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SND1 mediated downregulation of PTPN23 in HCCJariwala, Nidhi 01 January 2014 (has links)
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.
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SND1-Targeted Gene Therapy for Hepatocellular CarcinomaMckiver, Bryan D 01 January 2018 (has links)
Staphylococcal nuclease and tudor-domain containing 1 (SND1) is an oncogene for a wide variety of cancers, including hepatocellular carcinoma (HCC). SND1 is a multifunctional protein regulating gene expression of proto-oncogenes and tumor suppressor genes, making SND1 a prime target for developing cancer therapeutics. This notion is especially attributed to HCC as most patients are diagnosed in advanced stages and the therapeutic options available for these patients are severely limited. In this study, we evaluated the therapeutic potential of a replication-defective adenovirus vector delivering SND1 shRNA (Ad.SND1sh) to human HCC cell lines, HepG3, HuH-7, and Hep3B. Adenovirus infection in HCC cells was confirmed by Western blotting and immunofluorescence. The efficacy of Ad.SND1sh to knockdown SND1 expression was confirmed via Western blot, qRT-PCR, and immunofluorescence. Ad.SND1sh did not significantly affect proliferation of the three human HCC cells but significantly inhibited their invasive and migratory capacities, as determined by wound healing and Matrigel invasion assays, respectively. As a corollary, Ad.SND1sh treatment resulted in a decrease in mesenchymal markers, such as N-cadherin, Twist, Snail, and Slug, without affecting levels of epithelial marker E-Cadherin, indicating that SND1 knockdown induces mesenchymal conversion in HCC cells. Additionally, reductions in liver cancer stem cell marker CD133 and HCC marker α-fetoprotein (AFP) were observed with SND1 knockdown. HCC cells with aberrant expression of these markers are associated with tumor initiation, recurrence, and multi-drug resistance. Our findings indicate that Ad.SND1sh may potentially be an effective therapy for advanced HCC and needs to be studied further for its clinical application.
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