Abstract 4188: The role of microRNA-101 as a master tumor suppressor in cancer.

Abstract

Abstract Background: MicroRNAs are endogenous non-coding RNAs that can interfere with protein expression either by inducing the cleavage of specific target mRNAs or, in most cases, by inhibiting their translation. MicroRNA profiling studies using normal and cancer tissues suggested that a number of them are either overexpressed or down-regulated in tumors. Previously, we showed that miR-101 binds to a complementary sequence in the 3’UTR of EZH2, an oncogenic histone methyltransferase, and represses its expression. Our studies also demonstrated that ectopic miR-101 overexpression inhibits invasion of the aggressive prostate cell line DU145, and stable overexpression of miR-101 results in a reduction in tumor volume in vivo. Furthermore, we found that the genomic deletion of miR-101 during cancer progression leads to a concomitant increase in EZH2. COX2 is also a known target of miR-101 in colorectal cancers. Methods and Results: In the present study, bioinformatic analysis and functional studies revealed that miR-101 regulates multiple genes in prostate and breast cancer. Targets of miR-101 include oncoprotein STMN1 as well as Positive cofactor 4 (SUB1), a gene that is overexpressed in metastatic breast cancer. Investigation using 3’UTR luciferase reporter assays confirmed the regulation of these genes by miR-101. Furthermore, we validated the overexpression of STMN1 and SUB1 in aggressive prostate cancer by RTPCR and immunoblot analysis. We also demonstrated that ectopic overexpression of miR-101 in cancer cells down-regulated the expression of these genes. Immunohistochemical staining on prostate cancer tissue microarray representing aggressive and metastatic prostate cancer showed that STMN1 is highly expressed in metastatic prostate cancer. Tumor xenograft studies indicated that miR-101 target genes are involved in tumor growth. Together, these data identifies a critical tumor suppressive role for miR-101 and suggest that a loss of miR-101 in cancer leads to overexpression of multiple oncogenes. Conclusion: Overall, our studies indicate that miR-101 that is often down-regulated in multiple cancers due to genomic loss, acts as a master regulator of multiple oncogenes in cancer and reintroduction of miR-101 may have therapeutic benefit. Citation Format: Balabhadrapatruni V. S. K. Chakravarthi, Rohit Mehra, Rui Wang, Irfan A. Asangani, Qi Cao, Satya Pathi, Robert J. Lonigro, Christopher Maher, Daniel F. Camacho, Natalie McGregor, Nallasivam Palanisamy, Kenneth J. Pienta, Arul M. Chinnaiyan, Sooryanarayana Varambally. The role of microRNA-101 as a master tumor suppressor in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4188. doi:10.1158/1538-7445.AM2013-4188