) and 1.5T MRI for diagnosing metastatic lymph nodes (LN) in cervical cancer. A retrospective study was conducted at the Barretos Cancer Hospital. A total of 45 patients with cervical cancer who underwent MRI examination and pelvic and/or para‑aortic lymphadenectomy as part of surgical procedure were included. Data regarding LN images included size (short‑axis diameters), morphology (usual, rounded or amorphous), appearance (homogeneous or heterogeneous), limits (regular, irregular or imprecise), presence or absence of necrosis, diffusion (normal or greater restriction than expected for normal tissue) and aspect (suspected, undetermined or normal). These findings were compared with histopathological results. According to histology results, among the 45 patients, 14 (31.1%) LNs were tested positive for metastasis and 31 (68.9%) LNs were tested negative. A total of 41 metastatic positive LNs were detected from a total of 976 resected nodes. Twelve patients from the 45 (26.7%) had LN classified as metastatic by histology and suspected by MRI, 26 (57.8%) as negative in both evaluations, 2 (4.4%) as positive by histology and negative by MRI and five (11.1%) as negative by histology and positive by MRI. Based on these results, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were 85.7, 83.9, 70.6, 92.9 and 84.4%, respectively. The Cohen's κ test exposed a general outcome of 0.657 (P10 mm, T2 hypointensity, rounded morphology and greater restriction than expected for normal tissues are the four most common MRI findings associated with metastatic LN. The concordance between MRI and histology was substantial, indicating that this method using MRI for diagnosing suspected LN metastasis is reliable. The results of the current study revealed that the most important aspects to be evaluated in MRI include: Short axis >10 mm, T2 hypointensity, rounded morphology and greater restriction than expected for normal tissues. If these four characteristics are present in MRI, histological evaluation is likely to reveal positive lymph node metastasis.

Mitochondrial‑associated endoplasmic reticulum membrane interference in ovarian cancer (Review)

The mitochondria‑associated endoplasmic reticulum (ER) membrane (MAM), serving as a vital link between the mitochondria and ER, holds a pivotal role in maintaining the physiological function of these two organelles. Its specific functions encompass the participation in the biosynthesis and functional regulation of the mitochondria, calcium ion transport, lipid metabolism, oxidative stress and autophagy among numerous other facets. Scientific exploration has revealed that MAMs hold potential as effective therapeutic targets influencing the mitochondria and ER within the context of cancer therapy. The present review focused on elucidating the related pathways of mitochondrial autophagy and ER stress and their practical application in ovarian cancer, aiming to identify commonalities existing between MAMs and these pathways, thereby extending to related applications of MAMs in ovarian cancer treatment. This endeavor aimed at exploring new potential for MAMs in clinically managing ovarian cancer.

OTX1 promotes tumorigenesis and progression of cervical cancer by regulating the Wnt signaling pathway

Cervical cancer is a common malignant tumor in females. Orthodenticle homolog 1 (OTX1) serves a key role in the occurrence and progression of tumors. The present study aimed to investigate the role and potential mechanism of OTX1 in cervical cancer. OTX1 expression was analyzed by western blotting, reverse transcription‑quantitative PCR and immunohistochemistry. MTT assay was performed to assess cell viability. EdU and colony formation assay were used to measure cell proliferation. Wound healing and Transwell assays were performed to measure cell migration and invasion. Western blot assay was performed for the assessment of protein expression. Gene set enrichment analysis (GSEA) was performed to analyze signaling pathways regulated by OTX1. Co‑Immunoprecipitation assay was performed to confirm the interaction between OTX1 and Wnt9b. In cervical cancer tissue and cells, OTX1 was significantly upregulated. OTX1 overexpression promoted proliferation, migration and invasion of cervical cancer cells. OTX1 silencing significantly decreased cell proliferation, migration and invasion of cervical cancer. GSEA showed that OTX1 activated the Wnt signaling pathway. OTX1 silencing inhibited the increased levels of adenomatous polyposis coli (APC), glycogen synthase kinase (GSK)‑3β and axis inhibition protein (AXIN)2 and decreased levels of Wnt9b and β‑catenin. OTX1 overexpression decreased the levels of APC, GSK‑3β and AXIN2 and increased levels of Wnt9b and β‑catenin. However, XAV939 (a Wnt signaling inhibitor) and β‑catenin silencing partly eliminated the effect of OTX1 overexpression on cervical cancer cells. OTX1 promoted the progression of cervical cancer by activating the Wnt signaling pathway.

Fumarate hydratase functions as a tumor suppressor in endometrial cancer by inactivating EGFR signaling

Fumarase hydratase (FH) is an enzyme that catalyzes the reversible hydration and dehydration of fumarate to malate in the tricarboxylic acid cycle. The present study addressed the role of FH in endometrial cancer and clinically observed that the expression of FH was significantly lower in endometrial cancer tissues compared with normal endometrial tissues and, furthermore, that the decreased FH expression in endometrial cancer tissues was significantly associated with increased tumor size and lymph node metastasis. Further analysis in

TRIM27 regulates the expression of PDCD4 by the ubiquitin‑proteasome pathway in ovarian and endometrial cancer cells

Programmed cell death 4 (PDCD4) is regarded as an important tumor suppressor that is lowly expressed or deleted in numerous human types of cancer, including ovarian and endometrial cancer. Tripartite motif‑containing 27 (TRIM27) is closely related to the occurrence and development of tumors and is highly expressed in numerous types of cancer such as ovarian and endometrial cancer. PDCD4 can be degraded through ubiquitination, while TRIM27 has the E3 ubiquitin ligase activity. However, whether TRIM27 may regulate the expression of PDCD4 by ubiquitination effect remains unclear. In the present study, the expression of PDCD4 and TRIM27 in different ovarian and endometrial cancer cell lines was detected by reverse transcription‑quantitative PCR (RT‑qPCR), western blotting and immunocytochemistry. The impact of TRIM27 overexpression and knockdown on PDCD4 expression and the effective mechanism of TRIM27 regulating PDCD4 expression were also investigated

Garcinol inhibits the proliferation of endometrial cancer cells by inducing cell cycle arrest

Endometrial cancer (EC) is the most common gynecological cancer, and one of the most important causes of cancer‑related deaths in women worldwide. The long‑term survival rate is lower in advanced‑stage and recurrent EC, therefore it is important to identify new anticancer drugs. Garcinol, a polyisoprenylated benzophenone, is a promising anticancer drug for various cancer types but its effects on EC remain unclear. To investigate the anticancer effects of garcinol on EC, cell proliferation and cell cycle were assessed by real‑time cell proliferation, cell counting, and colony formation assays, flow cytometric analysis, and 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation assay, in EC Ishikawa (ISH) and HEC‑1B cell lines. Western blotting was used to evaluate the expression of cell cycle‑related protein cyclins, cyclin‑dependent kinase and tumor suppression proteins. Garcinol inhibited ISH and HEC‑1B cell proliferation in a dose‑dependent manner, and induced ISH and HEC‑1B cell cycle arrest at the G1 phase and G2/M phase, respectively, and decreased the S phase and DNA synthesis in these two cell lines. Following garcinol treatment the expression levels of p53 and p21 were increased, while the expression levels of CDK2, CDK4, cyclin D1 and cyclin B1 were gradually decreased in a dose‑dependent manner in both ISH and HEC‑1B cells. In addition, the expression levels of phosphorylated c‑JUN N‑terminal kinase (JNK) and p‑c‑JUN were significantly increased in both types of cells. Collectively, garcinol can induce EC cell cycle arrest and may be a promising candidate for EC chemotherapy.