Abstract
Abstract Staphylococcal nuclease domain containing-1 (SND1) is a multifunctional protein that modulates transcription, mRNA splicing and stability, and miRNA function. We previously documented that SND1 is markedly overexpressed in human hepatocellular carcinoma (HCC) patients in a stage-specific manner and inhibition of SND1 in human HCC cells significantly abrogates in vitro proliferation and in vivo tumorigenesis in nude mice. In the present study we document that migration and invasion of human HCC cells are significantly augmented in SND1-overexpressing clones and significantly inhibited in SND1 shRNA-expressing clones. Differential gene expression analysis between control clone and SND1 shRNA expressing clones by Affymetrix microarray revealed downregulation of TGF-β downstream genes upon SND1 inhibition. Additionally, a human angiogenesis array identified plasminogen activator inhibitor-1 (PAI-1), a TGF-β downstream gene, to be upregulated by SND1 and this upregulation was confirmed by ELISA. TGF-β expression is regulated by angiotensin II type 1 receptors (AT1R) and previous studies have documented that SND1 increases AT1R expression by increasing AT1R mRNA stability. We hypothesized that increased AT1R expression, conferred by SND1 overexpression, might facilitate activation of TGF-β signaling and subsequently PAI-1-mediated increase in migration and invasion. Indeed, we observed that AT1R and TGF-β expression was significantly increased in SND1-overexpressing clones and decreased in SND1 knockdown clones. The half-life of AT1R mRNA was significantly longer in SND1-overexpressing clones compared to the control clone confirming that SND1 modulates AT1R post-transcriptionally. The AT1R blocker Losartan Potassium and AT1R siRNA significantly inhibited SND1-induced TGF-β and PAI-1 expression with associated inhibition in migration and invasion. As a corollary, inhibition of PAI-1 by siRNA significantly abrogated migration and invasion of SND1-overexpressing cells. TGF-β induces epithelial-mesenchymal transition (EMT) and we observed increased expression of EMT markers vimentin, snail and slug and decreased expression of E-cadherin in SND1-overexpressing clones and vice versa in SND1-knockdown clones. Our studies thus unravel a novel mechanism in which post-transcriptional regulation of AT1R by SND1, with subsequent activation of TGF-β signaling, promotes invasion of human HCC cells thereby conferring an aggressive phenotype. Small molecule inhibitors of SND1, thus, might be effective therapeutic strategy for late-stage aggressive HCC. Citation Format: Prasanna K. Santhekadur, Rachel Gredler, Maaged Akiel, Paul Dent, Paul B. Fisher, Devanand Sarkar. The multifunctional protein staphylococcal nuclease domain containing-1 (SND1) promotes migration and invasion of hepatocellular carcinoma (HCC) cells by modulating angiotensin II type 1 receptor (AT1R) and transforming growth factor-β (TGF-β) s [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 2628. doi:10.1158/1538-7445.AM2013-2628
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