Abstract 234: Transcription factor LSF is a novel oncogene for hepatocellular carcinoma (HCC)

Abstract

Abstract While the incidence of overall cancers is decreasing, Hepatocellular Carcinoma (HCC) is one of the few cancers the incidence of which is on an increase. The mortality rate of HCC parallels that of incidence since HCC is a highly aggressive cancer with extremely limited currently available therapeutic strategies. Understanding the molecular mechanism of hepatocarcinogenesis will help develop novel, targeted and more effective therapeutic regimen to counteract this fatal disease. Here, we demonstrate that the cellular transcriptional factor Late SV40 Factor (LSF) functions as an oncogene in HCC. The level of LSF expression is significantly increased in human HCC patients compared to matched non-neoplastic controls and normal liver and LSF expression significantly correlates with the stages and grades of HCC. Ectopic overexpression of LSF in nontumorigenic human HCC cells leads to highly aggressive, multi-organ metastatic tumors while inhibition of LSF in aggressive human HCC cells profoundly inhibits tumorigenic and metastatic properties in athymic nude mice. Affymetrix microarray studies identified novel LSF-downstream genes that are associated with cell growth, angiogenesis, invasion, metastasis, chemoresistance, and senescence. Osteopontin, a key molecule mediating tumor progression, especially metastasis, was identified as a downstream target gene of LSF. Promoter-reporter and chromatin immunoprecipitation analyses confirmed that LSF transcriptionally upregulates OPN by binding to its promoter. Knockdown of OPN gene in LSF-overexpressing HCC cells markedly inhibits LSF-mediated tumor progression including metastasis. This is the first report on the novel function of LSF as an oncogene in any cancer indication. Since LSF expression correlates with the advanced stages of the disease, it might be employed as a diagnostic/prognostic marker for HCC. The DNA binding domain of LSF might be targeted with small molecule inhibitors that might be developed as potential HCC therapeutic. Our findings thus have significant translational implications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 234.