Abstract 3534: Epigenetic control of the tumor suppressive microRNA miR-34a in bladder cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Bladder cancer is the sixth most common cancer in the world and the incidence is particularly high in southwestern Taiwan. One of the hypotheses suggests that cancers arise from cancer stem-like cell (CSC) with surface antigen CD44. MicroRNAs (miRNAs) are endogenous, non-protein-coding RNAs that can regulate the expression of their target mRNAs. Up to 90% of human genes can be regulated by this mechanism. However, the role of miRNAs in the regulation of CSC in bladder cancer is not fully explored. Bioinformatics prediction identified that miR-34a regulates the expression of CD44. In this study, we aimed to investigate how miR-34a are regulated in bladder cancer. Expression analysis showed that miR-34a was down-regulated in UMUC3 bladder cancer cells. COBRA assay and bisulphite pyrosequencing demonstrated extensive DNA methylation of miR-34a in this cell. Treatment of DNMT inhibitor, 5-aza restored miR-34a expression in UMUC3 cells thus suggesting that miR-34a is epigenetically silenced in UMUC3 cells. Over-expression of miR-34a resulted in a reduction of chemo-resistance to cisplatin in UMUC3 cells. This may be due to a down-regulation of CD44 and another predicted miR-34a target, c-myc in this cell. Recently, additional mechanism namely, competitive endogenous RNA (ceRNA) hypothesis in controlling the function of miRNAs are demonstrated. To test this hypothesis in bladder cancer, we overexpressed 3′UTR of CD44 in TSGH8301 bladder cancer cells which expressed miR-34a, and resulted in an up regulation of another target of miR-34a, c-myc in this cells. Since amplification of chromosome 8q24 where c-myc resides is frequently observed in bladder cancer, we investigated the relationship between expression of c-myc and CD44 in a publicly available expression array data set (GDS1479) using 60 bladder cancer patients. Interestingly, a positive correlation was found between the expression of c-myc and CD44 (P=0.0016) in this data set. In conclusion, aberrant promoter methylation and ceRNA mechanism may contribute to attenuate the function of miR-34a in bladder cancer. The tumor suppressive role of miR-34a in controlling CSC phenotype in bladder cancer deserves further investigation. Citation Format: Wen-Yu Huang, Pi-Che Chen, Chia-Ming Yeh, Frank H.C. Cheng, Hsiao-Yen Hsieh, Cheng-Huang Shen, Cheng-Da Hsu, Michael WY Chan. Epigenetic control of the tumor suppressive microRNA miR-34a in bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3534. doi:10.1158/1538-7445.AM2014-3534