Abstract 2563: Upregulation of miR-155 is associated with cisplatin resistance in the head and neck cancer UMSCC-10B/15S cells

Abstract

Abstract Introduction: Cisplatin combination chemotherapy is the cornerstone of treatment for many cancers including head and neck cancer. These complexes bind to the DNA and form adducts such that they ultimately trigger apoptosis. Although initial platinum responsiveness is usually high, the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Thus, chemotherapy resistance is a major clinical obstacle in the successful treatment of head and neck cancer. This study aims to investigate the role of microRNAs (miRNAs) in cisplatin resistance and to better understand the underlying mechanism of cisplatin resistance in the head and neck cancer UMSCC-10B/15S cells. Methods: To determine whether aberrant miRNA expression is associated with cisplatin resistance in human head and neck cancer cells, we profiled miRNA expression in the cisplatin resistant UMSCC-10b/15S and the parental line UMSCC-10B cells by real-time PCR. Luciferase reporter assays and western blot were used to confirm targets for miR-155. We also suppressed miR-155 by anti-sense locked nucleic acid (LNA) oligo to further determine the role of miR-155 in cisplatin resistance. Results: We showed that several miRNAs were altered in UMSCC-10B/15S and among them, miR-155 was the most significantly upregulated miRNA. This was also confirmed by in situ hybridization. Furthermore, ectopic expression of miR-155 was able to increase the resistance of UMSCC-10B cells to cisplatin, which is likely in part through targeting DMTF1, a tumor suppressor that directly binds to the Arf promoter to activate its expression, thereby inducing p53-dependent cell cycle arrest and apoptosis. To determine whether miR-155 directly targets DMTF1, we cloned 1.2 kb 3′-untranslated region (UTR) of DMTF1 into a luciferase reporter and demonstrated that miR-155 was able to suppress luciferase activity by over 70%. We also showed that the endogenous DMFT1 protein was reduced by over 50% in the miR-155 highly expressed resistant cells compared to the parental sensitive cells. Experiments are under way to determine whether ectopic expression of DMTF1 or its suppression by RNAi impacts cisplatin resistance in these cells. Conclusion: These findings suggest that deregulation of miRNAs is in resistant head and neck cancer cells and miR-155 may play a causal role in cisplatin resistance through targeting the DMTF1 gene. As a result, suppression of miR-155 may provide a strategy to overcome the resistance in head and neck cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2563.