SND1 MEDIATED DOWNREGULATION OF PTPN23 IN HEPATOCELLULAR CARCINOMA By Nidhi Jariwala, MS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University, 2014. ADVISOR: Dr. Devanand Sarkar Associate Professor, Department of Human and Molecular Genetics Blick Scholar Associate Scientific Director, Cancer Therapeutics VCU Institute of Molecular Medicine Massey Cancer Center ABSTRACT Staphyloccocal nuclease domain containing protein 1 (SND1) is identified as an oncogene in multiple cancers, including hepatocellular carcinoma (HCC). SND1 regulates gene expression at transcriptional as well as post-transcriptional level and mediates molecular pathways that culminate into carcinogenesis. SND1 is a component of RNA-induced silencing complex (RISC) and functions as a nuclease for RNAi-mediated mRNA degradation. On the other hand SND1 also binds to specific mRNAs, increasing their stability and hence expression. The aim of the present study is to identify mRNAs to which SND1 binds and modulates them either by degradation or increasing stability which might facilitate promotion of HCC by SND1. We performed RNA immunoprecipitation followed by RNA sequencing (RIP-Seq) using anti-SND1 antibody and human HCC cell line QGY-7703. More than 350 mRNAs were identified to be interacting with SND1, of which Protein tyrosine phosphatase non-receptor 23 (PTPN23) was of particular interest, since PTPN23 has been identified to be a tumor suppressor and its role in HCC has not been studied. We document that SND1 can bind to PTPN23 mRNA and induce its degradation. There is an inverse correlation between SND1 and PTPN23 levels in human HCC cell lines and PTPN23 level is downregulated in HCC. Our study thus identifies a novel mechanism by which SND1 promotes hepatocarcinogenesis and identifies PTPN23 as a potential tumor suppressor in HCC. Further studies need to be performed to explore the relationship of these two molecules in in vivo models and to develop PTPN23 overexpression as a potential therapeutic approach for HCC. Advisors/Committee Members: Dr. Devanand Sarkar.