Therapeutic Target For Ovarian Cancer Research Articles

NOTCH signalling in ovarian cancer angiogenesis.

The Notch signalling pathway is involved in the new vessel formation process by regulating tip and stalk cells, which are key cells in the sprout formation. This process is essential in both normal ovary and cancer angiogenesis and is regulated by Notch-VEGF crosstalk. Furthermore, Notch has been linked in ovary with stem cell maintenance and epithelial mesenchymal transition processes. Dysregulation of the Notch pathway is frequent in ovarian cancer (OC) and it has been associated with impaired survival and advanced stages or lymph node involvement. Notch also plays a role in chemoresistance to platinum. In this context, this pathway has emerged as an attractive target for precision medicine in OC. Two main targets of this pathway concentrate the clinical development of compounds blocking Notch: gamma secretase and Delta-like ligand 4. Most of the clinical trials including OC patients have been developed in phase I or phase Ib. Despite being in an early phase, both of these compounds, navicixizumab or demcizumab, two monoclonal antibodies targeting Dll4, showed promising efficacy data in platinum-resistant OC patients in recent studies. This review will focus on the mechanisms of the Notch pathway with special interest in angiogenesis regulation and the implication of Notch as a potential therapeutic target in OC.

The Role of CCL20-CCR6 Axis in Ovarian Cancer Metastasis.

BackgroundChemokine networks play a key and complex role in tumor progression. CCL20 and its unique receptor CCR6 have been reported to mediate malignant biological activities in various cancers, but their role in ovarian cancer metastasis remains unclear.PurposeOur study aims to explore the effect of CCL20-CCR6 axis on ovarian cancer metastasis and its potential mechanism.MethodsThe transwell assay was used to detect the cell migration and invasion after CCL20 treatment. The CCK-8 assay was used to detect the cell viability after CCL20 treatment and CCR6 depletion. The mRNA and protein expression were assayed through qRT-PCR and Western blotting. The siRNAs and CRISPR-Cas9 system were adopted to suppress CCR6 expression. Intraperitoneal xenograft mouse model was constructed to test the pro-metastasis effect of CCL20-CCR6 axis in vivo. The differentially expressed genes induced by CCL20 were identified through RNA-sequencing, and immunohistochemistry staining was used to detect their protein expression in tumor tissues.ResultsOur results revealed that CCL20 treatment selectively promoted the migration and invasion of CCR6high ovarian cancer cells, but had no effect on CCR6low cells. Blockade of CCR6 expression effectively reversed the cell migration and invasion induced by CCL20 stimulation. Animal experiment proved that CCL20-CCR6 axis mediated ovarian cancer metastasis in vivo. The differentially expressed genes after CCL20 stimulation were associated with metastasis, and CCL20 induced an increased expression of CDH2 and VCAN and decreased CDH1 expression in cancer cells. Moreover, CCL20 stimulated the expression of N-cadherin and versican in tumor tissues and inhibited the expression of E-cadherin, while CCR6 knockout successfully blocked the expression changes.ConclusionOur findings revealed that CCL20-CCR6 axis promotes ovarian cancer metastasis both in vivo and in vitro, probably through increasing cancer cell adhesion and epithelial–mesenchymal transition. Blockade of CCL20-CCR6 axis might become a novel anti-tumor therapeutic target for ovarian cancer.

Circ_0015756 promotes the progression of ovarian cancer by regulating miR-942-5p/CUL4B pathway

BackgroundOvarian cancer (OC) is the gynecologic cancer with the highest mortality. Circular RNAs (circRNAs) play a vital role in the development and progression of cancer. This study aimed to explore the potential role of circ_0015756 in OC and its molecular mechanism.MethodsThe levels of circ_0015756, microRNA-942-5p (miR-942-5p) and Cullin 4B (CUL4B) were determined by quantitative real-time PCR (qRT-PCR) or Western blot assay. Cell proliferation, apoptosis, migration and invasion were assessed by Cell Counting Kit-8 (CCK-8), colony formation assay, flow cytometry and transwell assay. The levels of proliferation-related and metastasis-related proteins were measured by Western blot assay. The relationship between miR-942-5p and circ_0015756 or CUL4B was verified by dual-luciferase reporter assay, RNA immunoprecipitation assay and RNA pull-down assay. Xenograft assay was used to analyze tumor growth in vivo.ResultsCirc_0015756 and CUL4B levels were increased, while miR-942-5p level was decreased in OC tissues and cells. Depletion of circ_0015756 suppressed proliferation, migration and invasion and promoted apoptosis in OC cells. Down-regulation of circ_0015756 hindered OC cell progression via modulating miR-942-5p. Also, up-regulation of miR-942-5p impeded OC cell development by targeting CUL4B. Mechanistically, circ_0015756 up-regulated CUL4B via sponging miR-942-5p. Moreover, circ_0015756 silencing inhibited tumor growth in vivo.ConclusionKnockdown of circ_0015756 suppressed OC progression via regulating miR-942-5p/CUL4B axis, suggesting that circ_0015756 might be a potential therapeutic target for ovarian cancer.

ZNF703 promotes tumor progression in ovarian cancer by interacting with HE4 and epigenetically regulating PEA15

BackgroundIt is known that the transcription factor zinc finger protein 703 (ZNF703) plays an important role in physiological functions and the occurrence and development of various tumors. However, the role and mechanism of ZNF703 in ovarian cancer are unclear.Materials and methodsImmunohistochemistry was used to analyze the expression of ZNF703 in ovarian cancer patients and to assess the effect of ZNF703 expression on the survival and prognosis of ovarian cancer patients. ZNF703 overexpression and suppression expression experiments were used to evaluate the effect of ZNF703 on malignant biological behavior of ovarian cancer cells in vitro. Detecting the interaction between HE4 and ZNF703 by immunofluorescence colocalization and coprecipitation, and nuclear translocation. Chromatin immunoprecipitation-sequencing (ChIP-Seq), dual luciferase reporter assay, ChIP-PCR, in vivo model were applied to study the molecular mechanism of ZNF703 affecting the development of ovarian cancer.ResultsZNF703 was highly expressed in ovarian cancer tissues, and its expression level is related to the prognosis of ovarian cancer patients. In vivo and in vitro experiments confirmed that ZNF703 overexpression/inhibition expression will promoted/inhibited the malignant biological behavior of ovarian cancer. Mechanically, ZNF703 interacted with HE4, and HE4 promoted nuclear translocation of ZNF703. ChIP-Seq identified multiple regulatory targets of ZNF703, of which ZNF703 directly binds to the enhancer region of PEA15 to promote the transcription of PEA15 and thereby promoted the proliferation of cancer cells.ConclusionThe results showed that ZNF703 as an oncogene played an important role in the epigenetic modification of ovarian cancer proliferation, and suggested that ZNF703 as a transcription factor may become a prognostic factor and a potential therapeutic target for ovarian cancer.

Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer.

Objective: The objective of this study is to identify and validate novel therapeutic target(s) in ovarian cancer. Background: Development of targeted therapeutics in ovarian cancer has been limited by molecular heterogeneity. Although gene expression datasets are available, most of them lack appropriate pair-matched controls to define the alterations that result in the transformation of normal ovarian cells to cancerous cells. Methods: We used microarray to compare the gene expression of treatment-naïve ovarian cancer tissue samples to pair-matched normal adjacent ovarian tissue from 24 patients. Ingenuity Pathway Analysis (IPA) was used to identify target pathways for further analysis. Integrin-linked kinase (ILK) expression in SKOV3 and OV90 cells was determined using Western blot. ILK was knocked down using CRISPR/Cas9 constructs. Subcutaneous xenograft study to determine the effect of ILK knockdown on tumor growth was performed in NOD SCID gamma mice. Results: Significant upregulation of the ILK pathway was identified in 22 of the 24 cancer specimens, identifying it as a potential player that could contribute to the transformation of normal ovarian cells to cancerous cells. Knockdown of ILK in SKOV3 cells resulted in decreased cell proliferation and tumor growth, and inhibition of downstream kinase, AKT (protein kinase B). These results were further validated using an ILK-1 chemical inhibitor, compound 22. Conclusion: Our initial findings validate ILK as a potential therapeutic target for molecular inhibition in ovarian cancer, which warrants further investigation.

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. Invitro studies demonstrated that microRNA (miR)‑576‑3p overexpression increased the DDP sensitivity of DDP‑resistant ovarian cancer cells. A dual‑luciferase assay verified that both programmed death‑ligand 1 (PD‑L1) and cyclin D1 were targets of miR‑276‑3p and were reversely associated with the expression of miR‑576‑3p. Moreover, invivo studies indicated that tumorigenesis was inhibited by DDP, which was enhanced by further miR‑576‑3p overexpression in tumor tissues. Taken together, the results suggested that miR‑576‑3p overexpression increased DDP chemosensitivity of ovarian cancer cells via decreasing PD‑L1 and cyclin D1, indicating that miR‑576‑3p may serve as a promising therapeutic target for ovarian cancer.

Lipid Regulatory Proteins as Potential Therapeutic Targets for Ovarian Cancer in Obese Women.

Simple SummaryObesity is a recognized epidemic worldwide. Ovarian cancer (OvCa), the most lethal gynecologic malignancy, is characterized by widely disseminated metastatic implants in the peritoneal cavity. Metastatic lesions infiltrate the omentum, as well as perigonadal adipose and other visceral adipose depots. Meta-analyses support a link between obesity and OvCa progression, metastasis and survival. Recent studies demonstrated a crucial role of lipid regulatory proteins in OvCa growth and metastasis. The aim of this review is to summarize current understanding of the relationship between lipid regulatory proteins, obesity and OvCa progression, as well as the potential therapeutic targets for antitumor therapy in obese OvCa patients, with an emphasis on the role of sterol regulatory element binding protein 1 (SREBP1). Obesity has become a recognized global epidemic that is associated with numerous comorbidities including type II diabetes, cardiovascular disease, hypertension, and cancer incidence and progression. Ovarian cancer (OvCa) has a unique mechanism of intra-peritoneal metastasis, already present in 80% of women at the time of diagnosis, making it the fifth leading cause of death from gynecological malignancy. Meta-analyses showed that obesity increases the risk of OvCa progression, leads to enhanced overall and organ-specific tumor burden, and adversely effects survival of women with OvCa. Recent data discovered that tumors grown in mice fed on a western diet (40% fat) have elevated lipid levels and a highly increased expression level of sterol regulatory element binding protein 1 (SREBP1). SREBP1 is a master transcription factor that regulates de novo lipogenesis and lipid homeostasis, and induces lipogenic reprogramming of tumor cells. Elevated SREBP1 levels are linked to cancer cell proliferation and metastasis. This review will summarize recent findings to provide a current understanding of lipid regulatory proteins in the ovarian tumor microenvironment with emphasis on SREBP1 expression in the obese host, the role of SREBP1 in cancer progression and metastasis, and potential therapeutic targeting of SREBPs and SREBP-pathway genes in treating cancers, particularly in the context of host obesity.

Meta-analysis based gene expression profiling reveals functional genes in ovarian cancer.

Background: Ovarian cancer causes high mortality rate worldwide, and despite numerous attempts, the outcome for patients with ovarian cancer are still not well improved. Microarray-based gene expressional analysis provides with valuable information for discriminating functional genes in ovarian cancer development and progression. However, due to the differences in experimental design, the results varied significantly across individual datasets.Methods: In the present study, the data of gene expression in ovarian cancer were downloaded from Gene Expression Omnibus (GEO) and 16 studies were included. A meta-analysis based gene expression analysis was performed to identify differentially expressed genes (DEGs). The most differentially expressed genes in our meta-analysis were selected for gene expression and gene function validation.Results: A total of 972 DEGs with P-value < 0.001 were identified in ovarian cancer, including 541 up-regulated genes and 431 down-regulated genes, among which 92 additional DEGs were found as gained DEGs. Top five up- and down-regulated genes were selected for the validation of gene expression profiling. Among these genes, up-regulated CD24 molecule (CD24), SRY (sex determining region Y)-box transcription factor 17 (SOX17), WFDC2, epithelial cell adhesion molecule (EPCAM), innate immunity activator (INAVA), and down-regulated aldehyde oxidase 1 (AOX1) were revealed to be with consistent expressional patterns in clinical patient samples of ovarian cancer. Gene functional analysis demonstrated that up-regulated WFDC2 and INAVA promoted ovarian cancer cell migration, WFDC2 enhanced cell proliferation, while down-regulated AOX1 was functional in inducing cell apoptosis of ovarian cancer.Conclusion: Our study shed light on the molecular mechanisms underlying the development of ovarian cancer, and facilitated the understanding of novel diagnostic and therapeutic targets in ovarian cancer.

LINC00452 promotes ovarian carcinogenesis through increasing ROCK1 by sponging miR-501-3p and suppressing ubiquitin-mediated degradation.

Ovarian cancer refers to all sorts of cancerous growth that starts from the ovary. Dysregulation of long non-coding RNAs (lncRNAs) is associated with ovarian cancer development and progression. Cellular expression and localization of LINC00452 in ovarian cancer cells were detected by qPCR and FISH. The roles of LINC00452 in ovarian carcinogenesis were characterized by MTT, transwell and colony-formation assays in vitro as well as xenograft mouse model. The underlying mechanism was explored by microarray, RIP, Co-IP and luciferase reporter assays. This study identified a novel lncRNA LINC00452 being elevated in both ovarian cancer cells and tumor tissues in patients. Such aberrant expression of LINC00452 was negatively correlated with relapse-free survival of ovarian cancer patients. Overexpression of LINC00452 potentiated CaOV3 cell viability, migration and invasion in vitro as well as xenograft tumor growth in vivo. Evidence from the current study suggests that the carcinogenicity of LINC00452 is partially due to competitive sponging of miR-501-3p followed with release of repression on the ROCK1, a key effector in Rho signaling pathway. Irrespective of its miRNA sponge function, LINC00452 is capable of preventing ROCK1 protein from ubiquitin/proteasome-mediated degradation via their mutual physical interaction. Our study makes LINC00452 a potential therapeutic target for ovarian cancer.

MiR-409-3p inhibits the proliferation and migration of human ovarian cancer cells by targeting Rab10

Ovarian cancer is a leading cause of gynecological cancer-related mortality. It has been reported that miR-409-3p is involved in the proliferation and migration of cancer cells. However, the role of miR-409-3p in ovarian cancer has not been well studied. The present study aimed to investigate the functional role of miR-409-3p in the pathogenesis of ovarian cancer, and its potential mechanism. It was found that the expression levels of miR-409-3p in 6 ovarian cancer tissues were upregulated. Through proliferation, migration and colony formation assays, it was revealed that overexpression of miR-409-3p inhibited the proliferation and migration of ovarian cancer cells. It was predicted from bioinformatics assays that the complementary binding sites were within miR-409-3p and Rab10. It was also demonstrated that the downregulation of the expression of Rab10 reversed the miR-409-3p downregulation-induced abnormal proliferation of ovarian cancer cells. These results suggest that miR-409-3p expression can be used as a predictive marker for the prognosis of ovarian cancer. Thus, the miR-409-3p/Rab10 axis may be a novel therapeutic target for ovarian cancer.

SP1-induced lncRNA DANCR contributes to proliferation and invasion of ovarian cancer.

Transcription factor SP1 could manipulate pathways involved in ovarian cancer progression. LncRNAs are involved in SP1-mediated tumorigenesis. LncRNA DANCR could promote metastasis of ovarian cancer. However, the regulatory function and involvement of SP1-induced lncRNA DANCR in ovarian cancer remain elusive. Data from this study showed that SP1 was up-regulated in ovarian cancer tissues and cells (CAOV3, SKOV3, A2780), and SP1 could bind to the promoter region of DANCR through chromatin immunoprecipitation and leuciferase activity assays. Therefore, DANCR was transcriptionally induced by SP1 in ovarian cancer tissues and cells (CAOV3, SKOV3, A2780). Functionally, reduced expression of DANCR suppressed cell viability, migration and invasion of CAOV3, while enhanced DANCR expression contributed to SKOV3 growth. Over-expression of SP1 reversed the suppressive effects of DANCR interference on ovarian cancer progression. In conclusion, SP1-induced DANCR contributed to oncogenic potential of ovarian cancer, suggesting a promising therapeutic target for ovarian cancer.

The RNA-Binding Protein CELF2 Inhibits Ovarian Cancer Progression by Stabilizing FAM198B

An increasing number of studies have clarified the functional roles of RNA-binding proteins (RBPs) in driving post-transcriptional mechanisms of cancer progression. In this study, we integrated data from the RBP database and Gene Expression Omnibus (GEO) data with RNA sequencing (RNA-seq) data from 10 ovarian cancer tissues and 8 normal ovarian tissues and identified an RBP, CUGBP- and ETR-3-like family 2 (CELF2). We found that CELF2 expression was downregulated in ovarian cancer and positively correlated with the overall survival (OS) and progression-free survival (PFS) of patients with ovarian cancer. Altered CELF2 expression led to changes in the proliferation, migration, and invasion of ovarian cancer cells in vitro and in vivo. CELF2 expression increased the stability of its target, FAM198B, by binding to AU/U-rich elements (AREs) in the 3′ untranslated region (3′ UTR). FAM198B knockdown restored the CELF2-mediated suppression of proliferation and migration. We also found that CELF2/FAM198B may repress ovarian cancer progression by inhibiting the mitogen-activated protein kinase/extracellular-regulated protein kinase (MAPK/ERK) signaling pathway. Finally, a curcumin-induced increase in CELF2 expression resulted in increased ovarian cancer cell sensitivity to cisplatin. Our study elucidated a novel mechanism by which the CELF2/FAM198B axis regulates proliferation and metastasis in ovarian cancer, providing novel, potential therapeutic targets for ovarian cancer.

CYP27B1 Downregulation: A New Molecular Mechanism Regulating EZH2 in Ovarian Cancer Tumorigenicity.

BackgroundOvarian cancer has the highest mortality rate among gynecologic cancers, and most patients are diagnosed in advanced stages. Enhancer of zeste homolog 2 (EZH2) is a major tumor marker and an effective therapeutic target for ovarian cancer, but the underlying molecular mechanism remains unclear. The present study investigated the biological effects of EZH2 knockout in SKOV3 cells in vitro and in vivo and explored the molecular mechanism by integrated analysis of messenger RNA sequencing (mRNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data.MethodsThe CRISPR/Cas9 system was used to establish EZH2 knockout SKOV3 cells. Protein expression was evaluated by Western blotting. The effect of EZH2 on ovarian cancer was evaluated in vitro with MTT, wound healing, Transwell, and apoptosis assays and in vivo with a xenograft model. mRNA-seq and ChIP-seq were performed to explore the molecular mechanism underlying the biological function of EZH2. Immunohistochemical staining (IHC) of tissue arrays was used to analyze the correlations among EZH2 and CYP27B1 expressions and prognosis.ResultsWe obtained three EZH2 knockout subclones. EZH2 knockout SKOV3 cells exhibited significantly suppressed proliferation, migration, and invasion and a significantly increased apoptosis rate. The subcutaneous tumor formation rate decreased from 100 to 0% in the EZH2 knockout group. Integrated analysis of the mRNA-seq and ChIP-seq data identified 1,455 significantly upregulated genes with matching downregulated trimethylation of histone H3 lysine 27 (H3K27me3) methylation binding sites in 1b11H cells compared to SKOV3 cells. The set of downregulated genes in EZH2 knockout cells was highly enriched in genes regulating the activation of steroid biosynthesis; the top-ranked hub gene was CYP27B1. The EZH2 and CYP27B1 expression levels showed a statistically significant inverse correlation, which was also associated with unfavorable prognosis. The in vitro experiment demonstrated that CYP27B1 can suppress the proliferation, migration, and invasion of ovarian cancer cells. Moreover, the levels of AKT and p-AKT were significantly increased, whereas STAT3 was downregulated, in 1b11H cells compared to SKOV3 cells. Moreover, STAT3 and AKT overexpression was observed in 1b11H siRNA for CYP27B1 (siCYP27B1) cells.ConclusionEZH2 plays an important role in promoting cell proliferation, migration, and invasion in ovarian cancer by regulating the core steroid biosynthesis gene via H3K27me3 methylation. Moreover, CYP27B1, the steroid biosynthesis hub gene, might be a novel therapeutic target for ovarian cancer.

Analysis of Autophagy-Related Signatures Identified Two Distinct Subtypes for Evaluating the Tumor Immune Microenvironment and Predicting Prognosis in Ovarian Cancer

Background: Ovarian cancer (OC) is the gynecologic malignant tumor with the highest mortality rate. The interaction between autophagy and the tumor immune microenvironment(TIM) has clinical importance. Hence, it is necessary to explore reliable biomarkers associated with autophagy-related genes (ARGs) for risk stratification in OC. Methods: We obtained ARGs from the MSigDB database and downloaded the expression profile of OC from the Cancer Genome Atlas (TCGA) database. The k-means unsupervised clustering method was applied to classify patients. The single-sample gene set enrichment analysis (ssGSEA) method was used to quantify the levels of infiltration of 24 subtypes of immune cells. Metascape and GSEA were performed to reveal the differential gene enrichment in signaling pathways and cellular processes of the subtypes. Next, we established a risk signature by least absolute shrinkage and selection operator (LASSO) Cox regression. Time-dependent receiver operating characteristic (ROC) curve analysis, Kaplan-Meier survival analysis and univariate Cox regression were used to evaluate the efficiency of the risk signature. Then, we analyzed the correlation between the risk score and 7 ARGs and immune checkpoints. Finally, we selected ULK2 and GABARAPL1 and verified their expression by qRT-PCR, WB and immunohistochemistry. Findings: We divided patients into the cluster A and cluster B subtypes. Our research confirmed that the patients in cluster A have a significantly longer survival time and a higher level of immune infiltration than the patients in cluster B. We established a signature for risk stratification, according to which we could divide the patients into high-or low-risk groups and predict their outcomes. Clinical correlation analysis found that the risk score is more reliable than other indicators for predicting disease-free survival (DFS). ULK2 and GABARAPL1 may play important roles in ovarian tumorigenesis and may be potential therapeutic targets in OC. Interpretation: The autophagy-related gene risk signature might be effective for risk stratification in OC. Moreover, our study provides a promising prognostic indicator that may predict the clinical efficacy of immunotherapy treatments. Funding Statement: This work was supported by the project of degree and postgraduate education and teaching reform in Hunan Province (JG2018A003),the National Science Foundation of China (81874137),the National Science Foundation of Hunan Province (2019JJ50308). the Outstanding Youth Foundation of Hunan Province (2018JJ1047), the Hunan Province Science and technology talent promotion project (2019TJ-Q10). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained at all participating sites, and all the participants provided signed, written, informed consent.

RBBP6 aggravates the progression of ovarian cancer by targeting PIK3R6.

RBBP6 is identified to be a cancer-associated gene by bioinformatics analysis. This study aims to explore the role of RBBP6 in regulating proliferation and metastasis in ovarian cancer, thus providing theoretical references for ovarian cancer treatment. Differential expressions of RBBP6 in ovarian cancer and normal ones were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The relationship between RBBP6 and prognosis in ovarian cancer patients was analyzed. The interaction between RBBP6 and PIK3R6 was detected by bioinformatics analysis and Dual-Luciferase reporter assay. Moreover, regulatory effects of RBBP6 and PIK3R6 on proliferative and migratory potentials in A2780 and CAOV3 cells were examined by Cell Counting Kit-8 (CCK-8) and transwell assay, respectively. Finally, tumorigenicity assay was conducted in nude mice to illustrate the in vivo regulations of PBBP6 and PIK3R6 on ovarian cancer growth. RBBP6 was upregulated in ovarian cancer tissues than normal ones. RBBP6 was irrelevant to age, tumor size and tumor node metastasis (TNM) staging in ovarian cancer patients, but correlated to lymphatic metastasis and distant metastasis. RBBP6 was abundantly expressed in ovarian cancer cells, and among the tested cell lines, CAOV3 and A2780 expressed the highest level of RBBP6. Knockdown of RBBP6 attenuated in vitro proliferative and migratory potentials in CAOV3 and A2780 cells. PIK3R6 was the target gene binding RBBP6, which was positively regulated by RBBP6. Overexpression of PIK3R6 could abolish the inhibited proliferative and migratory potentials in ovarian cancer cells with RBBP6 knockdown. In addition, the knockdown of RBBP6 slowed the in vivo growth of ovarian cancer in nude mice, and the alleviated cancer progression was reversed by overexpression of PIK3R6. RBBP6 is highly expressed in ovarian cancer cases, which stimulates proliferative and migratory potentials by targeting PIK3R6. RBBP6 may be a novel therapeutic target for ovarian cancer.

Therapeutic targeting of PTK6 oncogene in ovarian cancer

Objective: PTK6 is expressed in all ovarian cancer subtypes, and PTK6 amplification has been reported in high-grade serous carcinomas. In addition, PTK6 expression has prognostic significance and may have a role in the development of resistance to platinum. This study aims to validate PTK6/Brk, a nonreceptor tyrosine kinase, as a novel candidate therapeutic target for ovarian cancer. We hypothesize that PTK6 inhibition can suppress platinum-resistant ovarian cancer cell growth and survival and impair metastatic growth.

Identification of WTAP-related genes by weighted gene co-expression network analysis in ovarian cancer

BackgroundWilms tumor 1 associated protein (WTAP) modulates other genes via transcriptional and post-transcriptional regulation, in particular, by acting as a N6-methyladenosine writer or binding to the 3’UTR of mRNA, and promotes a variety of tumuors. However, the roles and mechanisms of WTAP in ovarian cancer are unknown.ResultsIn this study, using univariate Cox analysis and online CPTA analysis, we found that WTAP was a poor prognostic factor for ovarian cancer, and its protein expression level was higher in ovarian cancer than in normal tissue. Functionally, WTAP promoted the proliferation, invasion, and migration capability of ovarian cancer, according to the results of real time cellular analysis (RTCA), EdU cell proliferation assay, transwell assay. Subsequently, we identified a module containing 133 genes that were carefully related to WTAP expression through weighted gene co-expression network analysis (WGCNA). By calculating the hazard ratios of these genes and comparing their differences in the WTAP high-expression group and the low-expression group, we observed that there was a significant positive correlation between WTAP and two poor survival-related genes, family with sequence similarity 76 member A (FAM76A) and HBS1 like translational GTPase (HBS1L), which was also verified by quantitative real-time PCR in SKOV3 and A2780 cells.ConclusionWTAP functions as an oncogenic factor that promotes the progression of ovarian cancer in which WTAP-HBS1L/FAM76A axis may be involved. Our study indicates the potential role of WTAP in prognostic biomarker and therapeutic target for ovarian cancer.

Lipocalin2 promotes cell proliferation and migration in ovarian cancer through activation of the ERK/GSK3β/β-catenin signaling pathway

Lipocalin2 (Lcn2) has been shown to be a vital regulator of tumorigenesis in a variety of different cancers. However, its expression patterns and possible roles in ovarian cancer remain obscure. The aim of this study was to investigate the expression of Lcn2 in ovarian cancer cells and to determine any potential association between Lcn2 and ovarian tumor development and cancer progression. Our results indicated that Lcn2 was upregulated in tumor tissue from ovarian cancer patients as well as in three ovarian cancer cell lines compared to normal tissues and cells. Overexpression of Lcn2 promoted both cell proliferation and migration in ovarian cancer cells. Conversely, knockdown of Lcn2 in cell lines suppressed both migration and proliferation. Moreover, upregulation of Lcn2 contributed to tumor growth in nude mice in vivo. Mechanistically, Lcn2 was found to lead to tumor progression in ovarian cancer cells through activation of the ERK/GSK3β/β-catenin signaling pathway. In summary, Lcn2 promotes cell proliferation and migration in ovarian cancer through activation of the ERK/GSK3β/β-catenin signaling pathway, suggesting that Lcn2 might be a novel therapeutic target for ovarian cancer.

RAB25 confers resistance to chemotherapy by altering mitochondrial apoptosis signaling in ovarian cancer cells.

Ovarian cancer remains one of the most frequent causes of cancer-related death in women. Many patients with ovarian cancer suffer from de novo or acquired resistance to chemotherapy. Here, we report that RAB25 suppresses chemotherapy-induced mitochondrial apoptosis signaling in ovarian cancer cell lines and primary ovarian cancer cells. RAB25 blocks chemotherapy-induced apoptosis upstream of mitochondrial outer membrane permeabilization by either increasing antiapoptotic BCL-2 proteins or decreasing proapoptotic BCL-2 proteins. In particular, BAX expression negatively correlates with RAB25 expression in ovarian cancer cells. BH3 profiling assays corroborated that RAB25 decreases mitochondrial cell death priming. Suppressing RAB25 by means of RNAi or RFP14 inhibitory hydrocarbon-stapled peptide sensitizes ovarian cancer cells to chemotherapy as well as RAB25-mediated proliferation, invasion and migration. Our data suggest that RAB25 is a potential therapeutic target for ovarian cancer.

HOXC10 promotes tumour metastasis by regulating the EMT-related gene Slug in ovarian cancer.

The mortality rate of ovarian cancer is the highest among gynaecological cancers, primarily due to metastatic symptoms. Recent studies have shown that HOX genes are crucial in tumour progression, but the underlying mechanisms remain unclear. Here, HOXC10 expression was examined in ovarian cancer tissues. The function of HOXC10 in ovarian cancer metastasis was investigated in vitroand via intraperitoneal injection in vivo. A total of 158 ovarian cancer patients with adequate records were enrolled for analysis. HOXC10 was associated with metastasis and poor prognosis in ovarian cancer. In vitro, HOXC10 overexpression promoted ovarian cancer cell migration. Moreover, HOXC10 positively regulated Slug expression, altering the migration ability of cancer cells. Furthermore, our study showed that miR-222-3p was a suppressor of HOXC10. In vivo, a decrease in hepatic metastasis was seen in xenograft mice harbouring tumours with stable HOXC10 overexpression after miR-222-3p agomir (an overexpression reagent) injection. This study provides the first evidence that HOXC10 promotes ovarian cancer metastasis by regulating the transcription of the EMT-related gene Slug. Moreover, we found that HOXC10 is regulated by miR-222-3p. These data highlight the crucial role of HOXC10 in enhancing ovarian cancer metastasis and may provide a therapeutic target for ovarian cancer.