Molecular Medicine Reports

Antitumor effects of aconitine in A2780 cells via estrogen receptor β‑mediated apoptosis, DNA damage and migration

Ovarian cancer (OVCA) is the deadliest type of malignant gynecological disease, and previous studies have demonstrated that estrogen receptor β (ERβ) serves important roles in this disease. Aconitine, a toxin produced by the Aconitum plant, displays potent effects against cancers. The aim of the study was to investigate the pharmacological activities and mechanisms of aconitum on OVCA. In the present study, the activity of aconitine in the human OVCA A2780 cell line was investigated. The results revealed that aconitine suppressed cell viability, colony formation and motility. Terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling, mitochondria membrane potential and comet assays showed that aconitine induced mitochondria apoptosis and DNA damage in A2780 cells. Investigation of the mechanism revealed that a high expression of ERβ and prolyl hydroxylase 2 was detected after aconitine treatment, and aconitine significantly suppressed the expression of vascular endothelial growth factor and hypoxia‑inducible factor 1α to activate ERβ signaling. Moreover, the expression levels of p53, Bax, apoptotic peptidase activating factor 1, cytochrome C, cleaved caspase‑3/9 and cleaved poly (ADP‑ribose) polymerase were upregulated, and the expression levels of Bcl‑2, Bcl‑xl and phosphorylated ATM serine/threonine kinase were downregulated by aconitine. Interestingly, aconitine also markedly downregulated the expression of matrix metalloproteinase 2 (MMP2) and MMP9, which are associated with tumor invasion. In addition, a molecular docking assay revealed that aconitine exerted strong affinity towards ERβ mainly through hydrogen bonding and hydrophobic effects. Collectively, these results suggested that aconitine suppressed OVCA cell growth by adjusting ERβ‑mediated apoptosis, DNA damage and migration, which should be considered a potential option for the future treatment of OVCA.

Sialylation of FGFR1 by ST6Gal‑I overexpression contributes to ovarian cancer cell migration and chemoresistance

Fibroblast growth factor receptors (FGFRs) have been implicated in the malignant transformation and chemoresistance of epithelial ovarian cancer; however, the underlying molecular mechanisms are poorly understood. Increased sialyltransferase activity that enhances protein sialylation is an important post‑translational process promoting cancer progression and malignancy. In the present study, α2,6‑sialyltransferase (ST6Gal‑I) overexpression or knockdown cell lines were developed, and FGFR1 was examined to understand the effect of sialylation on migration and drug resistance, and the underlying mechanisms. It was identified that cells with ST6Gal‑I overexpression had increased cell viability and migratory ability upon serum deprivation. Moreover, ST6Gal‑I overexpression cells had strong resistance to paclitaxel, as demonstrated by low growth inhibition rate and cell apoptosis level. A mechanistic study showed that ST6Gal‑I overexpression induced high α2,6‑sialylation of FGFR1 and increased the expression of phospho‑ERK1/2 and phospho‑focal adhesion kinase. Further study demonstrated that the FGFR1 inhibitor PD173047 reduced cell viability and induced apoptosis; however, ST6Gal‑I overexpression decreased the anticancer effect of PD173047. In addition, ST6Gal‑I overexpression attenuated the effect of Adriamycin on cancer cells. Collectively, these results suggested that FGFR1 sialylation plays an important role in cell migration and drug chemoresistance in ovarian cancer cells.

Propofol‑induced miR‑125a‑5p inhibits the proliferation and metastasis of ovarian cancer by suppressing LIN28B

Propofol, a commonly used intravenous anesthetic agent during surgery, has relatively widespread pharmacological actions. Previous studies have reported that propofol may act as an antitumor drug in several cancer types, such as pancreatic cancer, lung cancer and gastric cancer. However, the underlying mechanism in ovarian cancer remain unknown. Therefore, the present study investigated the pharmacological effect of propofol on microRNAs (miRNAs) in ovarian cancer treatment. Propofol (1, 5 or 10 µg/ml) was used to treat A2780 and SKOV3 ovarian cancer cells for 1, 2, 3, 4 or 5 days. The MTT assay was used to detect cell viability, while wound healing and Transwell assays were utilized to assess the invasive and migratory abilities. The bioinformatics prediction approach identified differentially expressed miRNAs (miRs) that were used in Gene Ontology, Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes analyses. The expression levels of miR‑125a‑5p and lin‑28 homolog B (LIN28B) were evaluated by reverse transcription‑quantitative PCR (RT‑qPCR). A luciferase assay was performed to identify the relationship between miR‑125a‑5p and LIN28B. Western blotting was conducted to measure the protein expression of LIN28B. It was demonstrated that propofol significantly upregulated miR‑125a‑5p to exert its antitumor activity. RT‑qPCR results suggested that propofol could upregulate miR‑125a‑5p and LIN28B expression levels in ovarian cancer cell lines. Western blot analysis also indicated that propofol could enhance the expression of LIN28B in ovarian cancer cell lines. The luciferase assay identified that miR‑125a‑5p could directly inhibit the expression of LIN28B to suppress proliferation and metastasis in ovarian cancer. In conclusion, these results suggested that propofol inhibited ovarian cancer proliferation and metastasis by enhancing miR‑125a‑5p, which targets LIN28B.

PLAC1 is an independent predictor of poor survival, and promotes cell proliferation and invasion in cervical cancer

Placenta‑specific protein 1 (PLAC1) is inversely associated with survival in several types of cancer. However, whether PLAC1 is involved in the progression of cervical cancer (CC) remains to be elucidated. Therefore, the present study aimed to evaluate the prognostic role of PLAC1 in CC by determining the relationship between clinicopathological factors,

miR‑576‑3p overexpression enhances cisplatin sensitivity of ovarian cancer cells by dysregulating PD‑L1 and cyclin D1

Cisplatin (DDP) resistance is a major obstacle in the chemotherapeutic efficacy of ovarian cancer. The present study aimed to explore the role of miR‑576‑3p in DDP sensitivity of ovarian cancer cells. Ovarian cancer cell lines SKOV3 and A2780 and DDP‑resistant ovarian cancer cell lines SKOV3/DDP and A2780/DDP were used in the present study.

Cucurbitacin I induces apoptosis in ovarian cancer cells through oxidative stress and the p190B‑Rac1 signaling axis

Ovarian cancer is a serious threat to women's life and health, with a high mortality rate. Therefore, in addition to improving surgery for ovarian cancer, it is particularly important to develop novel drug treatments. In the present study, the anticancer effects of cucurbitacin I, a natural product, were investigated. Cucurbitacin I impaired the viability of SKVO3 cells in a concentration‑ and time‑dependent manner. Apoptosis was involved in the process of cucurbitacin I‑induced cell death, with an increase observed in cleaved‑caspase 3 and BAX, and a decrease in Bcl‑2. Cucurbitacin I caused a notable increase in intracellular reactive oxygen species, and regulated Kelch‑like ECH‑associated protein 1 and nuclear factor erythroid‑derived 2‑like 2 to decrease the expression of antioxidant‑related genes. In addition, Cucurbitacin I induced cell shrinkage by regulating the p190BRhoGAP (p190B)‑Rac1 signaling axis related to the cytoskeleton. In brief, these results suggested that cucurbitacin I induced cell death through oxidative stress and the p190B‑Rac1 signaling axis in SKVO3 cells. The results may provide novel evidence for the treatment of ovarian cancer.

Upregulation of long non‑coding RNA CCEPR is associated with poor prognosis and contributes to the progression of ovarian cancer through regulating the Wnt/β‑catenin signaling pathway

Accumulating evidence has demonstrated that the expression of long non‑coding RNAs (lncRNAs) is altered in various types of cancer, which may prove beneficial for their use as biomarkers. Cervical carcinoma expressed PCNA regulatory lncRNA (CCEPR) is a recently identified lncRNA, which has an important role in regulating cell proliferation and apoptosis in cervical and bladder cancer; however, whether CCEPR is involved in the progression of ovarian cancer (OC) remains largely unclear. The aim of the present study was to determine the clinical significance of CCEPR in OC and to investigate its biological roles. Cell Counting Kit‑8 assay was used to analyze cell proliferation, Transwell assay was used to assess invasion, flow cytometric analysis was used to analyze apoptosis, and western blotting was used to perform mechanistic studies. CCEPR expression levels were significantly elevated in OC tissues compared with adjacent non‑cancer tissues. Similarly, significant increases in CCEPR expression were observed in OC cell lines (SK‑OV‑3 and OVCAR‑3) compared with the ovarian surface epithelial cell line, HOSEpiC. The increased expression levels of CCEPR were associated with increased invasion, higher International Federation of Gynecology and Obstetrics stage and a poorer overall survival rate. In vitro, the genetic silencing of CCEPR decreased the cell proliferation rate and invasive ability of OC cells, and promoted apoptosis. CCEPR‑silenced OC cells also demonstrated decreased expression levels of four proteins involved in the Wnt/β‑catenin signaling pathway: Cyclin D1, β‑catenin, Myc and matrix metallopeptidase‑7. In conclusion, the present study demonstrated that increased expression levels of CCEPR may predict poor prognosis in patients with OC and contribute to the progression of OC through regulating the Wnt/β‑catenin signaling pathway.

Development of an innovative approach for early diagnosis of cervical cancer using TCR‑like antibodies targeting HPV18 E6 and E7 peptides

Cervical cancer is the fourth most prevalent cancer among female patients globally, largely due to persistent infections with high‑risk human papillomavirus (HPV). Viral oncoproteins E6 and E7, produced by HPV, serve a role in driving cellular transformation and maintaining the malignant phenotype. T cell receptor (TCR)‑like antibodies serve as a potential diagnostic tool to capture the oncogenic peptide that is present in MHC. As these antibodies serve as innate antigen detectors, orchestrating immune responses against both cell surface and intracellular proteins. In the present study, a human domain antibody (DAB) phage library was screened by evaluating synthesized HPV18 (E6 and E7) peptide‑major histocompatibility complexes (p‑MHC‑A24) to identify target‑specific TCR‑like antibodies. The present study successfully identified three TCR‑like DABs that specifically target HPV18 (E6 and E7) p‑MHC‑A24 complexes. Characterization of the amino acid sequences in the complementarity‑determining regions 1, 2 and 3 was performed using VBASE2 and the international ImMunoGeneTics information system®/vquest databases. Evaluation of soluble TCR‑like antibodies confirmed strong and selective affinity for the targets through western blotting and ELISA. The present study aimed to clarify the specificity of TCR‑like antibodies against specific targets and demonstrated that TCR‑like antibodies may serve as early diagnostic and immunotherapeutic tools for HPV‑associated cervical cancer.

NUAK2 silencing inhibits the proliferation, migration and epithelial‑to‑mesenchymal transition of cervical cancer cells via upregulating CYFIP2

NUAK family kinase 2 (NUAK2) has been reported to be involved in various cancer cell processes, including proliferation, apoptosis and invasion, by targeting multiple genes. However, to the best of our knowledge, its biological function in cervical cancer (CC) has not yet been elucidated. Therefore, the present study aimed to measure the expression of NUAK2 and to evaluate its functions in CC. The expression levels of NUAK2 and cytoplasmic FMRP‑interacting protein 2 (CYFIP2) were detected in CC tissues and cell lines. In addition, the effects of NUAK2 and CYFIP2 knockdown on CC cell proliferation, migration, invasion and epithelial‑to‑mesenchymal transition (EMT) were evaluated

miR‑519d‑3p/HIF‑2α axis increases the chemosensitivity of human cervical cancer cells to cisplatin via inactivation of PI3K/AKT signaling

Cisplatin (DDP)‑based chemotherapy is a standard treatment for cervical cancer, although chemotherapy resistance remains a major concern. Hypoxia‑inducible factor‑2 α (HIF‑2α) plays an important role in chemotherapy resistance. MicroRNAs (miRs) can inhibit gene expression by binding to the 3'‑untranslated region of the target gene. The authors' previous study showed that miR‑519d‑3p plays an important role in the regulation of HIF‑2α expression under hypoxic conditions in cervical cancer. However, the function and regulatory mechanisms of the miR‑519d‑3p/HIF‑2α axis in DDP‑resistance in cervical cancer are not fully understood. Therefore, the aim of the present study was to investigate whether the miR‑519d‑3p/HIF‑2α axis increased DDP resistance by regulating the PI3K/AKT signaling pathway. It was found that the expression of miR‑519d‑3p was lower in DDP‑resistant cervical cancer cells (CaSki/DDP and HeLa/DDP) compared with CaSki and HeLa cells under hypoxic conditions. Additionally, miR‑519d‑3p overexpression decreased the IC50 value in CaSki/DDP and HeLa/DDP cells, and inhibited HIF‑2α protein expression and the PI3K/AKT signaling pathway under hypoxic conditions. Furthermore, it was demonstrated that HIF‑2α overexpression reduced the effect of miR‑519d‑3p overexpression on HeLa/DDP and CaSki/DDP cells. Moreover, the present results suggested that HIF‑2α overexpression increased the IC50 value in CaSki/DDP and HeLa/DDP cells. It was also found that HIF‑2α overexpression reduced the effect of miR‑519d‑3p overexpression on the PI3K/AKT signaling pathway. Therefore, the present results indicated that the miR‑519d‑3p/HIF‑2α axis increased DDP resistance of cervical cancer cells by suppressing the PI3K/AKT signaling pathway under hypoxic conditions.

SLC7A1, SGK1 and HMGB2 are overexpressed in cervical cancer tissues and the miR‑23b‑3p/HMGB2 axis regulates cell migration and invasion

MicroRNA (miRNA/miR)‑124‑3p and miR‑23b‑3p are tumor suppressor miRNAs that are associated with advanced cervical cancer (CC), regulating proliferation, migration, invasion, apoptosis and metastasis; however, the identity and function of the various genes regulated by these miRNAs remain unknown. The present study predicted the specific and shared targets of miR‑124‑3p and miR‑23b‑3p, cellular processes and signaling pathways involving the predicted targets.

Tryptophan 2, 3‑dioxygenase promotes proliferation, migration and invasion of ovarian cancer cells

Tryptophan 2,3‑dioxygenase (TDO2) is a key rate‑limiting enzyme in the kynurenine pathway and promotes tumor growth and escape from immune surveillance in different types of cancer. The present study aimed to investigate whether TDO2 serves a role in the development of ovarian cancer. Reverse transcription‑quantitative PCR and western blotting were used to detect the expression of TDO2 in different cell lines. The effects of TDO2 overexpression, TDO2 knockdown and TDO2 inhibitor on ovarian cancer cell proliferation, migration and invasion were determined by MTS, colony formation and Transwell assays. The expression of TDO2 in ovarian cancer tissues, normal ovarian tissues and fallopian tube tissues were analyzed using the gene expression data from The Cancer Genome Atlas and Genotype‑Tissue Expression project. Immune cell infiltration in cancer tissues was evaluated using the single sample gene set enrichment analysis algorithm. The present study found that RasV12‑mediated oncogenic transformation was accompanied by the upregulation of TDO2. In addition, it was demonstrated that TDO2 was upregulated in ovarian cancer tissues compared with normal ovarian tissues. TDO2 overexpression promoted proliferation, migration and invasion of ovarian cancer cells, whereas TDO2 knockdown repressed these phenotypes. Treatment with LM10, a TDO2 inhibitor, also repressed the proliferation, migration and invasion of ovarian cancer cells. The present study indicated that TDO2 can be used as a new target for the treatment of ovarian cancer.

[Retracted] 8‑bromo‑7‑methoxychrysin induces apoptosis by regulating Akt/FOXO3a pathway in cisplatin‑sensitive and resistant ovarian cancer cells

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the western blot data shown in Fig. 2C on p. 5104 were strikingly similar to data appearing in different form in another article written by different authors at different research institutes that had already been published in the journal

Mutually distinguishing microRNA signatures of breast, ovarian and endometrial cancers in�vitro

Early diagnosis and therapy in the first stages of a malignant disease is the most crucial factor for successful cancer treatment and recovery. Currently, there is a high demand for novel diagnostic tools that indicate neoplasms in the first or pre‑malignant stages. MicroRNAs (miRNA or miR) are small non‑coding RNAs that may act as oncogenes and downregulate tumor‑suppressor genes. The detection and mutual discrimination of the three common female malignant neoplasia types breast (BC), ovarian (OC) and endometrial cancer (EC) could be enabled by identification of tumor entity‑specific miRNA expression differences. In the present study, the relative expression levels of 25 BC, EC and OC‑related miRNAs were assessed by reverse transcription‑quantitative PCR and determined using the 2‑ΔΔCq method for normalization against the mean of four housekeeping genes. Expression levels of all miRNAs were analyzed by regression against cell line as a factor. An expression level‑based discrimination between BC and OC cell types was obtained for a subgroup of ten different miRNA types. miR‑30 family genes, as well as three other miRNAs, were found to be uniformly upregulated in OC cells compared with BC cells. BC and EC cells could be distinguished by the expression profiles of six specific miRNAs. In addition, four miRNAs were differentially expressed between EC and OC cells. In conclusion, miRNAs were identified as a potential novel tool to detect and mutually discriminate between BC, OC and EC. Based on a subset of 25 clinically relevant human miRNA types, the present study could significantly discriminate between these three female cancer types by means of their expression levels. For further verification and validation of miRNA‑based biomarker expression signatures that enable valuable tumor detection and characterization in routine screening or potential therapy monitoring, additional and extended in vitro analyses, followed by translational studies utilizing patients' tissue and liquid biopsy materials, are required.

Long non‑coding RNA SNHG12 regulates cell proliferation, invasion and migration in endometrial cancer by targeting miR‑4429

Long non‑coding RNA small nucleolar RNA host gene 12 (SNHG12) has been demonstrated to be oncogenic. The aim of the present study was to examine the effects of SNHG12 on the progression of endometrial cancer (EC). The expression levels of SNHG12 and microRNA (miR)‑4429 were assessed in EC cell lines by reverse transcription‑quantitative PCR. Plasmids, including SNHG12 short hairpin RNAs (shRNAs), shRNA negative control (NC), SNHG12 overexpression (OV), OV‑NC, miR‑4429 mimic and mimic‑NC, were transfected into RL95‑2 cells. Post‑transfection, Cell Counting Kit‑8, Transwell Matrigel and wound‑healing assays were performed to assess cell proliferation, invasion and migration, respectively. Cell cycle phase distribution was assessed by flow cytometry. The protein expression levels of matrix metalloproteinase (MMP)2 and MMP9 were detected by western blotting. miR‑4429 target genes were predicted by bioinformatics analysis using target prediction online tools; the findings of this analysis were verified using a dual‑luciferase reporter system. Identified as a target of miR‑4429, SNHG12 was overexpressed in EC cell lines with decreased expression of miR‑4429. Further experiments demonstrated that SNHG12 silencing and overexpression of miR‑4429 markedly suppressed proliferation, migration and invasion of RL95‑2 cells, arrested cells in the G1 phase, and markedly downregulated the expression of MMP2 and MMP9. The opposite effects were observed in miR‑4429 mimic‑transfected RL95‑2 cells after SNHG12 was overexpressed. The findings of the present study established the role of SNHG12 and miR‑4429 in EC. Therefore, targeting the SNHG12/miR‑4429 axis could serve as a potential future therapeutic target for treatment of EC.

CUL4A regulates endometrial cancer cell proliferation, invasion and migration by interacting with CSN6

Endometrial cancer (EC) is a common malignant gynecological tumor arising from the endometrium, with an annually increasing morbidity and mortality. The present study aimed to investigate the functions of cullin 4A (CUL4A) in EC, as well as the underlying mechanisms. CUL4A expression was assessed in several human EC cells and normal human endometrial epithelial cells (hEECs) via reverse transcription‑quantitative polymerase chain reaction and western blotting. Subsequently, short hairpin (sh)RNA‑CULA4 was transfected into cells, and cell proliferation, invasion and migration were detected using Cell Counting kit‑8, Transwell and wound healing assays, respectively. The STRING database identified that CSN6 interacted with CULA4, and immunoprecipitation was performed to verify the interaction. Subsequently, following CUL4A knockdown, pcDNA3.1‑CSN6 was transfected into cells and its effects on cell proliferation, invasion and migration were assessed. The expression levels of matrix metallopeptidase (MMP)2, MMP9 and p53 were evaluated via western blotting. The results indicated that CUL4A was highly expressed in EC cells, compared with hEECs. CULA4‑knockdown notably inhibited EC cell proliferation, invasion and migration. The expression levels of MMP2 and MMP9 were significantly decreased, while p53 expression was enhanced following CUL4A‑knockdown. The immunoprecipitation assay verified that COP9 signalosome subunit 6 (CSN6) interacted with CULA4. Furthermore, CSN6‑overexpression alleviated the inhibitory effects of CUL4A‑knockdown on EC cell proliferation, invasion and migration. Similarly, CSN6 overexpression reversed CUL4A‑knockdown‑mediated effects on the expression of MMP2, MMP9 and p53. In summary, the results demonstrated that CUL4A regulated EC cell proliferation, invasion and migration by interacting with CSN6.

LncRNA HOTTIP promotes the proliferation and invasion of ovarian cancer cells by activating the MEK/ERK pathway

Recent studies have revealed that long non‑coding RNAs (lncRNAs) serve important roles in carcinogenesis and that this type of gene may be used as biomarkers in cancer. A high level of lncRNA HOXA distal transcript antisense RNA (HOTTIP) is associated with unfavorable prognosis for patients with ovarian cancer (OC), but the mechanism of HOTTIP involved in OC development remains to be elucidated. The present study aimed to investigate the mechanism of HOTTIP in metastasis‑associated OC cell behaviors. HOTTIP levels in ovarian cells were quantified by reverse transcription‑quantitative PCR, cell proliferation was analyzed by colony formation assay, and apoptosis was assessed by flow cytometry. Cell migratory and invasive abilities were evaluated by wound healing and Transwell assays, respectively. The expression levels of mitogen‑activated protein kinase kinase (MEK)/ERK pathway‑associated proteins were detected by western blotting. The results demonstrated that knockdown of HOTTIP in OC cells significantly reduced the phosphorylation levels of MEK and ERK, inhibited the proliferation and invasion of OC cells and promoted their apoptosis. Furthermore, the effects of HOTTIP on cell migration and invasion were partly associated with the epithelial‑mesenchymal transition (EMT) process. Proliferation, invasion and EMT of OC cells were enhanced following overexpression of HOTTIP; however, these effects were reversed by the MEK/ERK pathway inhibitor U0126. In conclusion, HOTTIP was demonstrated to promote the proliferation, migration and invasion of OC cells by activating the MEK/ERK pathway. Therefore, HOTTIP may serve as a potential therapeutic target for OC.

Long non‑coding RNA NEAT1 modifies cell proliferation, colony formation, apoptosis, migration and invasion via the miR‑4500/BZW1 axis in ovarian cancer

Ovarian cancer (OC) is a frequently occurring malignant tumor in women. Increasing evidence has indicated that long non‑coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) participates in OC pathogenesis. Thus, the aim of the present study was to explore the function of NEAT1 during OC progression. The expression levels of NEAT1, microRNA (miR)‑4500 and basic leucine zipper and W2 domain‑containing protein 1 (BZW1) were assessed via reverse transcription‑quantitative PCR and western blotting. Furthermore, cell proliferation, colony formation, apoptosis, migration and invasion were assessed using Cell‑Counting Kit 8, colony formation, flow cytometry and Transwell assays, respectively. Cell glycolysis was analyzed using an XF96 metabolic flux analyzer, and the relationship between miR‑4500 and NEAT1 or BZW1 was verified via dual‑luciferase reporter and RNA binding protein immunoprecipitation assays. miR‑4500 expression levels were low, whereas NEAT1 expression levels were high in OC tissues and cell lines compared with control tissues and cell lines. Moreover, the results indicated that NEAT1 was a sponge of miR‑4500, which directly targeted BZW1. NEAT1 knockdown induced OC cell apoptosis, and inhibited OC cell proliferation, colony formation, migration, invasion and glycolysis. miR‑4500 inhibitor reversed NEAT1 knockdown‑mediated effects. Similarly, miR‑4500 mimic‑mediated effects on cell functions were reversed by BZW1 overexpression. In addition, the results indicated that BZW1 expression was regulated by NEAT1 and miR‑4500. Collectively, the present study suggested that NEAT1 modulated cell proliferation, colony formation, apoptosis, migration, invasion and glycolysis via the miR‑4500/BZW1 axis in OC; therefore, NEAT1 may serve as a therapeutic target for OC.

RTN2, a new member of circadian clock genes identified by database mining and bioinformatics prediction, is highly expressed in ovarian cancer

Increasing evidence suggests that core circadian genes have major roles in the carcinogenic mechanisms of multiple human malignancies. Among these genes, the role of reticulon 2 (RTN2) in ovarian cancer (OV) has so far remained elusive. In the present study, circadian clock gene (CCG) aberrations were systematically assessed across malignancies by using Gene Expression Omnibus and The Cancer Genome Atlas data. The results indicated that various core clock genes (ULK1, ATF3, CRY2, CSF3R, DAAM2, GAS7, NPTXR, PPPIR15A and RTN2) had elevated levels in tumors in comparison with normal tissues and their low expression levels were associated with a better prognosis in OV, indicating that they may be potential candidates for novel investigational approaches. The mRNA and protein expression levels of RTN2 in OV were then further analyzed by reverse transcription‑quantitative PCR and immunohistochemistry, respectively. The results indicated that RTN2 mRNA and protein levels were increased in OV specimens in comparison with control samples. Differentially expressed CCGs, such as RTN2, were suggested as indicators of asynchronous circadian rhythms in cancer, which may provide a theoretical basis for chrono‑therapy.

Analysis of CXCL8 and its receptors CXCR1/CXCR2 at the mRNA level in neoplastic tissue, as well as in serum and peritoneal fluid in patients with ovarian cance

Understanding the relationship between the coexistence of inflammatory and neoplastic processes in ovarian cancer, particularly those involving chemokines and their receptors, may help to elucidate the involvement of the studied parameters in tumor pathogenesis and could lead to improved clinical applications. Therefore, the present study aimed to analyze the levels of C‑X‑C motif chemokine ligand 8 (CXCL8), and its receptors C‑X‑C chemokine receptor (CXCR)1 and CXCR2, in the serum and peritoneal fluid of women with ovarian cancer, and to evaluate the association between the expression of these parameters in tumor tissue and patient characteristics, particularly the degree of histological differentiation. The study group included women with ovarian cancer diagnosed with serous cystadenocarcinoma International Federation of Gynecology and Obstetrics stage IIIc and a control group, which consisted of women who were diagnosed with a benign lesion (serous cystadenoma). The transcript levels of

Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells

Human cervical cancer is the fourth most common malignancy among women worldwide, and it is expected to result in 460,000 deaths per year by 2040. Moreover, patients with cervical cancer often display drug resistance and severe side effects; therefore, the development of effective novel chemotherapeutic agents is important. In the present study, the effects of metformin, a first‑line therapeutic drug for type 2 diabetes mellitus, were evaluated in cervical cancer. Compared with the control group, metformin significantly inhibited cell viability and migration, and induced apoptosis and cell cycle arrest in human cervical cancer cell lines (CaSki and HeLa). Following metformin treatment, the protein expression levels of p‑AMP‑activated protein kinase (p‑AMPK), which promotes cell death, and the tumor suppressor protein p‑p53 were remarkably upregulated in CaSki and C33A cells compared with the control group. Furthermore, compared with the control group, metformin significantly suppressed the PI3K/AKT signaling pathway in CaSki, C33A and HeLa cells. Compound C (an AMPK inhibitor) significantly reversed the effects of metformin on CaSki, C33A and HeLa cell viability, and AMPK and p53 phosphorylation. The results of the present study suggested that metformin induced AMPK‑mediated apoptosis, thus metformin may serve as a chemotherapeutic agent for human cervical cancer.

Chloroform extract of Citrus unshiu Markovich peel induces apoptosis and inhibits stemness in HeLa human cervical cancer cells

Cervical cancer is the second most common cancer among women worldwide. However, chemotherapies for this cancer often cause many side effects and chemoresistance.

The role of galectins‑1, 3, 7, 8 and 9 as potential diagnostic and therapeutic markers in ovarian cancer (Review)

The incidence of ovarian cancer is increasing, particularly throughout the highly developed countries, while this cancer type remains a major diagnostic and therapeutic challenge. The currently poorly recognized lectins called galectins have various roles in interactions occurring in the tumor microenvironment. Galectins are involved in tumor‑associated processes, including the promotion of growth, adhesion, angiogenesis and survival of tumor cells. Results of research studies performed so far point to a complex role of galectins‑1, 3, ‑7, ‑8 and ‑9 in carcinogenesis of ovarian cancer and elucidation of the mechanisms may contribute to novel forms of therapies targeting the proteins. In particular, it appears important to recognize the reasons for changes in expression of galectins. Galectins also appear to be a useful diagnostic and prognostic tool to evaluate tumor progression or the efficacy of therapies in patients with ovarian cancer, which requires further study.

LINC00861 inhibits the progression of cervical cancer cells by functioning as a ceRNA for miR‑513b‑5p and regulating the PTEN/AKT/mTOR signaling pathway

Long non‑coding RNAs (lncRNAs) have been discovered to serve important roles in a variety of types of cancer, including cervical cancer. The low expression of lncRNA long intergenic non‑protein coding RNA 861 (LINC00861) is related to poor prognosis in ovarian cancer. However, the effects and underlying mechanisms of LINC00861 in cervical cancer remain largely unknown. The present study aimed to examine the role of LINC00861 in the development and progression of ovarian cancer and its underlying mechanisms. The expression levels of LINC00861 and microRNA (miR)‑513b‑5p were analyzed using reverse transcription‑quantitative PCR analysis. Cell proliferation, migration and invasion were measured by using Cell Counting Kit‑8, colony formation, wound healing and Transwell assays, respectively. A luciferase assay was used to determine whether miR‑513b‑5p targeted LINC00861 and PTEN. The expression of protein was measured by using western blot assay. The results of the present study discovered that LINC00861 expression levels were significantly downregulated in cervical cancer tissues and CaSki and ME‑180 cell lines. Downregulated LINC00861 expression levels were identified to be associated with an advanced‑stage, lymph node metastasis and the poor survival of patients with cervical cancer. Gene Set Enrichment Analysis revealed that the PI3K/AKT/mTOR signaling pathway was significantly enriched in cervical tumors expressing low expression levels of LINC00861 compared with tumors expressing high levels of LINC00861. The overexpression of LINC00861 reduced cervical cancer cell proliferation, migration, invasion and epithelial‑mesenchymal transition (EMT) processes, upregulated PTEN protein expression levels and downregulated phosphorylated (p)‑AKT and p‑mTOR protein expression levels. The regulatory relationship between LINC00861, microRNA (miR)‑513b‑5p and PTEN was validated using a dual luciferase reporter gene assay. PTEN expression levels were significantly downregulated in the miR‑513b‑5p mimic group and significantly upregulated in the miR‑513b‑5p inhibitor group compared with the mimic NC and inhibitor NC in both cell lines. Furthermore, LINC00861 was suggested to serve as a competing endogenous RNA by sponging miR‑513b‑5p and consequently upregulating the expression levels of PTEN in cervical cancer cells. The expression of PTEN, the phosphorylation of Akt and mTOR and and the EMT phenotype were rescued following co‑transfection with LINC00861 and miR‑513b‑5p mimics. In conclusion, the findings of the present study indicated that the LINC00861/miR‑513b‑5p axis may inhibit the progression of cervical cancer cells through the PTEN/AKT/mTOR signaling pathway to suppress the EMT process.

Tripartite motif‑containing 14 regulates cell proliferation and apoptosis in cervical cancer via the Akt signaling pathway

Tripartite motif‑containing (TRIM) 14 is a protein of the TRIM family. Studies have indicated that TRIM14 may be used as an oncogene in tumor cells, such as osteosarcoma, non‑small cell lung cancer and breast cancer through different pathways. However, the functions of TRIM14 in cervical cancer cells remain unclear. Therefore, this study aimed to investigate the functions of TRIM14 in cervical cancer cells and its underlying mechanism. Caski cells stably expressing TRIM14 and SiHa, and HeLa cells stably expressing TRIM14 short hairpin RNA were constructed by lentivirus‑mediated overexpression or knockdown systems. The effects of TRIM14 on proliferation and apoptosis of cervical cancer cells were detected by Cell Counting Kit‑8 (CCK‑8) assay and flow cytometry, respectively. In addition, reverse transcription‑quantitative (RT‑q) PCR and western blotting were used to investigate the expression levels of TRIM14 and of signaling pathway marker protein including P21, caspase‑3, cleaved caspase‑3, Akt and phosphorylated Akt. The results of RT‑qPCR and western blotting revealed that TRIM14 was highly expressed in human cervical cancer tissues and cell lines compared with adjacent normal tissues and normal cervical epithelial cells. TRIM14 also regulated cell proliferation and apoptosis of human SiHa, HeLa and Caski cervical cancer cell lines through the Akt signaling pathway. Additionally, TRIM14 protein levels were related to the clinical and pathological features of cervical cancer. CCK‑8 assay and flow cytometry demonstrated that TRIM14 expression could promote cervical cancer cell proliferation and autophagy suppression. Taken together, TRIM14‑induced cell proliferation and apoptosis inhibition may by evoked by the activation of the Akt pathway. This study demonstrated the role of TRIM14 in cervical cancer, and reveals its mechanism of action as a potential therapeutic target for cervical cancer.

MicroRNA‑145‑5p suppresses fascin to inhibit the invasion and migration of cervical carcinoma cells

MicroRNAs (miRs) can affect the progression of cervical cancer (CC). The present study investigated the function of miR‑145‑5p in CC and demonstrated its association with fascin (FSCN1). The expression levels of miR‑145‑5p in CC tissues and cell lines were analyzed using reverse transcription‑quantitative PCR, and its direct targets were explored using a luciferase reporter assay. The viability, migration and invasion of HeLa cells transfected with small interfering FSCN1 or with miR‑145‑5p mimics and inhibitors were analyzed using Cell Counting Kit‑8 and Transwell assays. The expression levels of FSCN1 mRNA and protein were investigated using reverse transcription PCR and western blotting. miR‑145‑5p was downregulated in CC tissues and cell lines. Moreover, overexpression of miR‑145‑5p inhibited the migration, invasion and viability of HeLa cells. miR‑145‑5p directly targeted FSCN1, which regulated the suppressive functions of miR‑145‑5p in CC cells. Overall, miR‑145‑5p is a tumor suppressor gene and a promising target for CC treatment.

miR‑140‑5p inhibits cervical cancer cell phenotypes via downregulating FEN1 to halt the cell cycle

Cervical cancer (CC) is a frequently occurring cancer in women with a high mortality rate. Despite improvements to therapeutic strategies, the survival outcome for patients with CC remains poor. Therefore, the present study aimed to investigate the molecular mechanism underlying CC inhibition involving microRNA (miR)‑140‑5p and flap structure‑specific endonuclease 1 (FEN1). Bioinformatics analysis was conducted, which identified that FEN1 was associated with CC cell cycle progression. Subsequently, 3'untranslated region reporter assays were performed to assess the regulatory relationship between FEN1 mRNA and miR‑140‑5p. Functional assays, including EdU staining assay, flow cytometry, and wound healing assays, were conducted to observe CC cell phenotypes induced by alterations to miR‑140‑5p and FEN1 expression levels. FEN1 expression was high and miR‑140‑5p expression was low in CC tissues and cell lines compared with adjacent healthy tissues and a normal cervical epithelial cell line, respectively. miR‑140‑5p knockdown reversed small interfering RNA‑FEN1‑mediated suppressive effects on CC cell phenotypes, potentially via inducing cell cycle arrest at the G1 phase. Therefore, the present study suggested that miR‑140‑5p may serve as an antitumorigenesis factor in CC by targeting FEN1 mRNA.

MicroRNA‑130a‑3p promotes the proliferation and inhibits the apoptosis of cervical cancer cells via negative regulation of RUNX3

Aberrant expression of microRNAs (miRs) has been reported in various types of cancer. The aim of the present study was to investigate the role and underlying molecular mechanism of miR‑130a‑3p in cervical cancer (CC). The expression of miR‑130a‑3p in CC tissues and cell lines (CaSki and SiHa) was measured via reverse transcription‑quantitative PCR. SiHa and CaSki cells were transfected with miR‑130a‑3p mimics and a miR‑130a‑3p inhibitor, respectively. The proliferation, apoptosis and migration and invasion abilities of CC cells were then measured using MTT, flow cytometry, wound‑healing and Transwell assays, respectively. TargetScan and dual‑luciferase reporter gene assays were performed to analyze the association between miR‑130a‑3p and its predicted target gene Runt‑related transcription factor 3 (RUNX3). In addition, a xenograft tumor model was established in mice to evaluate the impact of miR‑130a‑3p on tumor growth in vivo. The expression of miR‑130a‑3p was markedly upregulated in CC tissues and cell lines compared with normal tissues and cells. Transfection with miR‑130a‑3p mimics significantly promoted the proliferation, migration and invasion, and inhibited the apoptosis of SiHa cells. Treatment of CaSki cells with a miR‑130a‑3p inhibitor resulted in opposite effects to those of miR‑130a‑3p mimics. RUNX3 was identified as the target gene of miR‑130a‑3p, and overexpression of RUNX3 eliminated the tumor‑promoting effect of miR‑130a‑3p mimics on CC cells. Overexpression of miR‑130a‑3p also promoted tumor growth in mice. In conclusion, miR‑130a‑3p promoted proliferation, migration and invasion, and inhibited the apoptosis of CC cells via targeting RUNX3, suggesting a novel treatment target for CC.

Mechanism underlying long non‑coding RNA ILF3‑AS1‑mediated inhibition of cervical cancer cell proliferation, invasion and migration, and promotion of apoptosis

Long non‑coding RNA ILF3 divergent transcript (ILF3‑AS1) displays a tumor‑suppressing effect. StarBase predicted that the potential target microRNA (miR) of ILF3‑AS1 was miR‑454‑3p; therefore, the present study investigated the effect of ILF3‑AS1 and its target miR‑454‑3p on cervical cancer (CC). Gene Expression Profiling Interactive Analysis was used to predict the expression of ILF3‑AS1 in CC and the overall survival rate of patients. The present study demonstrated that ILF3‑AS1 expression was significantly downregulated in human CC tissues and cells compared with adjacent tissues (ANTs) and normal cervical epithelial cells (NCEs), respectively. Patients with CC with high ILF3‑AS1 expression displayed higher survival rates compared with patients with low ILF3‑AS1 expression. Cell viability, apoptosis, migration and invasion were detected by performing Cell Counting Kit‑8, flow cytometry, wound healing and Transwell assays, respectively. Compared with the negative control (NC) group, ILF3‑AS1 overexpression significantly inhibited CC cell viability and migration, but significantly increased CC cell apoptosis. Moreover, ILF3‑AS1 overexpression significantly upregulated E‑Cadherin expression levels, but significantly downregulated N‑Cadherin and snail family transcriptional repressor 1 expression levels compared with the NC group. miR‑454‑3p expression was negatively correlated with ILF3‑AS1, and highly expressed in CC tissues and cells compared with ANTs and NCEs, respectively. PTEN, which was predicted and verified as the target gene for miR‑454‑3p, was significantly downregulated in CC tissues and cells compared with ANTs and NCEs, respectively. ILF3‑AS1 expression was positively correlated with PTEN expression, and ILF3‑AS1 overexpression partially reversed the inhibitory effect of miR‑454‑3p on PTEN expression. In conclusion, the present study indicated that ILF3‑AS1 inhibited CC cell proliferation and migration, and promoted CC cell apoptosis by inhibiting epithelial‑mesenchymal transition, and ILF3‑AS1 overexpression partially reversed the inhibitory effect of miR‑454‑3p on PTEN expression.

Comprehensive analysis of aberrantly expressed long non‑coding RNAs, microRNAs, and mRNAs associated with the competitive endogenous RNA network in cervical cancer

Cervical cancer is a common malignant disease that poses a serious health threat to women worldwide. Growing research efforts have focused on protein‑coding and non‑coding RNAs involved in the tumorigenesis and prognosis of various types of cancer. The potential molecular mechanisms and the interaction among long non‑coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs require further investigation in cervical cancer. In the present study, lncRNA, miRNA, and mRNA expression profiles of 304 primary tumor tissues from patients with cervical cancer and 3 solid normal tissues from The Cancer Genome Atlas (TCGA) dataset were studied via RNA sequencing (RNA‑seq). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using R package clusterProfiler to annotate the principal functions of differentially expressed (DE) mRNAs. Kaplan‑Meier analysis was also conducted to investigate the effects of DElncRNAs, DEmiRNAs, and DEmRNAs on overall survival. A total of 2,255 mRNAs, 133 miRNAs, and 150 lncRNAs that were differentially expressed were identified with a threshold of P2. Functional enrichment analysis indicated that DEmRNAs were enriched in cancer‑associated KEGG pathways. Furthermore, 255 mRNAs, 15 miRNAs, and 12 lncRNAs that were significantly associated with overall survival in cervical carcinoma were also identified. Importantly, an miRNA‑mediated competitive endogenous RNA (ceRNA) network was successfully constructed based on the expression profiles of DElncRNAs and DEmRNAs. More importantly, it was found that the lncRNA EPB41L4A‑AS1 may function as a pivotal regulator in carcinoma of the uterine cervix. Taken together, the present study has provided novel insights into investigating the potential mechanisms underlying tumorigenesis, development, and prognosis of cervical cancer, and presented new potential avenues for cancer therapeutics.

Circular RNA cSMARCA5 regulates the progression of cervical cancer by acting as a microRNA‑432 sponge

Circular RNAs (circRNAs) have been shown to be involved in the development of cancer. The aim of the present study was to investigate the role of circRNA SMARCA5 (cSMARCA5) in human cervical cancer. In the present study, cSMARCA5 expression was upregulated in cervical cancer tissues and cell lines. Furthermore, the proliferation rate of cells transduced with viral plasmids expressing small interfering RNA targeting cSMARCA5 was downregulated. Bioinformatics analysis predicted that microRNA (miR)‑432 targeted cSMARCA5, and miR‑432 was able to interact with epidermal growth factor receptor (EGFR) by binding to its 3'‑untranslated region. The expression levels of EGFR, ERK1 and ERK2 were increased in cervical cancer tissues. Furthermore, correlation analysis revealed that cSMARCA5 levels were positively correlated with ERK1 and ERK2 levels. In conclusion, the present findings suggested that cSMARCA5 may play an important role in the progression of cervical cancer via the ERK signaling pathway by modulating miR‑432.

miR‑218 functions as a tumor suppressor gene in cervical cancer

Previous microRNA (miR) microarray analysis revealed that miR‑218 is downregulated in cervical cancer tissues. The present study aimed to further evaluate the expression of miR‑218 in cervical cancer specimens, determine the association between its expression with disease progression, and investigate the roles of miR‑218 in cervical cancer cells. Tissue specimens were obtained from 80 patients with cervical squamous cell carcinoma, 30 patients with high‑grade cervical intraepithelial neoplasia [(CIN) II/III] and 15 patients with low‑grade CIN (CINI); in addition, 60 plasma samples were obtained from patients with cervical cancer, and 15 normal cervical tissue specimens and 30 plasma samples were obtained from healthy women. These samples were used for analysis of miR‑218 expression via reverse transcription‑-quantitative PCR. In addition, tumor cells were transfected with miR‑218 mimics, human papillomavirus (HPV)16 E6/E7 small interfering RNA, or their respective negative controls to determine the viability, colony formation, migration and invasion of cells using MTT, colony formation, wound healing and Transwell assays, respectively. Target genes of miR‑218 were bioinformatically predicted and analyzed using Gene Ontology (GO) terms. The results revealed that miR‑218 was downregulated in the tumor tissues and plasma of patients with cervical cancer, with expression associated with the advanced clinicopathological characteristics of patients, including HPV positivity, tumor size, blood vessel invasion and lymph node metastasis. Furthermore, miR‑218 overexpression reduced tumor cell viability and xenograft growth, and suppressed tumor cell migration and invasion. HPV was detected in 75% of the 80 patients with cervical cancer, and HPV positivity was inversely associated with miR‑218 expression. In addition, bioinformatics analysis predicted that roundabout guidance receptor 1 (ROBO1) was a target gene of miR‑218; miR‑218 overexpression significantly reduced ROBO1 levels. Furthermore, GO analysis revealed that ROBO1 was involved in regulating cell proliferation, adhesion and migration, and the cell cycle. In conclusion, the findings of the present study suggested that miR‑218 may possess antitumor activities in cervical cancer.

Prognostic and predictive roles of microRNA‑411 and its target STK17A in evaluating radiotherapy efficacy and their effects on cell migration and invasion via the p53 signaling pathway in cervical cancer

Cervical cancer is one of the most common gynecological malignancies worldwide. However, the pathogenesis of cervical cancer remains to be fully elucidated. Increasing evidence shows that microRNAs (miRNAs) may be involved in the pathogenesis of cervical cancer. The present study tested the hypothesis that the overexpression of miRNA (miR)‑411 may delay, whereas the overexpression of serine/threonine kinase 17a (STK17A) may contribute to, cervical cancer development and progression through the p53 pathway. Cervical cancer tissues and adjacent normal tissues were obtained from 141 patients with cervical cancer following radiotherapy, with efficacy evaluated. The receiver operating characteristic curve was plotted to show the value of miR‑411 and STK17A in predicting the efficacy of radiotherapy. Cox's proportional hazards regression model was utilized for multivariate analysis. A series of inhibitors, mimics or small interfering RNAs against STK17A were introduced to validate the regulatory mechanism of miR‑411 in governing STK17A, determined with a luciferase reporter gene assay. The expression of miR‑411 and STK17A, and the status of the p53 signaling pathway were evaluated. The colony forming ability, proliferation, migration, invasion and apoptosis of CaSki cells were assessed using a colony formation assay, 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay, Transwell assay and flow cytometry, respectively. miR‑411 was upregulated but STK17A was reciprocal in cervical tissues. The overexpression of miR‑411 and low expression of STK17A were correlated with high efficacy of radiotherapy. miR‑411 and STK17A had predictive value for the efficacy of radiotherapy; miR‑411 was the protective factor and STK17A was a risk factor for prognosis of cervical cancer. Increasing miR‑411 activated the p53 signaling pathway and promoted cell apoptosis, but inhibited cell proliferation, invasion and migration. STK17A, an miR‑411 target, increased following miR‑411 over‑expression, whereas the p53 signaling pathway was activated following STK17A inhibition. It was observed that the effect of miR‑411 inhibition was lost following STK17A silencing. These findings indicate that the miR‑411‑mediated direct suppression of STK17A induces apoptosis and suppresses the proliferation, migration and invasion of human cervical cancer cells via the p53 signaling pathway. Additionally, miR‑411 and STK17A have predictive value for the efficacy of radiotherapy.

FOXP3‑induced LINC00885 promotes the proliferation and invasion of cervical cancer cells

Cervical cancer (CC) is the fourth most common type of cancer in women worldwide. LINC00885, a novel oncogenic type of long non‑coding RNA, is upregulated in various types of cancer, but its expression in CC remains unknown. The aim of the present study was to investigate the expression of LINC00885 in CC, and its effect on the proliferation and invasion of CC cells

Knockdown of lncRNA NEAT1 suppresses proliferation and migration, and induces apoptosis of cervical cancer cells by regulating the miR‑377/FGFR1 axis

To investigate the role of NEAT1 and the microRNA (miR)‑377/fibroblast growth factor receptor 1 (FGFR1) axis in cervical cancer (CC), the expression levels of NEAT1, FGFR1 and miR‑377 were detected in CC tissues and cell lines. NEAT1 or FGFR1 was knocked down by transfection with short hairpin RNA (sh)‑NEAT1 or sh‑FGFR1, and miR‑377 was overexpressed by transfection with miR‑377 mimics in HeLa and C33A cells. Cell viability and migration were measured using MTT and Transwell assays, respectively. Cell apoptosis was determined by flow cytometry. A dual luciferase reporter assay was performed to confirm the presence of binding sites between miR‑377 and FGFR1. The results revealed that the expression levels of NEAT1 and FGFR1 were significantly elevated, whereas miR‑377 expression was markedly decreased in CC tissues and cell lines. In HeLa and C33A cells, after NEAT1 knockdown, miR‑377 expression was increased, cell viability and migration were inhibited, and apoptosis was induced. Similarly, silencing FGFR1 inhibited cell viability and migration, and induced apoptosis of HeLa and C33A cells. A dual luciferase reporter gene assay verified a targeting relationship between NEAT1 and miR‑377. Inhibition of miR‑377 or overexpression of FGFR1 reversed the effects of NEAT1 knockdown on cell function in HeLa and C33A cells. Moreover, a dual luciferase reporter assay confirmed that FGFR1 was a direct target of miR‑377. In conclusion, suppression of NEAT1 inhibited cell viability and migration, and promoted apoptosis of CC cells, and these effects were achieved through regulation of the miR‑377/FGFR1 axis.

Targeted reversal of multidrug resistance in ovarian cancer cells using exosome‑encapsulated tetramethylpyrazine

The objective of the present study was to develop exosomes (EXOs) encapsulating tetramethylpyrazine (TMP) for the reversal of drug resistance in ovarian cancer therapy. Human A2780 cells were incubated with TMP for 48 h. Purified TMP‑primed EXOs (EXOs‑TMP) were isolated through ultracentrifugation. The developed EXOs‑TMP were characterized using techniques such as transmission electron microscopy, nanoparticle tracking analysis, Fluorescence microscopy and western blotting. Subsequently, MTT, western blotting and flow cytometry assays were performed to evaluate the biological effects in drug‑resistant A2780T cells. The results demonstrated that the incorporation of TMP into EXOs exhibited an anti‑ovarian cancer effect and markedly enhanced the antitumor efficacy of paclitaxel (PTX). Furthermore, it was identified that the ability of EXO‑TMP to reverse cell resistance was associated with the downregulation of multidrug resistance protein 1, multidrug resistant‑associated protein 1 and glutathione S‑transferase Pi protein expression. Flow cytometry analysis revealed that EXO‑TMP induced apoptosis in drug‑resistant cells and enhanced the apoptotic effect when combined with PTX. EXOs are naturally sourced, exhibit excellent biocompatibility and enable precise drug delivery to target sites, thereby reducing toxic side effects. Overall, EXO‑TMP exhibited direct targeting capabilities towards A2780T cells and effectively reduced their drug resistance. EXOs‑TMP provide a novel and effective drug delivery pathway for reversing drug resistance in ovarian cancer.

Role of non‑coding RNA intertwined with the Wnt/β‑catenin signaling pathway in endometrial cancer (Review)

Endometrial cancer (EC) ranks as the sixth most common malignancy in women around the world. Although low‑grade and early‑stage EC commonly have an excellent prognosis, ~20% of EC patients experience an unfavorable prognosis. Identifying the pathogenesis and novel therapeutic targets may help address this group of patients. Non‑coding (nc)RNAs, such as long non‑coding RNAs (lncRNAs), microRNAs and circular RNAs (circRNAs), have been associated with EC occurrence and development. In addition, the aberrant activation of the Wnt/β‑catenin signaling pathway can promote the proliferation, invasion, migration and epithelial‑to‑mesenchymal transition (EMT) of EC cells. The network of ncRNAs has also been demonstrated to inhibit or activate the Wnt/β‑catenin signaling pathway. In the present review, ncRNAs, the Wnt/β‑catenin signaling pathway, and their crosstalk in EC were summarized and highlighted. This information is expected to provide novel insights into improving the management of EC using RNA as therapeutics.

Potential role of Fanconi anemia pathway in the pathogenesis of endometrial cancer (Review)

Endometrial cancer (EC) is a common gynecologic malignancy that often exhibits molecular features such as extensive somatic copy number alterations, microsatellite instability and frequent

Establishment and verification of a prognostic signature associated with fatty acid metabolism in endometrial cancer

Endometrial carcinoma (EC) is one of the leading causes of mortality in women. Metabolic disorders, such as abnormal fatty acid metabolism (FAM), are considered to be indicators of tumorigenesis. However, to the best of our knowledge, the relationship between EC and FAM remains unclear. The process of FAM is associated with the function of immune cells, thus samples from The Cancer Genome Atlas were grouped according to immune infiltration levels. Subsequently, prognostic gene signatures were constructed based on selected FAM‑associated genes. The signature effect was validated, and enrichment analyses were conducted based on sample classification. Nomograms were used to predict survival, merging clinical data and the gene signature. Samples were divided into high‑ and low‑risk groups based on the gene signature. The survival status, clinical characteristics, enrichment analysis and immune infiltration were significantly different between high‑ and low‑risk groups. According to the nomogram, low microsatellite instability‑high as well as a high tumor mutation burden can be observed in the low‑nomo‑score group. Immune checkpoint inhibitor‑associated genes were differentially expressed between groups and 35 sensitive compounds were identified. Comprehensive bioinformatics analysis in EC revealed potential roles of FAM in tumorigenesis, the tumor microenvironment and prognosis, suggesting that FAM‑associated signatures are promising biomarkers for EC. These findings may improve the understanding of FAM in EC and pave the way for a more accurate assessment of prognosis and immunotherapy outcomes.

CMBs carrying PTX and CRISPR/Cas9 targeting C‑erbB‑2 plasmids interfere with endometrial cancer cells

Development of combination therapy to decrease side effects of chemotherapeutic drugs and increase their utilization rate in combination with gene editing is a key research topic in tumor treatment. The present study aimed to investigate the effect of cationic microbubbles (CMBs) carrying paclitaxel (PTX) and

ZIC2 upregulates lncRNA SNHG12 expression to promote endometrial cancer cell proliferation and migration by activating the Notch signaling pathway

It was previously reported that long non‑coding RNA (lncRNA) small nucleolar RNA host gene 12 (SNHG12) promoted the proliferation, invasion and migration of endometrial cancer (EC) cells; however, the upstream underlying mechanism remains unclear. The present study aimed to determine the possible underlying mechanism of SNHG12 regulating EC. The Encyclopedia of RNA Interactomes database was used to analyze whether SNHG12 could bind to Zic family member 2 (ZIC2) and the expression levels of ZIC2 in patients with EC. ZIC2 expression levels in EC cell lines were analyzed using western blotting and reverse transcription‑quantitative PCR. RL95‑2 cells were subsequently transfected with short hairpin RNA targeting ZIC2, or ZIC2 or SNHG12 overexpression plasmids. Cell proliferation, migration and invasion were analyzed using Cell Counting Kit‑8, colony formation, wound healing and Transwell assays, respectively. The binding between ZIC2 and SHNG12 was verified using dual luciferase reporter and chromatin immunoprecipitation assays. The results of the present study revealed that the expression levels of ZIC2 were upregulated in the tissues of patients with EC and EC cell lines. ZIC2 knockdown inhibited RL95‑2 cell proliferation, migration and invasion. The protein expression levels of Ki67, proliferating cell nuclear antigen, MMP2 and MMP9 were also downregulated following the knockdown of ZIC2. ZIC2 was predicted to bind to SNHG12 and positively regulate SNHG12 expression. Further experiments demonstrated that the effects of the knockdown of ZIC2 on RL95‑2 cells were partially reversed by SNHG12 overexpression. In addition, ZIC2 knockdown inhibited Notch signaling activation, while SNHG12 overexpression reversed this effect. In conclusion, the findings of the present study indicated that ZIC2 may upregulate SNHG12 expression to promote EC cell proliferation and migration by activating the Notch signaling pathway.

MicroRNA‑199a/b‑5p inhibits endometrial cancer cell metastasis and invasion by targeting FAM83B in the epithelial‑to‑mesenchymal transition signaling pathway

Our previous study demonstrated the role of family with sequence similarity 83, member B (

Ginsenoside Rh2 stimulates the production of mitochondrial reactive oxygen species and induces apoptosis of cervical cancer cells by inhibiting mitochondrial electron transfer chain complex

Ginsenoside Rh2 (G‑Rh2) is a monomeric compound that extracted from ginseng and possesses anti‑cancer activities both

De novo assembly and transcriptome characterization: Novel insights into the mechanisms of primary ovarian cancer in Microtus fortis

The natural incidence of primary epithelial ovarian cancer (OVC) in adult female voles of some established strains of

MG132 induces cell type‑specific anticancer effects in uterine leiomyosarcoma cell lines

Uterine leiomyosarcoma (Ut‑LMS) is a rare and aggressive malignant tumor with limited therapeutic options. Therefore, exploration of novel treatment strategies is necessary. MG132 is a potent proteasome inhibitor that has shown promising potential in cancer therapy by inducing apoptosis through disruption of protein homeostasis. Despite its promising applications in various cancers, its effects on Ut‑LMS remains largely unexplored. Therefore, the present study investigated the effects of MG132 on Ut‑LMS cell lines (SK‑LMS‑1, SK‑UT‑1 and SK‑UT‑1B) in terms of cytotoxicity, apoptosis induction, cell cycle progression, autophagy and reactive oxygen species (ROS) production. Treatment with MG132 (0‑2

PLOD2 exacerbates cervical squamous cell carcinoma by suppressing p53 by binding to YAP1

Procollagen‑lysine, 2‑oxoglutarate 5‑dioxygenase 2 (PLOD2) has been identified as an oncogene involved in the progression of several human cancers. However, its role in cervical squamous cell carcinoma (CESC) and its underlying mechanisms are not well understood. In the present study, several public databases, RT‑qPCR and western blotting were employed to detect the expression of PLOD2 and the prognosis in CESC. Cell counting kit‑8 assay, wound healing assay, Transwell assay, western blotting and flow cytometry were utilized to assess the proliferation, migration and cell apoptosis of CESC cells. Cellular senescence was examined by RT‑qPCR and β‑galactosidase staining. Prediction of PLOD2 binding to Yes‑associated protein 1 (YAP1) was assessed using BioGrid, HDock and co‑immunoprecipitation, and p53 and p21 signaling were assessed using immunofluorescence staining. The findings indicated that the expression of PLOD2 was elevated in CESC tissues and cell lines, and PLOD2 silencing caused the inhibition of CESC cell proliferation, migration and the promotion of apoptosis and senescence of CESC cells. PLOD2 was predicted to be bound to YAP1 and YAP1 overexpression reversed the effects of PLOD2 silencing on CESC cell proliferation, cell migration, apoptosis and senescence. In addition, PLOD2 facilitated CESC progression by regulating the P53 pathway through YAP1. PLOD2 exerted pro‑oncogenic effects on CESC through the p53 pathway by binding to YAP1. These findings provide new perspectives for the future study of PLOD2‑targeted therapy for CESC.

Norcantharidin inhibits the malignant progression of cervical cancer by inducing endoplasmic reticulum stress

The antitumor effect of norcantharidin (NCTD) has been widely reported. However, whether NCTD can inhibit cervical cancer remains unknown. In the present study, it was shown that NCTD inhibited the viability of cervical cancer cells and caused cell cycle arrest in a concentration‑dependent manner. Further analysis revealed that the NCTD‑induced reduction in cell viability could be reversed by the inhibitor of apoptosis z‑VAD‑FMK and by the inhibitor of endoplasmic reticulum (ER) stress, 4‑phenylbutyric acid (4‑PBA). Additionally, NCTD led to the accumulation of reactive oxygen species as well as a decrease in the mitochondrial membrane potential in cervical cancer cells, whereas 4‑PBA pre‑treatment attenuated these alterations. In addition, NCTD increased the expression of the apoptosis‑related proteins Bip, activating transcription factor (ATF) 4 and C/EBP homologous protein in a concentration‑dependent manner. Moreover, NCTD significantly increased the expression of the ER stress‑related signaling molecules protein kinase R‑like ER kinase, inositol‑requiring enzyme 1 and ATF6, but 4‑PBA abolished these effects.

BRCA1 VUS: A functional analysis to differentiate pathogenic from benign variants identified in clinical diagnostic panels for breast cancer

Genetic testing for susceptibility genes through next‑generation sequencing (NGS) has become a widely used technique. Using this, a number of genetic variants have been identified, several of which are variants of unknown significance (VUS). These VUS can either be pathogenic or benign. However, since their biological effect remains unclear, functional assays are required to classify their functional nature. As the use of NGS becomes more mainstream as a diagnostic tool in clinical practice, the number of VUS is expected to increase. This necessitates their biological and functional classification. In the present study, a VUS was identified in the

Gli affects the stemness and prognosis of epithelial ovarian cancer via homeobox protein NANOG

Gli proteins are key transcription factors of the Hedgehog (HH) signaling pathway, which is associated with tumorigenesis and drug resistance. However, the role of the HH signaling pathway in epithelial ovarian cancer (EOC) remains unclear. Studies have demonstrated that in some tumors, homeobox protein NANOG (NANOG), a known stem cell marker, is a downstream effector of Gli. However, limited research has been conducted on the association between Gli and NANOG in EOC, particularly regarding their roles in the tumor stemness, such as tumor development, drug resistance and patient prognosis. Thus, the aim of the present study was to explore the aforementioned issues. In this study, Gli1, Gli2 and NANOG expression in EOC tissues was assessed using immunohistochemistry. Gene expression was also assessed using western blotting and reverse transcription‑quantitative PCR in SKOV3 cells treated with a Gli inhibitor and an HH agonist. Furthermore, cell proliferation, colony‑forming ability and cisplatin sensitivity were assessed using Cell Counting Kit‑8 and colony formation assays. The results showed that both Gli1 and NANOG were associated with cisplatin resistance and EOC disease stage, while the nuclear expression of Gli2 was significantly associated with cisplatin resistance. Together, the expression of Gli and NANOG predicted poor patient prognosis. Targeting Gli with GANT61 impeded tumor proliferation, reversed cisplatin resistance and colony formation, and reduced NANOG expression. To conclude, Gli and NANOG may be effective indicators of platinum resistance and prognosis in EOC. Targeting Gli may reduce the stemness of ovarian cancer cell, which may be achieved via indirect targeting of NANOG.

Long non‑coding RNA NEAT1 promotes ovarian cancer cell invasion and migration by interacting with miR‑1321 and regulating tight junction protein 3 expression

Previous studies have reported that long non‑coding RNAs (lncRNAs) have a significant role in the metastasis of tumors, including ovarian cancer (OC). The aim of the present study was to demonstrate the function and working mechanism of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in OC. The expressions of NEAT1 in OC were measured by reverse transcription‑quantitativePCR (RT‑qPCR). The effects of NEAT1 on cell proliferation, invasion, migration and epithelial‑mesenchymal transition (EMT) were detected by Cell Counting Kit‑8, transwell and wound healing assays, and western blotting. Dual‑luciferase reporter assays were performed to confirm the correlated between NEAT and miR‑1321, miR‑1321 and TJP3. The effect of NEAT1 on miR‑1321 and TJP3 was confirmed by RT‑qPCR and western blotting. Elevated expression of NEAT1 was observed in OC cell lines, and NEAT1 expression was found to be positively related to the expression of tight junction protein 3 (TJP3), which is important in cancer development. Moreover, the present results indicated that NEAT1 and TJP3 expression levels were negatively correlated with microRNA (miR)‑1321 expression in OC. Knockdown of NEAT1 attenuated the migration and invasion of OC cells, as well as increased miR‑1321 expression and in turn led to the reduction of TJP3. Thus, the present study demonstrated that NEAT1 regulates TJP3 expression by sponging miR‑1321 and enhances the epithelial‑mesenchymal transition, invasion and migration of OC cells. Overall, the present study identified the function and mechanism of NEAT1 in OC, suggesting that NEAT1 may be a promising therapeutic target for OC metastasis.

MicroRNA-196a promotes cell proliferation and inhibits apoptosis in human ovarian cancer by directly targeting DDX3 and regulating the PTEN/PI3K/AKT signaling pathway

MicroRNAs (miRNAs/miRs) are small noncoding RNAs 19‑24 nucleotides in length, which can play an important role in tumor development. However, the influence of miRNAs on the tumorigenicity of ovarian cancer cells has not been fully elucidated. Previously, DEAD box protein (DDX) 1 has been shown to play a role in tumor suppression of ovarian cancer progression. However, the functions of other DDX members in ovarian cancer development remain largely unknown. In the present study, it was demonstrated that overexpression of miR‑196a promoted ovarian cancer cell proliferation. In addition, DDX3 was significantly downregulated in ovarian cancer cell lines relative to the normal ovarian cell line. Moreover, DDX3 was identified as a direct target of miR‑196a in ovarian cancer cells. In addition, a preliminary mechanistic investigation indicated that downregulation of DDX3 promoted ovarian cancer cell proliferation through the PTEN/PI3K/AKT pathway. Taken together, this confirmed an association between DDX3 and miR‑196a in ovarian cancer, and showed that miR‑196a promoted the proliferation of ovarian cancer cells and attenuated apoptosis by downregulating the expression of DDX3 through the PTEN/PI3K/AKT pathway. Overall, the results of the present study suggested that DDX3 could be a novel target for ovarian cancer treatment.

Liriopesides B from Liriope spicata var. prolifera inhibits metastasis and induces apoptosis in A2780 human ovarian cancer cells

Ovarian cancer is the most frequent cause of death among gynecological cancers. In the present study, the anti‑cancer effect of liriopesides B, a steroidal saponin from Liriope spicata var. prolifera, against A2780 cells was investigated. Transwell chambers were adopted to assess its effect on cell invasion and chemotaxis abilities. Flow cytometry was used to analyze the cell cycle and apoptosis. Reverse transcription‑quantitative PCR was employed to examine gene expression levels. Western blot analysis was performed to detect protein expression levels. Liriopesides B inhibited the invasion and chemotactic movement ability of A2780 cells in a dose‑dependent manner. Furthermore, liriopesides B caused cell cycle arrest in A2780 cells at the G1 phase following incubation for 24, 48 and 72 h. Hoechst 33258 staining indicated that, following incubation for 48 h, liriopesides B induced cell apoptosis in a dose‑dependent manner. Flow cytometry verified that liriopesides B induced apoptosis in A2780 cells and induced late apoptosis in a dose‑dependent manner. Furthermore, liriopesides B significantly increased the mRNA expression levels of E‑CADHERIN, p21 and p27 and decreased the gene expression levels of BCL‑2, which was consistent with its protein expression levels. In conclusion, liriopesides B possess anti‑cancer properties, including inhibition of metastasis‑associated behaviors, cell cycle arrest and induction of apoptosis. Therefore, liriopesides B may be considered as a candidate drug against ovarian cancer.

Long non‑coding RNA HAND2‑AS1/miR‑106a/PTEN axis re‑sensitizes cisplatin‑resistant ovarian cells to cisplatin treatment

Cisplatin (DDP) resistance in patients suffering from ovarian cancer is a considerable hurdle to successful treatment. The present study aimed to identify a possible long non‑coding RNA (lncRNA)‑microRNA (miRNA)‑mRNA axis participating in ovarian cancer DDP‑resistance based on the critical roles of non‑coding RNAs, including lncRNAs and miRNAs, in carcinogenesis. According to online data and experimental results, lncRNA HAND2‑AS1 expression was significantly downregulated within ovarian carcinoma, especially within recurrent and DDP‑resistant ovarian carcinoma. The expression of HAND2‑AS1 was also shown to be markedly inhibited in SKOV3/DDP (DDP) cells with resistance to DDP. In SKOV3/DDP cells, HAND2‑AS1 overexpression inhibited cell viability and promoted cell apoptosis upon DDP treatment through the Bcl‑2/caspase‑3 apoptotic signaling. It was hypothesized that PTEN mRNA expression was also markedly inhibited in SKOV3/DDP ovarian cancer cells, while HAND2‑AS1 overexpression rescued PTEN proteins and blocked PI3K/AKT signaling activation. Moreover, miR‑106a was found to bind directly to PTEN 3' UTR and HAND2‑AS1. Upon DDP treatment, miR‑106a overexpression in SKOV3/DDP cells promoted cell viability. It inhibited cell apoptosis through the Bcl‑2/caspase‑3 apoptotic signaling pathway and downregulated the protein levels of PTEN and upregulated PI3K/AKT signaling activity. Furthermore, miR‑106a overexpression partially reversed the effect of HAND2‑AS1 overexpression upon PTEN proteins and SKOV3/DDP cell proliferation upon DDP treatment. In conclusion, a lncRNA HAND2‑AS1/miR‑106a/PTEN axis that re‑sensitizes DDP‑resistant SKOV3/DDP cells to DDP treatment has been established.

Propofol inhibits proliferation and cisplatin resistance in ovarian cancer cells through regulating the microRNA‑374a/forkhead box O1 signaling axis

Ovarian cancer is a prominent disease that demonstrates high incidence rates in women and often presents multidrug resistance. Propofol has been demonstrated to suppress the malignancy of various types of human cancer; however, the underlying molecular mechanisms of propofol in ovarian cancer remain largely unknown. The present study aimed to investigate whether and how propofol inhibits proliferation and cisplatin (DDP) resistance in ovarian cancer cells. Ovarian cancer cell viability was assessed by the Cell Counting kit‑8 assay; apoptosis and cell cycle progression were determined by flow cytometry; the relative expression levels of microRNA (miR)‑374a and forkhead box O1 (FOXO1) were analyzed using reverse transcription‑quantitative PCR; the binding ability of miR‑374a to FOXO1 was assessed by the dual‑luciferase reporter assay; cellular sensitivity to DDP was detected using the MTT assay; and finally, the protein expression levels of FOXO1, p27, and Bcl‑2‑like‑protein 11 (Bim) were analyzed by western blotting. Propofol reduced viability, promoted apoptosis and decreased miR‑374a expression levels in A2780 cells. In addition, the viability of A2780/DDP cells in the propofol + DDP treatment group was significantly inhibited, and the apoptotic rate was increased. In addition, miR‑374a overexpression increased cell viability and the proportion of cells in the S phase, and decreased the proportion of cells in the G0/G1 phase. Conversely, genetic knockdown of miR‑374a exerted the opposite effects on cell viability and cell cycle progression. Moreover, miR‑374a was demonstrated to bind to FOXO1. Propofol promoted the expression of FOXO1, p27 and Bim, induced cell cycle arrest and decreased ovarian cancer cell viability. In addition, treatment with propofol and DDP regulated FOXO1 and increased apoptosis of ovarian cancer cells. In conclusion, propofol downregulated miR‑374a and modulated the FOXO1 pathway to reduce proliferation and DDP resistance in ovarian cancer cells.

Upregulation of CCT3 promotes cervical cancer progression through FN1

The mechanisms underlying cervical cancer progression have not yet been fully elucidated; thus, further investigations are required. Chaperonin containing TCP1 subunit 3 (CCT3) expression was found to be upregulated in several types of human cancer. However, the roles of CCT3 in cervical cancer remain poorly understood. Thus, the present study aimed to determine the roles of CCT3 in the progression of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). For this purpose, the Tumor Immune Estimation Resource and Gene Expression Profiling Interactive Analysis databases were used to analyze the mRNA and protein expression levels of CCT3 in CESC samples. The effects of CCT3 on the proliferation and migration of CESC

KIF4A knockdown suppresses ovarian cancer cell proliferation and induces apoptosis by downregulating BUB1 expression

Ovarian cancer is one of the most common lethal gynecological malignancies worldwide. Abnormal kinesin family member 4A (KIF4A) expression has been implicated in ovarian cancer progression; however, the potential mechanism underlying KIF4A in ovarian cancer is not completely understood. The present study aimed to clarify the molecular basis of KIF4A in ovarian cancer. KIF4A and budding uninhibited by benzimidazoles 1 (BUB1) expression levels were detected via reverse transcription-quantitative PCR and western blotting. Cell Counting Kit-8, colony formation, wound healing, TUNEL and flow cytometry assays were performed to assess cell proliferation, migration, apoptosis and cell cycle distribution, respectively. Ki67 expression levels were detected by conducting immunofluorescence assays. The expression levels of migration- and apoptosis-related proteins were measured via western blotting. A co-immunoprecipitation assay was conducted to determine the association between KIF4A and BUB1. The results demonstrated that KIF4A was expressed at significantly higher levels in ovarian cancer cell lines compared with IOSE-80 cells. Compared with the short hairpin RNA-negative control group, KIF4A knockdown significantly inhibited cell viability, colony formation and migration, and markedly induced cell apoptosis. The results indicated that KIF4A could bind to BUB1 and regulate BUB1 expression. BUB1 overexpression weakened KIF4A knockdown-mediated effects on cell viability, colony formation, migration and apoptosis. Overall, the present study demonstrated that KIF4A knockdown suppressed ovarian cancer progression by regulating BUB1, and suggested the potential value of KIF4A and BUB1 as therapeutic targets for ovarian cancer.

Multi‑faceted role of cancer‑associated adipocytes in the tumor microenvironment (Review)

Adipocytes are a type of stromal cell found in numerous different tissues that serve an active role in the tumor microenvironment. Cancer‑associated adipocytes (CAAs) display a malignant phenotype and are found at the invasive tumor front, which mediates the crosstalk network between adipocytes (the precursor cells that will become cancer‑associated adipocytes in the future) and cancer cells. The present review covers the mechanisms of adipocytes in the development of cancer, including metabolic reprogramming, chemotherapy resistance and adipokine regulation. Furthermore, the potential mechanisms involved in the adipocyte‑cancer cell cycle in various types of cancer, including breast, ovarian, colon and rectal cancer, are discussed. Deciphering the complex network of CAA‑cancer cell crosstalk will provide insights into tumor biology and optimize therapeutic strategies.

Chemokine CCL20 promotes the paclitaxel resistance of CD44+CD117+ cells via the Notch1 signaling pathway in ovarian cancer

Studies have found that C‑C motif chemokine ligand 20 (CCL20)/C‑C motif chemokine receptor 6 (CCR6)/notch receptor 1 (Notch1) signaling serves an important role in various diseases, but its role and mechanism in ovarian cancer remains to be elucidated. The aim of the present study was to investigate the underlying mechanism of CCL20/CCR6/Notch1 signaling in paclitaxel (PTX) resistance of a CD44

MicroRNA‑193a‑5p exerts a tumor suppressive role in epithelial ovarian cancer by modulating RBBP6

Epithelial ovarian cancer (EOC), a gynecological tumor, is associated with high mortality. MicroRNAs (miRs) serve a crucial role in EOC; however, the mechanisms underlying the effect of miRNA‑193a‑5p in EOC are not completely understood. Therefore, the present study aimed to investigate the expression levels of miR‑193a‑5p in serum samples of patients with EOC and to determine the role of miR‑193a‑5p in EOC. Reverse transcription‑quantitative PCR was used to analyze the expression levels of miR‑193a‑5p in serum samples of patients with EOC and EOC cell lines. The effects of miR‑193a‑5p and RB binding protein 6, ubiquitin ligase (RBBP6) on the biological functions of EOC were determined by conducting a series of

Human epididymis protein 4 promotes P‑glycoprotein‑mediated chemoresistance in ovarian cancer cells through interactions with Annexin II

The aim of the present study was to investigate the effects of human epididymis protein 4 (HE4) on drug resistance and its underlying mechanisms. The associations among proteins were detected by immunoprecipitation and immunofluorescence assays. Then, stably transfected cell lines CAOV3‑HE4‑L and CAOV3‑A2‑L expressing HE4 short hairpin (sh)RNAs and ANXA2 shRNAs, respectively, were constructed. MTT assay, immunocytochemistry, western blotting, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and flow cytometry were employed to examine drug sensitivity, as well as the expression and activity of P‑glycoprotein (P‑gp). HE4 and P‑gp in epithelial ovarian cancer tissues were assessed via immunohistochemistry. MicroRNAs that targeted the P‑gp gene, ABCB1, were predicted using bioinformatics methods, and their expression was evaluated by RT‑qPCR. The common signaling pathways shared by HE4, ANXA2 and P‑gp were selected by Gene Set Enrichment Analysis (GSEA). The interaction of HE4, ANXA2 and P‑gp were confirmed. P‑gp expression was positively associated with HE4 and ANXA2 expression, respectively. Moreover, it was observed that there was no significant rescue of P‑gp expression in CAOV3‑A2‑L cells following the administration of active HE4 protein. In addition, the expression of HE4 and P‑gp in ovarian cancer tissues of drug‑resistant patients were higher compared with that of the drug‑sensitive group (P<0.05). Furthermore, the results revealed that hsa‑miR‑129‑5p was significantly increased accompanied by decreased HE4 or ANXA2 expression and P‑gp expression in CAOV3‑HE4‑L and CAOV3‑A2‑L cells. GSEA analyses disclosed that HE4, ANXA2 and P‑gp genes were commonly enriched in the signaling pathway involved in regulating the actin cytoskeleton. These results indicated that HE4 promotes P‑gp‑mediated drug resistance in ovarian cancer cells through the interactions with ANXA2, and the underlying mechanism may be associated with decreased expression of hsa‑miR‑129‑5p and dysregulation of the actin cytoskeleton signaling pathway.

Circular RNA ABCB10 promotes cell proliferation and invasion, but inhibits apoptosis via regulating the microRNA‑1271‑mediated Capn4/Wnt/β‑catenin signaling pathway in epithelial ovarian cancer

Circular RNA ABCB10 (circ‑ABCB10) modulates cellular functions and microRNA (miR)‑1271 in epithelial ovarian cancer (EOC). The present study aimed to investigate the interaction between circ‑ABCB10 and miR‑1271 in regulating EOC cellular function and the calpain small subunit 1 (Capn4)/Wnt/β‑catenin signaling pathway. circ‑ABCB10 and miR‑1271 expression levels were detected in EOC cells (OVCAR3, UWB1.289, SKOV3 and CAOV3) and normal ovarian epithelial cells (IOSE80) via reverse‑transcription quantitative PCR. SKOV3 cells were transfected with control short hairpin (sh)RNA plasmids, control inhibitor, circ‑ABCB10 shRNA plasmids and miR‑1271 inhibitor. UWB1.289 cells were transfected with control overexpression plasmids, control mimic, circ‑ABCB10 overexpression plasmids and miR‑1271 mimic. Subsequently, cell proliferation, apoptosis, invasion and the Capn4/Wnt/β‑catenin signaling pathway were assessed. In addition, a luciferase activity assay was performed. circ‑ABCB10 expression was significantly increased in OVCAR3, SKOV3 and CAOV3 cells compared with IOSE80 cells, but was not significantly altered in UWB1.289 cells. miR‑1271 expression was significantly decreased in OVCAR3, UWB1.289, SKOV3 and CAOV3 cells compared with IOSE80 cells. In both SKOV3 and UWB1.289 cells, circ‑ABCB10 negatively regulated miR‑1271, whereas miR‑1271 did not affect circ‑ABCB10. Furthermore, circ‑ABCB10 enhanced cell proliferation, invasion and the Capn4/Wnt/β‑catenin signaling pathway, but inhibited cell apoptosis, whereas miR‑1271 suppressed cell proliferation, invasion and the Capn4/Wnt/β‑catenin signaling pathway, but facilitated cell apoptosis. Moreover, miR‑1271 attenuated the proproliferative, proinvasive and antiapoptotic effects of circ‑ABCB10, and reversed the positive regulation of circ‑ABCB10 on the Capn4/Wnt/β‑catenin signaling pathway. Besides, the luciferase activity assay indicated that circ‑ABCB10 directly bound to miR‑1271. In conclusion, the present study indicated that circ‑ABCB10 promoted cell proliferation and invasion, and suppressed apoptosis by regulating the miR‑1271‑mediated Capn4/Wnt/β‑catenin signaling pathway in EOC.

Long non‑coding RNA OIP5‑AS1 facilitates the progression of ovarian cancer via the miR‑128‑3p/CCNG1 axis

Long non‑coding RNA (LncRNA) o‑phthalaldehyde-interacting protein 5 antisense transcript 1 (OIP5‑AS1) serves major roles in the progression of various types of cancer. The present study investigated its biological function in ovarian cancer (OC) and its mechanisms. The levels of OIP5‑AS1, microRNA‑128‑3p (miR‑128‑3p) and cyclin G1 (CCNG1) were examined by reverse transcription‑quantitative PCR. Cell viability, apoptosis, migration and invasion were detected to analyze cellular progression. Glycolytic metabolism was assessed by detecting the levels of glucose consumption and lactate production. CCNG1 and hexokinase 2 protein levels were measured by western blotting. Dual‑luciferase reporter assay, RNA immunoprecipitation and RNA pull‑down assays were performed to affirm the interaction between two molecules. OIP5‑AS1 was found to be upregulated in OC tissues and cells. Knockdown of OIP5‑AS1 suppressed cell viability, migration, invasion and glycolysis while promoting apoptosis in OC cells. OIP5‑AS1 interacted with miR‑128‑3p and functioned as an oncogene by sequestering miR‑128‑3p. In addition, CCNG1 was a target gene for miR‑128‑3p and miR‑128‑3p regulated the CCNG1‑induced effects on OC cells by downregulating CCNG1. OIP5‑AS1 upregulated the expression of CCNG1 via targeting miR‑128‑3p. OIP5‑AS1 knockdown also inhibited tumor growth of OC in vivo by modulating the expression of miR‑128‑3p and CCNG1. Collectively, these data illustrated that the oncogenic role of OIP5‑AS1 in OC was associated with the miR‑128‑3p/CCNG1 axis at least in part. OIP5‑AS1 might be a probable diagnostic and therapeutic biomarker for the treatment of OC patients.

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Ovarian cancer (OC) is a major contributor to cancer‑related mortality in women. Despite numerous drugs being available for the treatment and improving the prognosis of OC, resistance to clinical chemotherapy remains a major obstacle for the treatment of advanced OC. Therefore, determining how to reverse the chemoresistance of OC has become a research hotspot in recent years. The present study aimed to reveal the potential mechanism of OC chemoresistance. Reverse transcription‑quantitative PCR and western blot analysis were performed to detect the expression levels of Ubiquitin‑specific peptidase 46 (USP46) and Pumilio 2 (PUM2) in OC. Cell viability and apoptosis were evaluated by Cell Counting Kit‑8 assay and flow cytometry, respectively. The association between USP46 and PUM2 was assessed by RNA immunoprecipitation. The results of the present study revealed that the expression levels of USP46 which is associated with tumor progression, was downregulated, while PUM2 expression levels were upregulated in cisplatin (DDP)‑resistant OC cells and patient tissues. The downregulation of USP46 expression levels in SKOV3 cells significantly inhibited cell apoptosis and increased cell viability. In SKOV3/DDP cells, the upregulation of USP46 expression levels notably suppressed cell viability and increased cell apoptosis. The results of the RNA immunoprecipitation chip assay demonstrated that PUM2 bound to USP46 and regulated its expression. Furthermore, following the knockdown of USP46 expression, the mRNA and protein expression levels of the cell apoptosis‑related protein, Bcl‑2, were upregulated, whereas the expression levels of caspase‑3, caspase‑9 and Bax were significantly downregulated. In addition, phosphorylated AKT expression levels were notably upregulated. Following the overexpression of USP46 in SKOV3/DDP cells, the opposite trends were observed. In SKOV3 cells, the knockdown of PUM2 could reverse the DDP resistance induced by small interfering RNA‑USP46 as the expression levels of Bcl‑2 were downregulated whereas those of caspase‑3, caspase‑9 and Bax were upregulated compared with the small interfering‑USP46 group. Similarly, in SKOV3/DDP cells, the overexpression of PUM2 could reverse DDP sensitivity induced by the overexpression of USP46. In conclusion, the findings of the present study suggested that the downregulation of USP46 expression levels may promote DDP resistance in OC, which may be regulated by PUM2. Therefore, targeting PUM2/USP46 may be an effective way to reverse DDP resistance in OC.

miR‑34c‑5p targets Notch1 and suppresses the metastasis and invasion of cervical cancer

Micro (mi)RNAs are crucial participants in the progression of cervical cancer (CC). Growing evidence indicates that miRNA (miR)‑34c‑5p is a pivotal tumor suppressor in numerous types of cancer and its functions in CC require further investigating. The present study demonstrated that there was a decreased level of miR‑34c‑5p in CC‑associated cell lines compared with healthy control samples. It also demonstrated that miR‑34c‑5p targeted Notch1 and suppressed CC progression. Dual‑luciferase reporter assays verified the targeted relationship of miR‑34c‑5p and Notch1. The expression of Notch1 in HeLa cells was markedly reduced following miR‑34c‑5p overexpression and the proliferation, migration and invasion of HeLa cells were reduced although apoptosis was accelerated. However, overexpression of miR‑34c‑5p was reversed following the addition of Notch1, which supported the finding of the targeted relationship between miR‑34c‑5p and Notch1. Flow cytometry demonstrated that miR‑34c‑5p inhibited the proliferation of HeLa cells while accelerating apoptosis. The present study concluded that miR‑34c‑5p was a tumor suppressor in CC and may be a novel measure for the future treatment of CC.

miR‑302c‑3p and miR‑520a‑3p suppress the proliferation of cervical carcinoma cells by targeting CXCL8

The aim of the present study was to identify the differentially expressed microRNAs (miRs) in cervical carcinoma (CC) tissues and cells and to explore the function of miR‑302c‑3p and miR‑520a‑3p in the proliferation of CC cells. Potential dysregulated miRNAs in CC tissues and tumour‑adjacent tissues were detected. Reverse transcription‑quantitative PCR (RT‑qPCR) was performed to determine the expression of miR‑302c‑3p, miR‑520a‑3p and CXCL8 in CC tissues and cell lines. The target genes of the miRNAs were predicted using miRTarBase and verified by luciferase reporter assays. RT‑qPCR and western blotting were performed to measure the expression of C‑X‑C motif ligand (CXCL)8 after transfection. The effect on proliferation was verified by Cell Counting Kit assay and ethynyl‑2‑deoxyuridine staining. Flow cytometry was utilised to assess the effect on apoptosis. In the present study, miR‑302c‑3p and miR‑520a‑3p were markedly downregulated in CC cell lines compared to the normal cervical cell line H8. Functionally, overexpression of miR‑302c‑3p and/or miR‑520a‑3p inhibited proliferation and promoted the apoptosis of CC cell lines

Notoginsenoside R1 induces DNA damage via PHF6 protein to inhibit cervical carcinoma cell proliferation

Notoginsenoside R1 (NGR1), a monomer of Traditional Chinese medicine, is from the

Interference of PTK6/GAB1 signaling inhibits cell proliferation, invasion, and migration of cervical cancer cells

Protein tyrosine kinase 6 (PTK6) has shown important cancer‑promoting effects in a variety of cancer types. Nonetheless, its vital role in cervical cancer has not been completely elucidated. The present study sought to address whether PTK6 is involved in the malignant progression of cervical cancer via its interaction with GRB2‑associated binding 1 (GAB1). Western blotting was used to examine PTK6 and GAB1 expression levels. Cell Counting Kit‑8, Transwell, wound healing, and terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assays were performed to estimate the corresponding proliferative, migratory, invasive, and apoptotic abilities of the cells. Co‑immunoprecipitation (Co‑IP) assays confirmed binding of PTK6 to GAB1. The results revealed that the expression levels of PTK6 and GAB1 were markedly increased in cervical cancer cell lines compared with those noted in normal cervical epithelial cells. The cell proliferative, invasive, and migratory activities of cervical cancer cells were reduced in the absence of PTK6 expression, whereas the induction of apoptosis was aggravated under these conditions. The results of the Co‑IP assay indicated that PTK6 expression was positively associated with GAB1. In addition, the suppressive effect of PTK6 silencing on the malignant phenotypes of cervical cancer cells was reversed following overexpression of GAB1. In summary, the present study indicated that knockdown of PTK6 expression protected against the malignant progression of cervical cancer, while overexpression of GAB1 counteracted the inhibitory effects of PTK6 knockdown on cervical cancer cells.

T‑cadherin and its impact on human diseases (Review)

Role of DNA methylation and non‑coding RNAs expression in pathogenesis, detection, prognosis, and therapy‑resistant ovarian carcinoma (Review)

Ovarian cancer is the deadliest gynecological cancer globally, with epithelial ovarian cancer (EOC) comprising up to 90% of cases. A molecular characterization linking the histological subtypes with tumor grade in EOC has been suggested. Variations in genetic biomarkers such as BRCA1/2, MSH2, MLH1/6, BRIP1, and RAD51C/D have been studied in EOC. In addition, molecular characteristics, including DNA methylation and RNA transcription, are being explored as potential new biomarkers for the diagnosis and prognosis of this type of neoplasia. The present review focused on the role of DNA methylation and non‑coding RNA expression in the development of ovarian carcinomas and their association with diagnosis, prognosis, and the resistance of cancer cells to radiotherapy and chemotherapy. The present review considered the transition from the DNA structure to the RNA expression in ovarian carcinoma.

miR‑145 and miR‑23b co‑transfection decreases proliferation, migration, invasion and protein levels of c‑MYC, ZEB1 and ABCB1 in epithelial ovarian cancer cell lines

MicroRNAs (miRs) are non‑coding RNAs that prevent the translation of mRNAs. miRs participate in cellular processes such as cell proliferation, migration and invasion, acting as oncogenes or tumor suppressors. In epithelial ovarian cancer (EOC), a decrease in tumor suppressor miRs, such as miR‑145 and miR‑23b, regulates the mRNAs of oncogenic proteins. The present study aimed to determine whether the co‑transfection of two oncosuppressor miRs (miR‑145‑5p and miR‑23b‑3p) decreased the proliferation, migration, invasion, and protein levels of c‑MYC, zinc finger E‑box binding homeobox 1 (ZEB1) and ATP binding cassette subfamily B1 (ABCB1) in EOC cell lines (A2780, SKOV‑3 and OV‑90). Reverse transcription‑quantitative PCR was employed to determine miR expression after co‑transfection. Cell proliferation was evaluated by Ki‑67 immunofluorescence staining and Ki‑67 positive cell counting. Transwell inserts, both with and without Matrigel, were used to assess invasion and migration, respectively. c‑MYC, ZEB1 and ABCB1 protein expression was determined by western blot analysis. The co‑transfection of miR‑145 and miR‑23b resulted in decreased proliferation, migration and invasion, along with reduced protein expression levels of c‑MYC, ZEB1 and ABCB1 in EOC cells. The combination of miR‑23b and miR‑145 transfection in EOC cells exhibited good antitumor effects, thus supporting the design of future complementary therapies for EOC.

miR‑802 inhibits the epithelial‑mesenchymal transition, migration and invasion of cervical cancer by regulating BTF3

MicroRNA (miR)-802 has been discovered to be involved in the occurrence and development of numerous types of tumor; however, studies into the role of miR‑802 in cervical cancer are limited. Therefore, the present study aimed to investigate the regulatory effects of miR‑802 in cervical cancer cells. miR‑802 expression levels in cervical cancer tissue and cells were analyzed using reverse transcription‑quantitative (RT‑q)PCR, a dual‑reporter luciferase activity assay was used to identify the direct target gene of miR‑802, and RT‑qPCR and western blotting were performed to determine the relationship between miR‑802 and basic transcription factor 3 (BTF3). Cell viability, and migration and invasion were analyzed using Cell Counting Kit‑8 and Transwell assays, respectively. Finally, the expression levels of metastasis‑associated proteins, N‑cadherin and E‑cadherin, were determined using RT‑qPCR and western blotting. Decreased expression levels of miR‑802 were found in cervical cancer tissues and cells, and the overexpression of miR‑802 inhibited cell viability, migration and invasion. Moreover, miR‑802 was discovered to directly target BTF3 to inhibit its expression. Notably, the overexpression miR‑802 markedly reversed the promotive effect of BTF3 on cell viability, in addition to the migratory and invasive abilities of the cells. Simultaneously, the overexpression of miR‑802 significantly suppressed epithelial‑mesenchymal transition, and the expression levels of matrix metallopeptidase (MMP)2 and MMP9 in cells through regulating BTF3. In conclusion, the present study revealed that miR‑802 may suppress cervical cancer progression by decreasing BTF3 expression levels, indicating that it may represent a potential therapeutic target for the treatment and prognosis of patients with cervical cancer.

Dual‑regulated oncolytic adenovirus carrying ERCC1‑siRNA gene possesses potent antitumor effect on ovarian cancer cells

Ovarian cancer is a multifactorial and deadly disease. Despite significant advancements in ovarian cancer therapy, its incidence is on the rise and the molecular mechanisms underlying ovarian cancer invasiveness, metastasis and drug resistance remain largely elusive, resulting in poor prognosis. Oncolytic viruses armed with therapeutic transgenes of interest offer an attractive alternative to chemical drugs, which often face innate and acquired drug resistance. The present study constructed a novel oncolytic adenovirus carrying

Knockdown of MIR9‑3HG inhibits proliferation and promotes apoptosis of cervical cancer cells by miR‑498 via EP300

Cervical cancer is a serious gynecological cancer and one of the primary causes of mortality in female patients with cancer. Despite advances in cancer research, the molecular mechanism underlying cancer remains poorly understood. High levels of MIR9‑3 host gene (HG) are associated with the occurrence and development of cervical cancer. However, the specific role of MIR9‑3HG during the development of cervical cancer is unclear. In the present study, the expression of MIR9‑3HG was silenced in C33A and SiHa cervical cancer cell lines. Proliferation and apoptosis were measured in these cells using 5‑ethynyl‑2'‑deoxyuridine assay and flow cytometry, respectively. In addition, targeting microRNAs (miRs) of MIR9‑3HG and mRNAs of miR‑498 were predicted using public databases. The predicted interactions between these molecules were validated using RNA immunoprecipitation, RNA pull‑down and luciferase reporter assays. Lastly, C33A cells transfected with short hairpin MIR‑3HG alone or in combination with miR‑498 inhibitor or PC‑EP300 were subcutaneously injected into mice. The levels of miR‑498, EP300 and Ki67 in tumor tissue were measured via reverse transcription‑quantitative PCR or western blotting. MIR9‑3HG knockdown inhibited the proliferation of cervical cancer cells, whilst promoting apoptosis. MIR9‑3HG sponged miR‑498 and inhibited its expression. Additionally, miR‑498 interacted with EP300 and inhibited its expression. Transfection with miR‑498 inhibitor significantly decreased apoptosis levels; this effect was abolished following EP300 silencing

WWOX promotes apoptosis and inhibits autophagy in paclitaxel‑treated ovarian carcinoma cells

Although paclitaxel (PTX) is a first‑line chemotherapeutic agent for the treatment of epithelial ovarian cancer (EOC), its clinical use is restricted by chemoresistance. Autophagy is believed to promote drug resistance, and WW domain‑containing oxidoreductase (WWOX) has been predicted to serve an essential role in apoptosis induction and to suppress autophagy in various tumor cell types. In the present study, the role of WWOX was demonstrated using PTX‑treated EOC cells. Cell viability and apoptosis were detected using Cell Counting Kit‑8, morphological and flow cytometric analyses. WWOX and phosphorylated (p)‑WWOX were highly expressed in PTX‑treated sensitive EOC cells (A2780), which was accompanied by activation of the apoptosis‑related proteins caspase‑3 and poly (ADP‑ribose) polymerase (PARP). Conversely, PTX‑resistant EOC cells (A2780/T) were characterized by reduced WWOX expression and constant phosphorylation levels, as well as undetectable levels of activated caspase‑3 and PARP when cells were treated with PTX. The altered expression of WWOX between the two cell types was further validated by reverse transcription‑-quantitative PCR. The apoptosis‑inducing role of WWOX was also confirmed by flow cytometry after WWOX overexpression was induced in PTX‑treated A2780 cells. These findings indicated that WWOX activation may inhibit chemoresistance and trigger cancer cell death. The upregulated expression levels of the autophagy‑related protein 12‑5 complex, Beclin‑1 and LC3, as well as the downregulation of P62, were also detected following PTX treatment, suggesting that PTX induced autophagic flux in both types of EOC cells. This conclusion was further supported by visualizing the accumulation of autophagosome and autolysosome vesicles, using confocal microscopy and transmission electron microscopy. PTX was also shown to inhibit mTOR signaling, indicated by a decreased level of p‑mTOR and increased expression of eukaryotic translation initiation factor 4E‑binding protein 1. Finally, the interaction between WWOX, mTOR and autophagy was investigated via WWOX transfection experimentation, and indicated that WWOX activated mTOR whilst inhibiting autophagy. These data indicated that WWOX may serve a critical role in PTX‑induced apoptosis and could suppress autophagy by downregulating essential autophagic effectors in EOC cells via mTOR signaling.

PARP inhibitor resistance and TP53 mutations in patients treated with olaparib for BRCA-mutated cancer: Four case reports

Loss‑of‑function BRCA mutations are frequent in high‑grade serous ovarian carcinoma. BRCA1 and ‑2 mutations lead to homologous recombination (HR) deficiency. Poly(ADP‑ribose) polymerases (PARP) are enzymes involved in DNA repair. PARP inhibitors (PARPi) lead to DNA damage accumulation in cells deficient in HR. Olaparib (a PARPi) is currently used for the treatment of high‑grade serous ovarian carcinoma with germline or somatic BRCA mutations; however, numerous patients do not respond or eventually develop resistance to these agents. The TP53 gene encodes the p53 protein, which is often referred to as the 'guardian of the genome'. TP53 mutations at diagnosis are known to promote resistance to chemotherapy. In the present study, four cases of patients with BRCA‑mutated cancer treated with olaparib, who progressed following the PARPi treatment, are reported. Exome analyses were performed on a primary tumor biopsy at diagnosis, then on a progressing metastasis following olaparib treatment. Exome analyses following olaparib treatment identified

MicroRNA‑199a‑3p inhibits ovarian cancer cell viability by targeting the oncogene YAP1

MicroRNA‑199a‑3p (miR‑199a‑3p) is aberrantly expressed in various types of cancer where it exhibits a tumor suppressive role. However, the biological role of miR‑199a‑3p in ovarian cancer (OC) remains unclear. The present study aimed to investigate whether miR‑199a‑3p was a tumor suppressor in OC and to identify the possible mechanisms. It was found that miR‑199a‑3p expression was significantly downregulated in the tumor tissues and blood samples of patients with OC, as well as in three OC cell lines. In addition, its low expression was closely associated with International Federation of Gynecology and Obstetrics disease stage, histological grade and lymph node metastasis. It was demonstrated that overexpression of miR‑199a‑3p inhibited the viability and promoted apoptosis of OV90 and SKOV‑3 cells. In addition, Yes‑associated protein 1 (YAP1), a well‑known oncogene, was identified as a direct target of miR‑199a‑3p in OC cells. Additionally, it was observed that YAP1 was significantly increased and inversely correlated with miR‑199a‑3p expression in OC tissues. Notably, YAP1 overexpression abrogated the tumor suppressive effects of miR‑199a‑3p

IGF2BP3‑stabilized SIX4 promotes the proliferation, migration, invasion and tube formation of ovarian cancer cells

The mortality rate of ovarian cancer (OC) is the highest among the different types of female reproductive system cancers. SIX homeobox 4 (SIX4), a member of the homeobox family, subfamily SIX, fulfills an important role in metastasis and angiogenesis in a variety of types of cancer. The aim of the present study was to investigate both the effects and the underlying mechanism of SIX4 on angiogenesis in OC. The Gene Expression Profiling Interactive Analysis and Encyclopedia of RNA Interactomes databases were employed to predict the expression levels of SIX4 in OC tissues, and its association with the overall survival (OS) rate of patients with OC. The expression levels of SIX4 in OC cell lines were detected by reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. Following silencing of SIX4, the proliferation, invasion, migration and angiogenesis of OC cells were investigated via Cell Counting Kit‑8, colony formation, wound healing, Transwell and tube formation assays. Subsequently, the levels of insulin‑like growth factor 2 mRNA binding protein 3 (IGF2BP3) in OC cell lines were detected by RT‑qPCR and western blot analysis. The ability of IGF2BP3 to bind to SIX4 mRNA was detected via an RNA immunoprecipitation assay, and the stability of SIX4 mRNA was assessed by RT‑qPCR following Actinomycin D treatment. Finally, the effects of transfection of sh‑SIX4 and overexpression of IGF2BP3 simultaneously were examined to further delineate the mechanism involved. It was revealed that SIX4 was highly expressed in OC tissues and cells, and its expression was associated with low OS rates in patients with OC. SIX4 knockdown with short hairpin RNA inhibited the proliferation, migration and invasion of cells, as well as angiogenesis. In addition, IGF2BP3 overexpression led to an improvement in the stability of SIX4 mRNA. Overexpression of IGF2BP3 also reversed the inhibitory effect of SIX4 interference on the malignant phenotypes of OC cells. Taken together, the results of the present study demonstrated that IGF2BP3‑stabilized SIX4 promoted the proliferation, metastasis and angiogenesis of SKOV3 cells.

Glycogene expression profiles from a HaCaT cell line stably transfected with HPV16 E5 oncogene

The altered expression of glycan antigens has been reported during cervix transformation, demonstrating increased mRNA levels of certain glycogenes. Human papillomavirus (HPV) is the aetiological agent of cervical cancer. High risk HPV E5 is considered an oncogene and has been implicated in cell transformation. E6 and E7 HPV oncoproteins modify the expression of certain glycogenes. The role of the E5 HPV protein in glycogene expression changes has not yet been reported. The aim of the present study was to determine the effects of HPV16 E5 oncoprotein on glycogene expression. For these, a microarray assay was performed using the HaCaT cell line and altered glycogenes were identified. The mRNA levels of certain glycogenes were determined via reverse transcription‑quantitative PCR (RT‑qPCR). Using in silico analysis, the present study identified that glycosylation pathways were altered by E5. Microarray analysis revealed alterations in certain glycogenes, including the upregulation of ST6GAL1, ST3GAL3, CHST2 and MANBA, and the downregulation of UGT2B15, GALNT11, NDST2 and UGT1A10. Increased mRNA levels were confirmed via RT‑qPCR for sialyltransferases genes. Additionally, in silico analysis was performed to identify glycosylation networks altered in the presence of the E5 oncoprotein. The analysis revealed that E5 could modify glycan sialylation, the N‑glycosylation pathway, keratan sulfate and glycosaminoglycan synthesis. To the best of our knowledge, the current study was the first to determine the role of the HPV16 E5 oncoprotein in glycogene expression changes. The results indicated that increased sialyltransferase mRNA levels reported in pre‑malignant and malignant cervical tissues could be the result of E5 oncoprotein expression. The results provide a possible role of HPV infection on glycosylation changes reported during cervix transformation.

miR‑96 exerts an oncogenic role in the progression of cervical cancer by targeting CAV‑1

Cervical cancer is the 4th most common malignant tumor type affecting women worldwide; however, its molecular mechanisms are not fully understood. Previous studies have indicated that microRNAs (miRs) serve crucial roles in the cellular functions of tumors. miR‑96 is involved in the tumorigenesis of many cancer types. The aim of the present study was to investigate the role and mechanism of miR‑96 in the progression of cervical cancer. The present results suggested that overexpression of miR‑96 significantly enhanced the proliferative, migratory and invasive abilities of cervical cancer cells, while inhibiting miR‑96 had the opposite effects. Additionally, activation of the Akt/mTOR signaling pathway was enhanced by miR‑96 overexpression, while it was inhibited by the miR‑96 inhibitor. Moreover, it was identified that miR‑96 may directly target caveolin‑1 (CAV‑1) to decrease its expression level. Furthermore, overexpression of CAV‑1 could reverse the increase in cell proliferation, migration and invasion induced by miR‑96, as well as the upregulation of the Akt/mTOR signaling pathway. In conclusion, the present results suggested that miR‑96 may have an oncogenic role in the progression of cervical cancer by targeting CAV‑1. Therefore, miR‑96 may be a potential target for cervical cancer therapy.

LncRNA ANCR downregulates hypoxia‑inducible factor�1α and inhibits the growth of HPV‑negative cervical squamous cell carcinoma under hypoxic conditions

Long non‑coding RNA (lncRNA) anti‑differentiation non‑coding RNA (ANCR) has been reported to participate in numerous types of malignancies. The present study aimed to investigate the function of lncRNA ANCR in cervical squamous cell carcinoma (CSCC). The expression of ANCR in the cervical tissues (tumor tissues in patients with CSCC) and serum of patients with CSCC in addition to healthy female controls was detected using reverse transcription‑quantitative polymerase chain reaction. Diagnostic values of ANCR expression in cervical tissue and serum for CSCC were determined using receiver operating characteristic curve analysis. LncRNA ANCR and hypoxia‑inducible factor 1α (HIF‑1α) expression vectors were constructed and transfected into CSCC cell lines, and cell proliferation under normal O2 and hypoxic conditions (8% O2) was detected using a Cell Counting kit‑8 assay. Expression of HIF‑1α was determined using western blot analysis. It was observed that ANCR was downregulated in human papillomavirus (HPV)‑negative patients with CSCC compared with in normal female cases and HPV‑positive patients with CSCC in cervical tissues and in the serum, and the downregulation of ANCR effectively distinguished HPV‑negative patients with CSCC from healthy controls. ANCR overexpression inhibited the proliferation of HPV‑negative CSCC cells under hypoxic conditions, whilst HIF‑1α overexpression reversed this effect. ANCR overexpression inhibited HIF‑1α expression in HPV‑negative CSCC cells, while HIF‑1α overexpression exhibited no significant effect on ANCR expression. It was therefore concluded that ANCR may inhibit the growth of HPV‑negative cervical squamous cell carcinoma under hypoxic conditions by downregulating HIF‑1α.

Analysis of differentially expressed long non‑coding RNAs revealed a pro‑tumor role of MIR205HG in cervical cancer

Cervical cancer is the fourth most common female malignancy for both incidence and mortality worldwide and is one of the major threats to women's health. The role of long non‑coding RNAs (lncRNAs) in cervical cancer remains largely unknown. In the present study, the differentially expressed lncRNAs in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tissues were retrieved form The Cancer Genome Atlas (TCGA) and were analyzed. The expression analysis of related genes was performed with GEPIA. The proliferation and migratory and invasive abilities of MIR205HG knockdown CESC cells were analyzed using Cell Counting Kit‑8 and transwell assays. The expression of Ki‑67 and p16 was detected by immunofluorescence. A total of 203 differentially expressed lncRNAs were identified. The results demonstrated that MIR205HG was overexpressed in CESC tissues. Furthermore, the genes related to MIR205HG were enriched in cancer‑related pathways. MIR205HG knockdown significantly decreased the proliferation and migratory and invasive abilities of CESC cells. In addition, silencing of MIR205HG significantly decreased the expression of p16 in C‑33 A cells. The expression of fibroblast growth factor receptor 3, thymidine phosphorylase and GTPase HRas was downregulated in MIR205HG knockdown CESC cells. These findings revealed some potential lncRNA candidates for cervical cancer research and suggested that MIR205HG may have a pro‑tumor role in CESC.

hsa_circ_0101119 facilitates the progression of cervical cancer via an interaction with EIF4A3 to inhibit TCEAL6 expression

Recently, circular RNAs (circRNAs/circs) have attracted increased attention due to their regulatory role in a variety of cancer types. However, the role and molecular mechanisms of circRNAs in cervical cancer (CC) remain unknown. The present study aimed to investigate the function of hsa_ circ_0101119 on CC and its potential mechanisms. The differentially expressed circRNAs associated with CC were screened out using R software, according to the database of Gene Expression Omnibus (GEO). The expression levels of hsa_circ_0101119, eukaryotic initiation factor 4A‑3 (EIF4A3) and transcription elongation factor A‑like 6 (TCEAL6) in CC cells were detected via reverse transcription‑quantitative (RT‑q)PCR, and their expression levels in CC tissues were analyzed based on the database of GEO and the Cancer Genome Atlas. Moreover, the accurate functions of hsa_circ_0101119 and TCEAL6 on the proliferation, apoptosis, migration and invasion of SiHa and HeLa cells was examined using colony formation assay, 5‑ethynyl‑20‑deoxyuridine incorporation assay, flow cytometry and Transwell assay. Next, the underlying mechanisms of hsa_circ_0101119 on CC progression were determined via bioinformatics analysis, RNA immunoprecipitation assay, RNA pull down assay, RT‑qPCR and western blotting. It was found that hsa_circ_0101119 was highly expressed in CC tissues and cells, while TCEAL6 was lowly expressed. Knockdown of hsa_circ_0101119 or TCEAL6 overexpression significantly inhibited the proliferation, migration and invasion of SiHa and HeLa cells, but facilitated apoptosis. It was also demonstrated that hsa_circ_0101119 could recruit EIF4A3 to inhibit TCEAL6 expression in CC. Furthermore, knockdown of TCEAL6 could reverse the effects of silencing hsa_circ_0101119 on the proliferation, apoptosis, migration and invasion of HeLa cells. In conclusion, the present study revealed that hsa_circ_0101119 could facilitate cell proliferation, migration and invasion, and suppress apoptosis in CC via an interaction with EIF4A3 to inhibit TCEAL6 expression, which may provide a potential therapeutic target for CC treatment.

Survival‑related DLEU1 is associated with HPV infection status and serves as a biomarker in HPV‑infected cervical cancer

Human papillomavirus (HPV) is the most common risk factor for the occurrence of cervical cancer (CC). In recent years, the important roles of long non‑coding RNAs (lncRNAs) in CC have emerged, but studies on the relationship between lncRNAs and HPV‑positive (HPV+) CC remain scarce. The present study aimed to investigate whether lncRNA deleted in lymphocytic leukemia 1 (DLEU1) is associated with HPV infection and explore the clinical significance of DLEU1 in HPV+ patients with CC. DLEU1 expression was detected by reverse transcription‑quantitative PCR. The ability of DLEU1 to screen patients with CC from controls and differentiate individuals with different HPV infection status was evaluated by receiver operating characteristic analysis. The association of DLEU1 with the survival prognosis of patients with CC was assessed by Kaplan‑Meier survival analysis and Cox regression analysis. The RNA Interactome Database was used to predict molecules interacting with DLEU1. The results indicated that DLEU1 expression was significantly upregulated in CC tissues and cell lines, particularly in those that were HPV+. In addition, DLEU1 had a high diagnostic value in discriminating patients with CC and differentiating between HPV+ and HPV‑ patients with CC, and had a certain ability to screen HPV+ controls. DLEU1 was correlated with HPV infection in CC patients. Furthermore, DLEU1 was indicated to be associated with survival prognosis in both total patients with CC and HPV+ patients with CC, and independently predict the prognosis of patients with CC. Most of the molecules interacting with DLEU1 were microRNAs. In conclusion, abnormal DLEU1 expression is associated with HPV infection and may serve as a diagnostic and prognostic biomarker for HPV+ patients with CC.