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Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer.

ABSTRACT: BACKGROUND: We recently demonstrated that increased expression of the RNA-binding protein RBM3 is associated with a favourable prognosis in breast cancer. The aim of this study was to examine the prognostic value of RBM3 mRNA and protein expression in epithelial ovarian cancer (EOC) and the cisplatin response upon RBM3 depletion in a cisplatin-sensitive ovarian cancer cell line. METHODS: RBM3 mRNA expression was analysed in tumors from a cohort of 267 EOC cases (Cohort I) and RBM3 protein expression was analysed using immunohistochemistry (IHC) in an independent cohort of 154 prospectively collected EOC cases (Cohort II). Kaplan Meier analysis and Cox proportional hazards modelling were applied to assess the relationship between RBM3 and recurrence free survival (RFS) and overall survival (OS). Immunoblotting and IHC were used to examine the expression of RBM3 in a cisplatin-resistant ovarian cancer cell line A2780-Cp70 and its cisplatin-responsive parental cell line A2780. The impact of RBM3 on cisplatin response in EOC was assessed using siRNA-mediated silencing of RBM3 in A2780 cells followed by cell viability assay and cell cycle analysis. RESULTS: Increased RBM3 mRNA expression was associated with a prolonged RFS (HR = 0.64, 95% CI = 0.47-0.86, p = 0.003) and OS (HR = 0.64, 95% CI = 0.44-0.95, p = 0.024) in Cohort I. Multivariate analysis confirmed that RBM3 mRNA expression was an independent predictor of a prolonged RFS, (HR = 0.61, 95% CI = 0.44-0.84, p = 0.003) and OS (HR = 0.62, 95% CI = 0.41-0.95; p = 0.028) in Cohort I. In Cohort II, RBM3 protein expression was associated with a prolonged OS (HR = 0.53, 95% CI = 0.35-0.79, p = 0.002) confirmed by multivariate analysis (HR = 0.61, 95% CI = 0.40-0.92, p = 0.017). RBM3 mRNA and protein expression levels were significantly higher in the cisplatin sensitive A2780 cell line compared to the cisplatin resistant A2780-Cp70 derivative. siRNA-mediated silencing of RBM3 expression in the A2780 cells resulted in a decreased sensitivity to cisplatin as demonstrated by increased cell viability and reduced proportion of cells arrested in the G2/M-phase. CONCLUSIONS: These data demonstrate that RBM3 expression is associated with cisplatin sensitivity in vitro and with a good prognosis in EOC. Taken together these findings suggest that RBM3 may be a useful prognostic and treatment predictive marker in EOC.

SUBMITTER: Ehlen A

PROVIDER: S-EPMC2936876 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer.

Ehlén Asa A Brennan Donal J DJ Nodin Björn B O'Connor Darran P DP Eberhard Jakob J Alvarado-Kristensson Maria M Jeffrey Ian B IB Manjer Jonas J Brändstedt Jenny J Uhlén Mathias M Pontén Fredrik F Jirström Karin K

Journal of translational medicine 20100820

<h4>Background</h4>We recently demonstrated that increased expression of the RNA-binding protein RBM3 is associated with a favourable prognosis in breast cancer. The aim of this study was to examine the prognostic value of RBM3 mRNA and protein expression in epithelial ovarian cancer (EOC) and the cisplatin response upon RBM3 depletion in a cisplatin-sensitive ovarian cancer cell line.<h4>Methods</h4>RBM3 mRNA expression was analysed in tumors from a cohort of 267 EOC cases (Cohort I) and RBM3 p ...[more]

PMID: 20727170

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Project description:BackgroundOvarian cancer is the most common gynecological malignancy and is difficult to manage due to the emergence of resistance to various chemotherapeutic drugs. New efforts are urgently awaited. Aspirin, which is traditionally considered a nonsteroidal anti-inflammatory drug (NSAID), has been reported to exert potential chemopreventive effects. Therefore, we aimed to investigate the anticancer effect and explore the underlying molecular mechanisms of aspirin on epithelial ovarian cancer (EOC) cells.MethodsWe conducted wound healing, transwell migration, EdU cell proliferation, colony formation and apoptosis detection assays to observe the effects of aspirin on the migration, proliferation and apoptosis of EOC cells (A2870, Caov-3, and SK-OV-3). EOC cells were treated with a combination of aspirin and cisplatin (CDDP) to observe the effect of aspirin on enhancing CDDP sensitivity. Orthotopic xenograft models of ovarian cancer established with A2780-Luciferase-GFP cells were applied to compare tumor growth inhibition in the control, CDDP and CDDP plus aspirin groups through in vivo imaging, which can be used to continuously monitor tumor growth. The expression and acetylation levels of p53 in EOC cells treated with aspirin were determined using western blotting, and p53 acetylation levels were examined in tumors harvested from the transplanted mice. Quantitative real-time PCR was used to assess the mRNA expression of p53 target genes.ResultsAspirin inhibited migration and proliferation and induced apoptosis in EOC cell lines in a concentration-dependent manner. In vitro, aspirin enhanced the sensitivity of EOC cells to CDDP by increasing its inhibitory effect on proliferation and its effect on inducing apoptosis. In vivo, the differences in the tumor growth inhibition rates among the different CDDP experimental groups were statistically significant (p < 0.05). Aspirin did not affect p53 protein expression but increased the p53 acetylation level in a concentration-dependent manner. In addition, the mRNA levels of CDKN1A, BAX, FOXF1, PUMA, and RRAD in EOC cells were significantly increased by the aspirin treatment.ConclusionsAspirin inhibits tumor progression and enhances the CDDP sensitivity of EOC cells. These antitumor effects of aspirin might be mediated by p53 acetylation and subsequent activation of p53 target genes.

Project description:Aquaporins (AQPs) are important mediators of water permeability and are closely associated with tumor cell proliferation, migration, angiogenesis and chemoresistance. Moreover, the chemosensitivity of tumor cells to cisplatin (CDDP) is potentially affected by osmotic pressure. The present study was undertaken to determine whether hyperosmosis regulates ovarian cancer cell sensitivity to CDDP in vitro and to explore whether this is associated with AQP expression. The hyperosmotic stress was induced by D-sorbitol. 3AO ovarian cancer cells were treated with different concentrations of hypertonic medium and/or CDDP for various times, followed by measuring the inhibition rate of cell proliferation using an MTT assay. In addition, AQP expression in response to osmotic pressure and/or CDDP was measured by reverse transcription-quantitative polymerase chain reaction and western blotting. Cell proliferation in response to hypertonic stress was also measured when AQP5 was knocked down by small interfering (si)RNA. 3AO cell proliferation was inhibited by hyperosmotic stress, while the expression of AQP5, but not that of AQP1, AQP3 or AQP9, was increased in a dose- and time-dependent manner in hypertonic sorbitol-containing medium. When AQP5 was silenced by siRNA, cells were susceptible to hypertonic stress. MTT analyses showed that the inhibition of cell proliferation by a low dose of CDDP increased significantly with exposure to a hyperosmotic stimulus, and this effect was reduced when a high dose of CDDP was used. AQP5 expression was induced by a low dose of CDDP, but was reduced by a high dose of CDDP. However, hyperosmosis enhanced AQP5 mRNA expression at every dose of CDDP tested, compared with isotonic medium. With prolonged treatment time, AQP5 expression was reduced by CDDP in hypertonic and isotonic culture medium. Thus, the effects of hyperosmosis on cell sensitivity to CDDP were associated with AQP5 expression. These results suggest that AQP5 expression in ovarian cancer cells is induced by hypertonic medium, and that the sensitivity of ovarian cancer cells to CDDP can be regulated by hyperosmosis associated with AQP5 expression.

Project description:BACKGROUND: Plasminogen activator inhibitor 1 (PAI-1) overexpression is an important prognostic and predictive biomarker in human breast cancer. SERBP1, a protein that is supposed to regulate the stability of PAI-1 mRNA, may play a role in gynaecological cancers as well, since upregulation of SERBP1 was described in ovarian cancer recently. This is the first study to present a systematic characterisation of SERBP1 expression in human breast cancer and normal breast tissue at both the mRNA and the protein level. METHODS: Using semiquantitative realtime PCR we analysed SERBP1 expression in different normal human tissues (n = 25), and in matched pairs of normal (n = 7) and cancerous breast tissues (n = 7). SERBP1 protein expression was analysed in two independent cohorts on tissue microarrays (TMAs), an initial evaluation set, consisting of 193 breast carcinomas and 48 normal breast tissues, and a second large validation set, consisting of 605 breast carcinomas. In addition, a collection of benign (n = 2) and malignant (n = 6) mammary cell lines as well as breast carcinoma lysates (n = 16) were investigated for SERBP1 expression by Western blot analysis. Furthermore, applying non-radioisotopic in situ hybridisation a subset of normal (n = 10) and cancerous (n = 10) breast tissue specimens from the initial TMA were analysed for SERBP1 mRNA expression. RESULTS: SERBP1 is not differentially expressed in breast carcinoma compared to normal breast tissue, both at the RNA and protein level. However, recurrence-free survival analysis showed a significant correlation (P = 0.008) between abundant SERBP1 expression in breast carcinoma and favourable prognosis. Interestingly, overall survival analysis also displayed a tendency (P = 0.09) towards favourable prognosis when SERBP1 was overexpressed in breast cancer. CONCLUSIONS: The RNA-binding protein SERBP1 is abundantly expressed in human breast cancer and may represent a novel breast tumour marker with prognostic significance. Its potential involvement in the plasminogen activator protease cascade warrants further investigation.

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Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer.

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Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer.

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