International Journal of Molecular Medicine

Adipocyte‑rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator‑activated receptor gamma/ABCG2 in epithelial ovarian cancer

The effects of adipocyte‑rich microenvironment (ARM) on chemoresistance have garnered increasing interest. Ovarian cancer (OVCA) is a representative adipocyte‑rich associated cancer. In the present study, epithelial OVCA (EOC) was used to investigate the influence of ARM on chemoresistance with the aim of identifying novel targets and developing novel strategies to reduce chemoresistance. Bioinformatics analysis was used to explore the effects of ARM‑associated mechanisms contributing to chemoresistance and treated EOC cells, primarily OVCAR3 cells, with human adipose tissue extracts (HATES) from the peritumoral adipose tissue of patients were used to mimic ARM in vitro. Specifically, the peroxisome proliferator‑activated receptor γ (PPARγ) antagonist GW9662 and the ABC transporter G family member 2 (ABCG2) inhibitor KO143, were used to determine the underlying mechanisms. Next, the effect of HATES on the expression of PPARγ and ABCG2 in OVCAR3 cells treated with cisplatin (DDP) and paclitaxel (PTX) was determined. Additionally, the association between PPARγ, ABCG2 and chemoresistance in EOC specimens was assessed. To evaluate the effect of inhibiting PPARγ, using DDP, a nude mouse model injected with OVCAR3‑shPPARγ cells and a C57BL/6 model injected with ID8 cells treated with GW9662 were established. Finally, the factors within ARM that contributed to the mechanism were determined. It was found that HATES promoted chemoresistance by increasing ABCG2 expression via PPARγ. Expression of PPARγ/ABCG2 was related to chemoresistance in EOC clinical specimens. GW9662 or knockdown of PPARγ improved the efficacy of chemotherapy in mice. Finally, angiogenin and oleic acid played key roles in HATES in the upregulation of PPARγ. The present study showed that the introduction of ARM‑educated PPARγ attenuated chemoresistance in EOC, highlighting a potentially novel therapeutic adjuvant to chemotherapy and shedding light on a means of improving the efficacy of chemotherapy from the perspective of ARM.

Downregulation of hsa_circ_0026123 suppresses ovarian cancer cell metastasis and proliferation through the miR‑124‑3p/EZH2 signaling pathway

Circular RNAs (circRNAs) play a role in various types of cancer. The present study suggested that hsa_circ_0026123 expression was upregulated in ovarian cancer (OVA), which was associated with its role in OVA. However, the role of hsa_circ_0026123 in OVA cell invasion and proliferation remains unclear. In the present study, OVA tissues and cell lines were used to investigate the functions of hsa_circ_0026123. The associations between hsa_circ_0026123, miR‑124‑3p and enhancer of zeste homolog 2 (EZH2) were examined using a luciferase reporter assay. RT‑qPCR and western blot analysis were used for gene and protein expression analysis, respectively. Tumor growth was detected using nude mouse tumor xenografts derived from SKOV3 cells, with or without hsa_circ_0026123 downregulation. The results confirmed that hsa_circ_0026123 expression was upregulated in OVA tissues and cell lines, while hsa_circ_0026123 silencing suppressed cell proliferation and migration; it also suppressed the expression of cancer stem cell (CSC) differentiation‑related markers in either in vivo or in vitro experiments. The data revealed that hsa_circ_0026123 downregulation suppressed EZH2 expression by miR‑124‑3p 'sponging', which was confirmed by rescue experiments and luciferase reporter assays. The results revealed that hsa_circ_0026123 silencing suppressed ovarian cancer cell progression via the miR‑124‑3p/EZH2 signaling pathway. Overall, the findings demonstrated that hsa_circ_0026123 knockdown inhibited OVA cell progression by regulating the miR‑124‑3p/EZH2 axis. This methodology may thus be used for the targeted therapy of OVA, as well as a candidate biomarker for the diagnosis and treatment of OVA.

LINC00324 facilitates cell proliferation through competing for miR‑214‑5p in immature ovarian teratocarcinoma

Immature ovarian teratocarcinoma (IOT) is a rare and malignant type of ovarian teratoma, and the molecular mechanisms underlying the pathogenesis and malignant phenotype of IOT remain uncharacterized. The present study examined a long non‑coding RNA (lncRNA), long‑chain intergenic non‑coding RNA324 (LINC00324), which may serve a crucial role in pathogenesis of IOT. According to the results, LINC00324 was upregulated in IOT tissues and cells, as determined by reverse transcription‑quantitative PCR, and its depletion impaired cell proliferation ability and improved cell apoptosis ability in IOT. Furthermore, LINC00324 acted as a miR‑214‑5p sponge to derepress cyclin dependent kinase 6 (CDK6), cyclin D1 (CCND1), murine double minute homolog 2 (MDM2), and mouse double minute 4 (MDM4) expression, thus increasing IOT cell proliferation and repressing apoptosis. Taken together, these results demonstrated that LINC00324 could serve as a competing endogenous RNA to facilitate IOT cell proliferation by regulation of miR‑214‑5p‑CDK6/CCND1/MDM2/MDM4 network, which possibly provide a novel therapeutic target for IOT.

Chrysin induces autophagy through the inactivation of the ROS‑mediated Akt/mTOR signaling pathway in endometrial cancer

Endometrial cancer (EC) is widely known as an aggressive malignancy. Due to the limited therapeutic options and poor prognosis of patients with advanced‑stage EC, there is a need to identify effective alternative treatments. Chrysin is a naturally active flavonoid (5,7‑dihydroxyflavone), which has been demonstrated to exert anticancer effects and may present a novel strategy for EC treatment. However, the role of chrysin in EC remains largely unclear. The aim of the present study was to examine the anticancer effects of chrysin on EC. The results revealed that, in addition to apoptosis, chrysin increased the LC3II expression levels and markedly accelerated the autophagic flux, suggesting that chrysin induced both the autophagy and apoptosis of EC cells. Furthermore, the inhibition of autophagy by chloroquine enhanced the inhibitory effect on cell proliferation and the promotion of the chrysin‑induced apoptosis of EC cells, indicating that chrysin‑induced autophagy was a cytoprotective mechanism. Additionally, chrysin led to the production of intracellular reactive oxygen species (ROS).

Methylation‑associated silencing of miR‑638 promotes endometrial carcinoma progression by targeting MEF2C

Promoter methylation‑associated silencing of cancer‑associated microRNAs (miRNAs) is a common epigenetic mechanism during tumorigenesis in various types of human cancer. However, this has not been comprehensively examined in endometrial carcinoma (EC). In the present study, an miRNA microarray consisting of 1,347 common human miRNAs was used to select potential tumor suppressive miRNAs that were hyper‑methylated in EC. This led to the identification of miR‑638, miR‑210 and miR‑3665. The methylation status of miR‑638 was examined by bisulfite sequencing polymerase chain reaction and miR‑638 expression was measured by TaqMan miRNA assays. EC cell lines transfected with vectors overexpressing miR‑638, its target gene myocyte enhancer factor 2C (MEF2C) or both, were constructed. Dual‑luciferase reporter assays, a xenograft mouse model and rescue experiments were designed to study miR‑638 and its target gene MEF2C. The results indicated that the promoter region of miR‑638 was highly methylated and the expression of miR‑638 was significantly downregulated in cancerous tissues from 42 patients with EC who underwent surgical resection. Additionally, a low expression of miR‑638 was significantly associated with advanced Federation of Gynecology and Obstetrics stage and was demonstrated to indicate shorter disease‑free survival. Functional studies indicated that the overexpression of miR‑638 in EC cell lines inhibited in vitro tumor progression and in vivo tumorigenicity. MEF2C was verified as a direct target of miR‑638 and was demonstrated to mediate the tumor‑suppressive function of miR‑638 in EC.

Long non‑coding RNA ASAP1‑IT1 suppresses ovarian cancer progression by regulating Hippo/YAP signaling

Long non‑coding RNAs (lncRNAs) are a class of non‑protein coding transcripts that are involved in the regulation of gene expression in mammalian cells. Transcriptional co‑activator Yes associated protein 1 (YAP1) plays a key role in the progression of ovarian cancer. However, the regulation of Hippo/YAP signaling in ovarian cancer remains elusive. In the present study, the expression levels of lncRNA

Role of solute carrier transporters in ovarian cancer (Review)

Solute carrier (SLC) transporters are involved in various biological processes associated with metabolic reprogramming and cancer, supporting the increased requirement of nutrients and energy. Over the past decade, there have been significant advancements in understanding the expression and function of SLCs in ovarian cancer (OC). This gynecological condition has a high mortality rate and limited treatment options; thus, early diagnosis remains a target clinically. OC exhibits complexity and heterogeneity, resulting in different clinical characteristics, resistance to chemotherapy drugs and poor prognosis. Additionally, SLCs have a different expression pattern between healthy and tumor tissue, and consequently, their inhibition or activation could modify signaling pathways involved in the tumor growth process, such as cell proliferation, apoptosis and drug accumulation. The present review aims to consolidate current data to provide a comprehensive understanding of the potential importance of SLCs in OC. Additionally, it seeks to offer guidance for further research on utilizing SLCs as prognostic biomarkers and therapeutic targets.

PSAT1 regulated by STAT4 enhances the proliferation, invasion and migration of ovarian cancer cells via the PI3K/AKT pathway

Epithelial ovarian cancer, the most prevalent form of ovarian cancer, is a health concern worldwide. Phosphoserine aminotransferase 1 (PSAT1), as the rate‑limiting enzyme in serine synthesis, is key in the conversion of 3‑phosphoglycerate to serine. The present study explored the role of PSAT1 expression in epithelial ovarian tumors. Gene Expression Profiling Interactive Analysis was used for gene expression and survival analyses. The effects of PSAT1 overexpression and knockdown on invasion, migration, proliferation and cell cycle progression of ovarian cancer cell lines were investigated both

Resveratrol inhibits the progression of cervical cancer by suppressing the transcription and expression of HPV E6 and E7 genes

Resveratrol is a representative polyphenol of diet‑derived putative cancer chemopreventive agents, which have attracted increasing interest in the cancer chemoprevention community. The inhibition of the action of human papillomavirus (HPV) E6 and E7 has been considered a key approach for cervical cancer therapy. Resveratrol has been shown to induce the apoptosis, and reduce both the viability and mitotic index of a number of cancer cell lines, including human cervical cancer cells. In the present study, it was confirmed that resveratrol inhibited the HPV E6 mRNA, HPV E6 protein and phosphorylated retinoblastoma protein (p‑pRb1) levels, and increased the p53 protein levels in HeLa and Ca Ski cells, as well as in subcutaneous tumor tissue grown from HeLa cells. High‑risk HPV uses a bicistronic RNA to control E6 and E7 genes simultaneously. On the whole, the present study demonstrates that resveratrol inhibits cervical cancer development by suppressing the transcription and translation of E6 and E7, and also by promoting the apoptosis and G1/S phase transition arrest. These findings may provide the basis for the development of resveratrol as a candidate for cervical cancer therapy.

Expression of BMP7 in cervical cancer and inhibition of epithelial‑mesenchymal transition by BMP7 knockdown in HeLa cells

The aim of the present study was to investigate the expression of bone morphogenetic protein 7 (BMP7) in cervical cancer tissues, the effect of BMP7 on the proliferation, migration and epithelial‑mesenchymal transition (EMT) of cervical cancer HeLa cells and the possible mechanism involved. Immunohistochemistry was used to stain the cervical cancer tissues and benign or precancerous lesions. Lentivirus containing BMP7 knockdown was transfected in HeLa cells and western blotting was performed to analyze BMP7 expression. At the same time, the influence of BMP7 knockdown on the expression of phosphorylated (p)‑mothers against decapentaplegic homolog 1/5/9 and EMT‑related markers [epithelial‑cadherin, neural‑cadherin, Vimentin, Snail and Slug] was detected. Cell Counting Kit‑8 was used to detect cell proliferation. Transwell migration and invasion assays were performed to measure cell invasion and migration. The cell cycle was detected by flow cytometry. Compared with normal cervical epithelial and paracancerous cells, the positive rate of BMP7 expression in cervical cancer tissues was significantly increased. As compared with the control group, the expression of BMP7 was decreased in HeLa cells transfected with lentivirus. The knockdown of BMP7 in cervical cancer HeLa cells inhibited cell proliferation, migration and invasion, resulted in G1 cell cycle arrest and reversed the EMT process. In addition, the expression of p‑Smad1/5/9 was significantly decreased in HeLa cells with BMP7 knockdown. BMP7 is expected to be a possible target for the treatment of cervical cancer.

Claudin 1, 4, 6 and 18 isoform 2 as targets for the treatment of cancer (Review)

p53 and ANXA4/NF‑κB p50 complexes regulate cell proliferation, apoptosis and tumor progression in ovarian clear cell carcinoma

Annexin IV (ANXA4) is highly expressed in ovarian clear cell carcinoma (OCCC); however, its underlying molecular mechanism in OCCC remains unknown. The present study aimed to identify the molecule that ANXA4 may act on and to determine its underlying molecular mechanism. Immunohistochemistry, co‑immunoprecipitation and western blotting were performed to detect the expression and interaction of ANXA4, and its associated proteins. Furthermore, MTT assay, flow cytometry, western blotting and gene expression profile enrichment analysis were performed to identify the potential role and molecular mechanism of ANXA4 in OCCC. The results demonstrated that ANXA4 and nuclear factor‑κ‑light‑chain‑enhancer of activated B cells (NF‑κB) p50 nuclear expression levels were significantly higher in OCCC tissues compared with other subtypes of ovarian cancer, such as serous and mucinous. In addition, a significantly positive correlation was observed between ANXA4 and NF‑κB p50 expression in OCCC; however, the expression levels of mutant p53 and ANXA4 were negatively correlated in a linear manner. These results suggest that ANXA4 and NF‑κB p50 may be potential independent risk factors for poor prognosis. ANXA4 and NF‑κB p50 were demonstrated to interact and their expression was co‑localized. The cBioPortal database was used to construct a protein‑protein interaction network between ANXA4, NF‑κB p50 and p53, and functional pathway analysis indicated that the genes were predominantly enriched in the cell cycle and during apoptosis. Transfection of the ANXA4 gene increased the expression of NF‑κB p50, as well as its downstream targets, Cyclin D1 and B‑cell lymphoma‑2 (Bcl‑2). Furthermore, transfection of the ANXA4 gene increased proliferation and decreased apoptosis of OCCC cells. Treatment with the NF‑κB inhibitor, BAY 11‑7082, decreased Cyclin D1 and Bcl‑2 expression levels. Collectively, the results of the present study suggest that wild p53 activates ANXA4 transcription, promotes its expression and enhances NF‑κB p50 and ANXA4 interaction. This in turn activates the NF‑κB signaling pathway, promotes cell cycle progression and inhibits apoptosis, thus contributing to the malignant progression of OCCC. Thus, ANXA4 and NF‑κB p50 may be used as prognostic biomarkers, and may be molecular therapeutic targets in OCCC.

Bcl‑2 family: Novel insight into individualized therapy for ovarian cancer (Review)

Chemoresistance to platinum‑based chemotherapy for ovarian cancer in the advanced stage remains a formidable concern clinically. Increasing evidence has revealed that apoptosis represents the terminal events of the anti‑tumor mechanisms of a number of chemical drugs and has a close association with chemoresistance in ovarian cancer. The B‑cell lymphoma‑2 (Bcl‑2) family plays a crucial role in apoptosis and has a close association with chemoresistance in ovarian cancer. Some drugs that target Bcl‑2 family members have shown efficacy in overcoming the chemoresistance of ovarian cancer. A BH3 profiling assay was found to be able to predict how primed a cell is when treated with antitumor drugs. The present review summarizes the role of the Bcl‑2 family in mediating cell death in response to antitumor drugs and novel drugs that target Bcl‑2 family members. The application of the new functional assay, BH3 profiling, is also discussed herein. Furthermore, the present review presents the hypothesis that targeting Bcl‑2 family members may prove to be helpful for the individualized therapy of ovarian cancer in clinical practice and in laboratory research.

MicroRNA‑195 suppresses cell proliferation, migration and invasion in epithelial ovarian carcinoma via inhibition of the CDC42/CCND1 pathway

Epithelial ovarian carcinoma (EOC) is the most common cause of gynecological cancer mortality, and poses a threat to women. MicroRNA‑195 (miR‑195) has been reported to induce apoptosis of human OVCAR‑3 cells by inhibiting the VEGFR2/AKT pathway. However, the role of miR‑195 in EOC remains unknown. A previous study reported that cell division cycle 42 (CDC42) can serve as a target gene of miR‑195 and mediate malignant progression of esophageal squamous cell carcinoma (ESCC). The aim of the present study was to investigate the role of miR‑195 in EOC and the regulation in CDC42/CCND1 pathway. Tissues samples and clinical materials were collected from 78 enrolled patients with EOC to analyze the expression and clinical significance of miR‑195, CDC42 and cyclin D1 (CCND1). Human EOC cell lines OVCA420, OVCAR‑3, A2780 and SKOV3 cell lines were used to assess the expression and function of miR‑195, CDC42 and CCND1 in vitro. Cell proliferation, the cell cycle and apoptosis, as well as the cell migratory and invasive abilities were detected in vitro using BrdU incorporation, colony formation, wound healing and Transwell invasion assays, along with flow cytometry. miR‑195 was downregulated, while CDC42 and CCND1 were upregulated in human EOC tissues and cells, and the aberrant expression of both was associated with increased EOC malignancy. Moreover, miR‑195 expression was negatively correlated with CDC42 and CCND1 expression levels, and negatively regulated these expression levels. Thus, it was suggested that miR‑195 functions as a tumor suppressor, but CDC42 and CCND1 act as tumor promoters based their abilities to enhance cell proliferation, cell cycle entry, migration and invasion, as well as decrease apoptosis in OVCAR‑3 cells. the present results demonstrated that miR‑195 inhibited human EOC progression by downregulating CDC42 and CCND1 expression. Furthermore, it was identified that miR‑195, CDC42 and CCND1 may be effective biomarkers for EOC diagnosis and treatment.

Exosomal microRNA‑146a derived from mesenchymal stem cells increases the sensitivity of ovarian cancer cells to docetaxel and taxane via a LAMC2‑mediated PI3K/Akt axis

The carrier role of exosomes from human umbilical cord mesenchymal stem cells (hUCMSCs) containing microRNAs (miRNAs) has been implicated in gene and drug therapy. The aim of the present study was to investigate the role of exosomal microRNA‑146a (miR‑146a) from hUCMSCs in ovarian cancer (OC). Following the generation of docetaxel (DTX)‑resistant SKOV3 cells and taxane‑resistant A2780 cells, exosomes were isolated from hUCMSCs and added to the chemoresistant cells. Microarray analysis revealed that miR‑146a expression was upregulated in DTX/SKOV3 cells among 15 ectopically expressed miRNAs. Analysis using the StarBase and miRSearch databases demonstrated that miR‑146a targeted laminin γ2 (LAMC2), which was further verified using dual‑luciferase reporter assays. Subsequently, miR‑146a inhibitor or LAMC2 overexpression vectors were transfected into hUCMSCs or OC cells, respectively, and their effects on growth and chemoresistance in OC cells were assessed. The hUCMSC‑derived exosomes reduced cell growth and chemoresistance in OC. Furthermore, hUCMSC‑derived exosomes with miR‑146a expression knocked down increased OC cell growth and chemoresistance, which was mediated by the PI3K/Akt signaling pathway via LAMC2.

Inhibitory effects of brusatol delivered using glycosaminoglycan‑placental chondroitin sulfate A‑modified nanoparticles on the proliferation, migration and invasion of cancer cells

Breakthroughs in cancer management result from the development of drugs that can be used for early diagnosis and effective treatment. Surgery, chemotherapy, radiotherapy and hormone therapy are the main anticancer therapies. However, traditional cancer chemotherapy is associated with serious systemic side effects. Nanoparticles (NPs) provide an effective solution for cancer treatment via the targeted delivery of drugs to cancer cells, while minimizing injury to normal cells. Glycosaminoglycan‑placental chondroitin sulfate A (plCSA) is expressed in a number of tumor cells and trophoblasts. A plCSA‑binding peptide (plCSA‑BP) was isolated from malaria protein VAR2CSA, which can effectively promote the binding of lipid polymer NPs to tumor cells, thereby significantly enhancing the anticancer effect of encapsulated drugs. Brusatol is an important compound derived from Brucea javanica that exerts a multitude of biological effects, including inhibiting tumor cell growth, reducing the reproduction of malaria parasites, reducing inflammation and resisting virus invasion. In the present study, brusatol‑loaded NPs (BNPs) or coumarin 6 NPs (CNPs), plCSA‑BP and scrambled control peptide‑bound BNPs or CNPs were prepared. Ovarian cancer cells (SKOV3), endometrial cancer cells (HEC‑1‑A) and lung cancer cells (A549) were treated with the NPs. The uptake of plCSA‑CNPs by tumor cells was found to be markedly higher compared with that of other types of NPs. Further studies demonstrated that the plCSA‑BNPs promoted the apoptosis of cancer cells more effectively and inhibited their proliferation, invasion and migration, accompanied by downregulation of matrix metalloproteinase (MMP)‑2, MMP‑9 and B‑cell CLL/lymphoma 2 (BCL2) levels, but upregulation of BCL2‑associated X protein BAX and cleaved caspase‑3 levels. The results demonstrated the potential of brusatol delivered by plCSA‑modified NPs as a chemotherapeutic agent for the targeted therapy of tumors by regulating the BCL2, BAX, cleaved caspase‑3, MMP‑2 and MMP‑9 pathways, and indicated that it may be an effective and safe strategy for the treatment of various tumors.

PLAG1 silencing promotes cell chemosensitivity in ovarian cancer via the IGF2 signaling pathway

Ovarian cancer (OC) is one of the most lethal gynecological diseases. Novel prognostic biomarkers and therapeutic targets for OC are urgently required. The aim of this study was to investigate the mechanisms that govern how pleomorphic adenoma gene 1 (PLAG1) influences the biological processes and chemosensitivity of OC cells via the insulin‑like growth factor‑2 (IGF2) signaling pathway. Differentially expressed genes in OC were selected based on bioinformatics data. OC and adjacent tissue specimen were collected, followed by the determination of the expression of PLAG1 and IGF2 signaling pathway‑associated genes. The regulatory mechanisms of PLAG1 in OC cells were analyzed following treatment with pcDNA or small interfering RNA (siRNA), and included the assessment of cell proliferation, migration, invasion and cisplatin resistance. PLAG1 was identified as an upregulated gene in OC. OC tissues exhibited increased expression of PLAG1 and IGF2 compared with the controls. Moreover, PLAG1 was observed to positively regulate the IGF2 signaling pathway. The siRNA‑mediated silencing of PLAG1 resulted in decreased expression of IGF2, IGF1 receptor and insulin receptor substrate 1, as well as inhibited proliferation, migration, invasion and cisplatin resistance of OC cells. Furthermore, the effect of PLAG1 was dependent on IGF2. PLAG1 may therefore be considered as a possible target for the treatment of OC.

Apoptotic SKOV3 cells stimulate M0 macrophages to differentiate into M2 macrophages and promote the�proliferation and migration of ovarian cancer�cells by activating the ERK signaling pathway

Ovarian cancer has a high rate of recurrence, with M2 macrophages having been found to be involved in its progression and metastasis. To examine the relationship between macrophages and ovarian cancer in the present study, M0 macrophages were stimulated with apoptotic SKOV3 cells and it was found that these macrophages promoted tumor proliferation and migration. Subsequently, the mRNAs and proteins expressed at high levels in these M2 macrophages were examined by RNA‑Seq and quantitative proteomics, respectively, which revealed that M0 macrophages stimulated by apoptotic SKOV3 cells also expressed M2 markers, including CD206, interleukin‑10, C‑C motif chemokine ligand 22, aminopeptidase‑N, disabled homolog 2, matrix metalloproteinase 1 and 5'‑nucleotidase. The abundance of phosphorylated Erk1/2 in these macrophages was increased. The results indicate that apoptotic SKOV3 cells stimulate M0 macrophages to differentiate into M2 macrophages by activating the ERK pathway. These results suggest possible treatments for patients with ovarian cancer who undergo chemotherapy; inhibiting M2 macrophage differentiation during chemotherapy may reduce the rate of tumor recurrence.

Silencing of the long noncoding RNA LINC01132 alleviates the oncogenicity of epithelial ovarian cancer by regulating the microRNA‑431‑5p/SOX9 axis

To date, the role of lncRNA long intergenic non‑protein‑coding RNA 1132 (LINC01132) expression in epithelial ovarian cancer (EOC) has not been explored. Thus, LINC01132 expression in EOC was assessed and the regulatory activity of LINC01132 on the malignant behaviours of EOC cells was investigated. Additionally, the molecular events that occurred downstream of LINC01132 in EOC cells were also revealed. In the present study, LINC01132 expression in EOC was verified by employing RT‑qPCR. The effects of LINC01132 on the aggressive behaviours of EOC cells were revealed utilizing multiple functional experiments. The targeting interaction among LINC01132, microRNA‑431‑5p (miR‑431‑5p) and SRY‑box 9 (SOX9) was demonstrated by RNA immunoprecipitation and luciferase reporter assay. Herein, LINC01132 was overexpressed in EOC and was significantly associated with poor patient prognosis. Functionally, cell experiments revealed that LINC01132 depletion produced cancer‑suppressive effects in EOC cells and regulated cell proliferation, migration, invasion and apoptosis

Estrogen disorders: Interpreting the abnormal regulation of aromatase in granulosa cells (Review)

Ovarian granulosa cells (GCs) are the most important source of estrogen. Therefore, aromatase (estrogen synthase), which is the key enzyme in estrogen synthesis, is not only an important factor of ovarian development, but also the key to estrogen secretion by GCs. Disorders of the ovarian estrogen secretion are more likely to induce female estrogen‑dependent diseases and fertility issues, such as ovarian cancer and polycystic ovary syndrome. Hence, aromatase is an important drug target; treatment with its inhibitors in estrogen‑dependent diseases has attracted increasing attention. The present review article focuses on the regulation and mechanism of the aromatase activity in the GCs, as well as the specific regulation of aromatase promoters. In GCs, follicle‑stimulating hormone (FSH) is dependent on the cyclic adenosine monophosphate (cAMP) pathway to regulate the aromatase activity, and the regulation of this enzyme is related to the activation of signaling pathways, such as phosphatidylinositol 3‑kinase (PI3K) and extracellular signal‑regulated kinase (ERK). In addition, endocrine‑disrupting substance and other related factors affect the expression of aromatase, which eventually create an imbalance in the estrogen secretion by the target tissues. The present review highlights these useful factors as potential inhibitors for target therapy.

Long non‑coding RNA LINC01006 exhibits oncogenic properties in cervical cancer by functioning as a molecular sponge for microRNA‑28‑5p and increasing PAK2 expression

As previously reported, long intergenic non‑protein‑coding RNA 1006 (LINC01006) plays crucial roles in prostate, pancreatic and gastric cancers. However, whether it plays important roles in cervical cancer remains unclear. The present study thus aimed to determine the precise role of LINC01006 in cervical cancer and elucidate its regulatory mechanisms. The expression of LINC01006 in cervical cancer was examined by reverse transcription‑quantitative polymerase chain reaction. Cell proliferation assay, flow cytometric analysis, Transwell migration and invasion assays, and tumor xenograft model experiments were performed to elucidate the roles of LINC01006 in cervical cancer. Bioinformatics analysis, luciferase reporter assay, RNA immunoprecipitation and rescue experiments were performed for mechanistic analyses. The expression of LINC01006 was found to be upregulated in cervical cancer and to be associated with a poor prognosis. The absence of LINC01006 inhibited the proliferation, migration and invasion of cervical cancer cells, whereas it promoted cell apoptosis

Lycorine upregulates the expression of RMB10, promotes apoptosis and inhibits the proliferation and migration of cervical cancer cells

Although there are numerous treatment strategies, including surgery and chemotherapy, the prognosis of cervical cancer remains far from satisfactory. There is an urgent need to develop more effective, more tolerable and safer therapeutics for the treatment of cervical cancer. Lycorine is a natural plantextract that has been previously found to confer anti‑tumor activities. Therefore, in the present study, the effects of lycorine and its possible mechanism of action in cervical cancer were investigated. Cell Counting Kit‑8, wound healing and Transwell assays were used to verify the proliferation and migration of HeLa cells following lycorine intervention. The results demonstrated that lycorine significantly inhibited the proliferation and migration of HeLa cells. RNA binding motif 10 (RBM10) is a protein associated with apoptosis. It has been suggested that lycorine can affect the expression of RBM10. Flow cytometry demonstrated that lycorine may inhibit the initiation and progression of cervical cancer by promoting apoptosis, which may be mediated through the upregulation of RBM10 expression and increasing TNF‑α levels. Xenograft mouse experiments indicated that when lycorine was injected through the tail vein, HeLa tumor growth was inhibited. Mechanistically, western blotting demonstrated that lycorine significantly inhibited the activation of the Akt signaling pathway and potentially reversed epithelial‑mesenchymal transition, which was also mediated by RBM10. Furthermore, following RBM10 knockdown with small interfering‑RNA, the inhibitory effects of lycorine on cervical cancer was significantly abrogated. Overall, results of the present study suggest that lycorine can upregulate the expression of RBM10 and inhibit the proliferation and migration of cervical cancer cells.

ZG16B: A key regulator of tumor progression and immune microenvironment modulation in cancer (Review)

Research progress on TMEM proteins in cancer progression and chemoresistance (Review)

[Expression of Concern] Suppression of SIK1 by miR‑141 in human ovarian cancer cell lines and tissues

Following the publication of this paper, for the western blots shown in Fig. 1A, where the expression levels of salt‑inducible kinase 1 were detected in ovarian cancer tissues, it was drawn to the Editor's attention by a concerned reader that the β‑actin loading controls for patients 4, 6 and 7 were strikingly similar in appearance. Moreover, several of the protein bands in this figure were strikingly similar to data which subsequently appeared in another paper written by different authors at different research institutes that was published in the journal

Crosstalk between ferroptosis and endoplasmic reticulum stress: A potential target for ovarian cancer therapy (Review)

Ferroptosis is a unique mode of cell death driven by iron‑dependent phospholipid peroxidation, and its mechanism primarily involves disturbances in iron metabolism, imbalances in the lipid antioxidant system and accumulation of lipid peroxides. Protein processing, modification and folding in the endoplasmic reticulum (ER) are closely related regulatory processes that determine cell function, fate and survival. The uncontrolled proliferative capacity of malignant cells generates an unfavorable microenvironment characterized by high metabolic demand, hypoxia, nutrient deprivation and acidosis, which promotes the accumulation of misfolded or unfolded proteins in the ER, leading to ER stress (ERS). Ferroptosis and ERS share common pathways in several diseases, and the two interact to affect cell survival and death. Additionally, cell death pathways are not linear signaling cascades, and different pathways of cell death may be interrelated at multiple levels. Ferroptosis and ERS in ovarian cancer (OC) have attracted increasing research interest; however, both are discussed separately regarding OC. The present review aims to summarize the associations and potential links between ferroptosis and ERS, aiming to provide research references for the development of therapeutic approaches for the management of OC.

Paeoniflorigenone inhibits ovarian cancer metastasis through targeting the MUC1/Wnt/β‑catenin pathway

Ovarian cancer (OC) is one of the most common gynecological malignancies. Currently, chemoradiotherapy is the primary clinical treatment approach for OC; however, it has severe side effects and a high rate of recurrence. Thus, there is an urgent need to develop innovative therapeutic options. Paeoniflorigenone (PFG) is a monoterpene compound isolated from the traditional Chinese medicine Paeoniae Radix Rubra. PFG can inhibit the proliferation of tumor cells; however, its anticancer activity against OC has yet to be elucidated. Mucin 1 (MUC1) is highly expressed in various malignant tumors, and is associated with tumor proliferation, metastasis and epithelial‑mesenchymal transition (EMT). In addition, MUC1 affects numerous signaling pathways in tumor cells. In order to develop a possible treatment approach for metastatic OC, the antitumor activity of PFG in OC cells was investigated using Cell Counting Kit‑8 assay, Edu assay, flow cytometry, Transwell assay and western blot analysis. In addition, it was assessed how PFG affects MUC1 expression and function. The experiments revealed that PFG significantly inhibited OC cell proliferation, migration, invasion and EMT. PFG also induced S‑phase cell cycle arrest in OC cells. Furthermore, PFG inhibited MUC1 promoter activity, which led to a decrease in MUC1 protein expression. By contrast, MUC1 promoted OC progression, including cell proliferation, cell cycle progression and cell migration. Stable knockdown of MUC1 in OC cells improved the ability of PFG to block the Wnt/β‑catenin pathway, and to limit tumor cell invasion and migration, whereas MUC1 overexpression partially counteracted the antitumor effects of PFG. In conclusion, the present study demonstrated that PFG may inhibit the MUC1/Wnt/β‑catenin pathway to induce anti‑metastatic, anti‑invasive and anti‑EMT effects on OC. Notably, MUC1 may be a direct target of PFG. Thus, PFG holds promise as a specific antitumor agent for the treatment of OC.

Role of circular RNA as competing endogenous RNA in ovarian cancer (Review)

Circular RNA (circRNA), a type of non‑coding RNA, plays a regulatory role in biological processes. The special loop structure of circRNA makes it highly stable and specific in diseased tissues and cells, especially in tumors. Competing endogenous RNAs (ceRNAs) compete for the binding of microRNA (miRNA) at specific binding sites and thus regulate gene expression. ceRNAs play an important role in various diseases and are currently recognized as the most prominent mechanism of action of circRNAs. circRNAs can modulate the proliferation, migration, invasion and apoptosis of tumor cells through the ceRNA mechanism. With further research, circRNAs may serve as novel markers and therapeutic targets for ovarian cancer (OC). In the present review, the research progress of circRNAs as ceRNAs in OC was summarized, focusing on the effects of the circRNA/miRNA/mRNA axis on the biological functions of OC cells through mediating pivotal signaling pathways. The role of circRNAs in the diagnosis, prognostic assessment and treatment of OC was also discussed in the present review.

Promising predictive molecular biomarkers for cervical cancer (Review)

Cervical cancer (CC) constitutes a serious public health problem. Vaccination and screening programs have notably reduced the incidence of CC worldwide by >80%; however, the mortality rate in low‑income countries remains high. The staging of CC is a determining factor in therapeutic strategies: The clinical management of early stages of CC includes surgery and/or radiotherapy, whereas radiotherapy and/or concurrent chemotherapy are the recommended therapeutic strategies for locally advanced CC. The histopathological characteristics of tumors can effectively serve as prognostic markers of radiotherapy response; however, the efficacy rate of radiotherapy may significantly differ among cancer patients. Failure of radiotherapy is commonly associated with a higher risk of recurrence, persistence and metastasis; therefore, radioresistance remains the most important and unresolved clinical problem. This condition highlights the importance of precision medicine in searching for possible predictive biomarkers to timely identify patients at risk of treatment response failure and provide tailored therapeutic strategies according to genetic and epigenetic characteristics. The present review aimed to summarize the evidence that supports the role of several proteins, methylation markers and non‑coding RNAs as potential predictive biomarkers for CC.

MicroRNA‑15a‑5p‑targeting oncogene YAP1 inhibits cell viability and induces cell apoptosis in cervical cancer cells

MicroRNAs (miRNAs) have been reported to have important regulatory roles in the progression of several types of cancer, including cervical cancer (CC). However, the biological roles and regulatory mechanisms of miRNAs in CC remain to be fully elucidated. The aim of the present study was to examine the functions of miRNAs in CC and the possible mechanisms. Using a microarray, it was identified that miRNA‑15a‑5p (miR‑15a‑5p) was one of the most downregulated miRNAs in CC tissues compared with adjacent noncancerous tissues. The low expression of miR‑15a‑5p was observed in CC tumor tissues with distant metastasis and in CC cell lines. In addition, the effects of miR‑15a‑5p upregulation on cell viability, apoptosis, invasion and migration of CC cells were investigated using CCK‑8, flow cytometry, Transwell and wound healing assays, respectively. It was demonstrated that upregulation of miR‑15a‑5p significantly suppressed the viability, migration and invasion, and promoted the apoptosis of SiHa and C‑33A cells. Furthermore, yes‑associated protein 1 (YAP1), a well‑known oncogene, was confirmed to be directly targeted by miR‑15a‑5p and was found to be negatively regulated by miR‑15a‑5p. Further correlation analysis indicated that miR‑15a‑5p expression was negatively correlated with YAP1 expression in CC tissues. Notably, overexpression of YAP1 abrogated the tumor suppressive effects of miR‑15a‑5p in CC cells. Taken together, these present findings indicated that the miR‑15a‑5p/YAP1 axis may provide a novel strategy for the clinical treatment of CC.

RCE‑4, a potential anti‑cervical cancer drug isolated from Reineckia carnea, induces autophagy via the dual blockade of PI3K and ERK pathways in cervical cancer CaSki cells

The steroidal saponin RCE‑4 (1β, 3β, 5β, 25S)‑spirostan‑1, 3‑diol 1‑[α‑L‑rhamnopyranosyl‑(1→2)‑β‑D‑xylopyranoside], isolated from Reineckia carnea, exerts significant anti‑cervical cancer activity by inducing apoptosis. The potential effect of RCE‑4 on proliferation inhibition and autophagy induction has rarely been studied. Therefore, the focus of the present study was to investigate the effects of RCE‑4 on proliferation, and to elucidate the detailed mechanisms involved in autophagy induction in cervical cancer cells. CaSki cells were treated with RCE‑4 or/and autophagy inhibitors, and the effect of RCE‑4 on cellular proliferation was assessed by MTT assay. The pro‑autophagic properties of RCE‑4 were subsequently confirmed using monomeric red fluorescent protein‑green fluorescent protein‑microtubule‑associated proteins 1A/1B light chain 3B (LC3) adenoviruses and CYTO‑ID autophagy assays, and by assessing the accumulation of lipid‑modified LC3 (LC3II). The mechanisms of RCE‑4‑induced autophagy were investigated by western blot analysis. The results demonstrated that inhibiting autophagy significantly promoted RCE‑4‑induced cell death, indicating that autophagy served a protective role following RCE‑4 treatment. In addition, RCE‑4‑induced autophagy was reflected by increased expression levels of the serine/threonine‑protein kinase ULK1, phosphorylated (p)‑ULK1, p‑Beclin‑1 and LC3II, the formation of autophagosomes and autolysosomes, and sequestosome 1 (p62) degradation. Subsequent analysis indicated that RCE‑4 activated the AMP‑activated protein kinase (AMPK) pathway by upregulating AMPK and p‑AMPK, and also inhibited the PI3K and extracellular signal‑regulated kinase (ERK) signaling pathways by downregulating p‑PI3K, p‑Akt, p‑mTOR, Ras, c‑Raf, p‑c‑Raf, dual specificity mitogen‑activated protein kinase kinase (MEK)1/2, p‑MEK1/2 and p‑Erk1/2. Additionally, with increased treatment times RCE‑4 may impair lysosomal cathepsin activity and inhibit autophagy flux by suppressing the expression of AMPK, p‑AMPK, ULK1, p‑ULK1 and p‑Beclin‑1, and upregulating that of p62. These results indicated that the dual RCE‑4‑induced inhibition of the PI3K and ERK pathways may result in a more significant anti‑tumor effect and prevent chemoresistance, compared with the inhibition of either single pathway; furthermore, dual blockade of PI3K and ERK, and the AMPK pathway may be involved in the regulation of autophagy caused by RCE‑4. Taken together, RCE‑4 induced autophagy to protect cancer cells against apoptosis, but AMPK‑mediated autophagy was inhibited in the later stages of RCE‑4 treatment. In addition, autophagy inhibition improved the therapeutic effect of RCE‑4. These data highlight RCE‑4 as a potential candidate for cervical cancer treatment.

Role of exosomal non‑coding RNAs in ovarian cancer (Review)

Ovarian cancer (OC) is a common gynecological disease with a high mortality rate worldwide due to its insidious nature and undetectability at an early stage. The standard treatment, combining platinum‑based chemotherapy with cytoreductive surgery, has suboptimal results. Therefore, early diagnosis of OC is crucial. All cell types secrete extracellular vesicles, particularly exosomes. Exosomes, which contain lipids, proteins, DNA and non‑coding RNAs (ncRNAs), are novel methods of intercellular communication that participate in tumor development and progression. ncRNAs are categorized by size into long ncRNAs (lncRNAs) and small ncRNAs (sncRNAs). sncRNAs further include transfer RNAs, small nucleolar RNAs, PIWI‑interacting RNAs and microRNAs (miRNAs). miRNAs inhibit protein translation and promote messenger RNA (mRNA) cleavage to suppress gene expression. By sponging downstream miRNAs, lncRNAs and circular RNAs can regulate target gene expression, thereby weakening the interactions between miRNAs and mRNAs. Exosomes and exosomal ncRNAs, commonly present in human biological fluids, are promising biomarkers for OC. The present article aimed to review the potential role of exosomal ncRNAs in the diagnosis and prognosis of OC by summarizing the characteristics, processes, roles and isolation methods of exosomes and exosomal ncRNAs.