Abstract 3077: TMPRSS2-ERG regulation of miRNA in prostate cancer.

Abstract

Abstract Prostate cancer is the cause of the second highest number of cancer related deaths in men in the United States, with the highest number of new estimated cases every year. In addition, the survival rate in localized and regional prostate cancer is 100%, while metastatic prostate cancer is about 29%, with a wide spectrum of biological deregulations. MicroRNA (miRNA) is a small non-coding RNA, about 22 nucleotides long, that mostly targets the 3’UTR of a gene for translational repression or mRNA degradation. More recently, miRNAs have been shown to play an important role in tumorigenesis, cancer progression, and metastasis. MiR-200c is one of the miRNA widely studied in cancer, as it has a role in regulating epithelial-mesenchymal transition (EMT). One of the ways in which miR-200c inhibits EMT is through its ability to downregulate ZEB1, an EMT activator that primarily functions by repressing E-cadherin. ERG is a transcription factor that is often fused with TMPRSS2 in prostate cancer and promotes cancer progression. In our study, we investigated the interaction of ERG and miR-200c, two factors that play important role in cancer progression, in prostate cancer. First, we identified ERG regulated miRNAs through utilizing miRNA profiling in LNCaP cells that were overexpressing ERG and in VCaP cells that have ERG knocked down. We selected miRNAs that are repressed upon ERG overexpression and derepressed upon ERG knockdown and also overlapped the results with ERG ChIP-seq data to identify ERG regulated miRNAs. Through this process we discovered that miR-200c is a good ERG-targeted miRNA. To validate the bioinformatics results, we used ERG overexpression in LNCaP and ERG knockdown in VCaP to measure mature miR-200c levels by miRNA assay. In addition, ERG ChIP-qPCR and miR-200c promoter luciferase assays showed that ERG binds at the miR-200c promoter. Next, to identify functional roles of miR-200c in ERG overexpressed cells, we performed invasion and migration assays to show that miR-200c plays an important role in the inhibition of ERG-mediated cancer progression. This study identifies an important factor, miR-200c, whose loss mediates the progression of TMPRSS2:ERG fusion-positive prostate cancer. According to our results, it might be possible to use miR-200c as a future therapeutic for ERG positive patients. This work was supported in part by the Research Scholar Award RSG-12-085-01 (to J.Y.) from the American Cancer Society, Department of Defense PC080665 (to J.Y.) and NRSA pre-doctoral fellowship T32 CA080621 (to J.K.). Citation Format: Jung Kim, Longtao Wu, Hong-Jian Jin, Jonathan Zhao, Jindan Yu. TMPRSS2-ERG regulation of miRNA in prostate 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 3077. doi:10.1158/1538-7445.AM2013-3077