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Overexpression of JARID1B is associated with poor prognosis and chemotherapy resistance in epithelial ovarian cancer.

ABSTRACT: JARID1B, a histone demethylase, has been reported to be highly expressed in various human cancers. In the present study, we investigated the association of JARID1B level with epithelial ovarian cancer (EOC) and prognosis of patients with EOC. We analyzed JARID1B expression in 20 normal ovaries, 20 benign ovarian tumor (BOT) samples, and 45 epithelial ovarian carcinoma specimens by quantitative PCR (qRT-PCR) and western blotting analyses. JARID1B was further examined in 120 EOC specimens from patients with different histological stages via immunohistochemistry. Possible correlations between JARID1B levels and prognosis as well as chemotherapy resistance of EOC patients were determined by univariate and multivariate analyses. JARID1B level was significantly increased in EOC, as compared to normal ovaries and BOT. Among 120 EOC cases examined, the 5-year progression-free survival (PFS) rates were 17 and 85% in patients with high and low JARID1B expression, respectively (hazard ratio = 17.85, 95% confidence interval (CI) 6.31-50.51, P < 0.001). Similarly, the 5-year overall survival (OS) rates for patients with high and low JARID1B expression were 28 and 92% respectively (hazard ratio = 21.8, 95% CI 5.92-71.81, P < 0.001). Positive correlation between JARID1B level and chemotherapy resistance was observed in patients with EOC (odds ratio (OR) 36.81, 95% CI 4.84-280.11, P < 0.001). JARID1B could serve as an important biomarker for prognosis and chemotherapy resistance of EOC patients.

SUBMITTER: Wang L

PROVIDER: S-EPMC4428534 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose:Ovarian cancer is a major type of gynecological malignancy which characterized by the chemoresistance, heterogeneity and highly metastasis. However, the mechanism underlying the progression of ovarian cancer remains elusive. Pyruvate dehydrogenase kinase family plays critical roles in tumorigenesis, and PDK4 has been demonstrated to be an oncogene in many types of cancers. The aim of this study was to identify the role of PDK4 in ovarian cancer. Methods:We explored the PDK4 expression according to the public database containing patients with different effect of chemotherapy. Cell proliferation and invasion assays were used to determine the function of PDK4. Mice xenograft experiment was conducted to test the pro-tumorigenesis function of PDK4 in vivo. Cell apoptosis under treatment of chemo drugs was detected by flow cytometry and TUNEL analysis. Spheroid formation assay and CD133+ cell population were used to determine the PDK4-induced stem-like traits. Immunohistochemical staining was performed to test the expression of PDK4 in ovarian cancer tissues, and Kaplan- Meier curve with log-rank test was performed to determine the association between PDK4 expression and ovarian cancer patients' prognosis. Results:Overexpression of PDK4 markedly promoted cell proliferation, invasion and tumor growth in vivo. Furthermore, PDK4 confers cell resistant to chemotherapy-induced apoptosis. Mechanically, we demonstrated that PDK4 induced stem-like traits. Meanwhile, PDK4 expression was significantly evaluated in ovarian cancer tissues compared to that in adjacent non-cancer tissues, and high expression of PDK4 was associated with poor overall survival and progression-free survival of ovarian cancer patients. Conclusion:These results identify a novel role of PDK4 in regulating cell stem-like trait, which directly enhances the cell proliferation, invasion and chemoresistance in ovarian cancer, and targeting PDK4 could be a potential approach for ovarian cancer treatments.

Project description:BackgroundEpithelial ovarian cancer (EOC) is a spectrum of different diseases, which makes their treatment a challenge. Forkhead box M1 (FOXM1) is an oncogene aberrantly expressed in many solid cancers including serous EOC, but its role in non-serous EOCs remains undefined. We examined FOXM1 expression and its correlation to prognosis across the three major EOC subtypes, and its role in tumorigenesis and chemo-resistance in vitro.MethodsGene signatures were generated by microarray for 14 clear-cell and 26 endometrioid EOCs, and 15 normal endometrium snap-frozen biopsies. Validation of FOXM1 expression was performed by RT-qPCR and immunohistochemistry in the same samples and additionally in 50 high-grade serous EOCs and in their most adequate normal controls (10 luminal fallopian tube and 20 ovarian surface epithelial brushings). Correlations of FOXM1 expression to clinic-pathological parameters and patients' prognosis were evaluated by Kaplan-Meier and Cox proportional-hazards analyses. OVCAR-3 and two novel deeply characterized EOC cell lines (EOC-CC1 and OSPC2, with clear-cell and serous subtype, respectively) were employed for in vitro studies. Effects of FOXM1 inhibition by transient siRNA transfection were evaluated on cell-proliferation, cell-cycle, colony formation, invasion, and response to conventional first- and second-line anticancer agents, and to the PARP-inhibitor olaparib. Gene signatures of FOXM1-silenced cell lines were generated by microarray and confirmed by RT-qPCR.ResultsA significant FOXM1 mRNA up-regulation was found in EOCs compared to normal controls. FOXM1 protein overexpression significantly correlated to serous histology (p = 0.001) and advanced FIGO stage (p = 0.004). Multivariate analyses confirmed FOXM1 protein overexpression as an independent indicator of worse disease specific survival in non-serous EOCs, and of shorter time to progression in platinum-resistant cases. FOXM1 downregulation in EOC cell lines inhibited cell growth and clonogenicity, and promoted the cytotoxic effects of platinum compounds, doxorubicin hydrochloride and olaparib. Upon FOXM1 knock-down in EOC-CC1 and OSPC2 cells, microarray and RT-qPCR analyses revealed the deregulation of several common and other unique subtype-specific FOXM1 putative targets involved in cell cycle, metastasis, DNA repair and drug response.ConclusionsFOXM1 is up-regulated in all three major EOCs subtypes, and is a prognostic biomarker and a potential combinatorial therapeutic target in platinum resistant disease, irrespective of tumor histology.

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Overexpression of JARID1B is associated with poor prognosis and chemotherapy resistance in epithelial ovarian cancer.

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