Abstract 4952: Functional characterization of microRNAs associated with the response to cisplatin of ovarian cancer cells

Tumor cells are often characterized by a rapid cell division rate and defects in their DNA damage response, which is exploited in the clinic by the use of DNA damaging anticancer agents. Platinum-based chemotherapy (e.g. cisplatin) is used for the treatment of many different cancers including ovarian cancer. Unfortunately, the success of chemotherapy is hampered by the development of drug resistance, and most ovarian tumors eventually become refractory to multiple drugs. The molecular and cellular processes that lead to therapy resistance have been extensively studied at the transcriptional and posttranslational level. Another level of gene regulation is exerted by the recently discovered microRNAs, small non-coding RNAs that interfere with the expression of protein-coding genes. The essential role microRNAs play in the cellular response to genotoxic agents is only just being elucidated. In this project we aim to identify and functionally characterize microRNAs that alter the sensitivity to cisplatin in ovarian cancer cells. LNA™ modified oligonucleotide arrays were used to map the initial microRNA response (up to 24 h) of two human primary epithelial cell lines to cisplatin and γ-irradiation, anticancer therapies that induce different kinds of DNA damage (DNA crosslinks and double strand DNA breaks, respectively). We examined the response to both a low dose and a high dose treatment. Both general DNA damage responsive microRNAs and treatment- and dose-specific microRNAs were identified. Next, we examined whether these microRNAs were also differentially regulated in cisplatin-sensitive and resistant cell lines derived from ovarian cancer, colon cancer and bladder cancer. Indeed, several microRNAs were found to be associated with cisplatin resistance. By ectopically modulating the expression of five microRNAs in ovarian cancer cell lines, we found two microRNAs – not previously linked to cisplatin resistance – for which overexpression resulted either in enhanced sensitivity or enhanced resistance to cisplatin. In search of relevant target genes we discovered genes that were regulated by both microRNAs. SiRNA experiments in which gene expression was knocked down recapitulated the microRNA overexpression results. Interestingly, these target genes belong to major signal transduction routes and have not been previously associated with the response to platinum containing chemotherapy. In summary, we have identified microRNAs that are regulated after DNA damage and are associated with cisplatin resistance. Modulation of the levels of these microRNAs in ovarian cancer cells altered the survival response to cisplatin, suggesting they may sensitize tumors to chemotherapy. Furthermore, we have identified some of the genes through which these microRNAs mediate their effects on cisplatin sensitivity, shedding a new light on the molecular basis of cisplatin resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4952. doi:10.1158/1538-7445.AM2011-4952