Numerous studies suggest that inactivation of one or more tumor suppressor genes may represent early and/or necessary steps in the neoplastic transformation of liver. Human chromosome 11 has been implicated in the pathogenesis of several human tumors, including hepatoblastoma and hepatocellular carcinoma, and is syntenic to rat chromosome 1, which is structurally altered in many rat liver tumor cell lines, suggesting that these chromosomes may contain a common liver tumor suppressor gene. We have suggested that chromosome tranfer studies utilizing human chromsomes and rat liver tumor cell lines may facilitate the facile localization, identification, and cloning of human genes responsible for tumor suppression in liver. To this end, we have employed a microcell hybrid model to demonstrate the existence of a liver tumor suppressor on human chromosome 11, map its location to 11p11.2, and identify candidate ESTs/genes. The continuing long-term goal of this research project is to determine the role of the human 11p11.2 liver tumor suppressor gene in the molecular pathogenesis of hepatocellular carcinoma, and to determine the mechanisms that govern the loss of function of this tumor suppressor in multi-step hepatocarcinogenesis in humans. The proposed investigations focus on a small group of candidate liver tumor suppressor genes that were identified during the initial funding period, and extend/advance our ongoing studies aimed at characterizing these candidate genes. The goals of this proposal are to (i) characterize the involvement of candidate liver tumor suppressor genes in the suppression of the neoplastic phenotype of rat liver tumor cell lines using siRNA in vitro and in vivo, (ii) determine the ability of candidate genes to express tumor suppressor activity in vivo using transfected cell lines, (iii) evaluate the possible contributions of epigenetic mechanisms to the regulation of candidate liver tumor suppressor gene expression, (iv) examine the role of genetic alterations (LOH and/or mutation) in the inactivation of candidate liver tumor suppressor gene expression, (v) determine if alterations in candidate liver tumor suppressor gene expression represent early or later molecular alterations in multi-step hepatocarcinogenesis, and (vi) identify molecular targets and pathways in liver tumor cell lines that are subject to direct or indirect modification in response to candidate gene expression.
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