Abstract 236: Sleeping Beauty transposon integration within the Dlk1-Dio3 imprinted domain is associated with hepatocellular carcinoma development

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed and deadliest cancers worldwide. In the United States, age-adjusted incidence has tripled over the last three decades. While traditional cancer treatments, such as radiation and chemotherapy, are ineffective in treating HCC, therapeutic approaches targeted at the underlying molecular causes are proving to be more efficacious. However, compared to other common cancers, relatively little is known about the molecular pathogenesis of HCC. We have used a Sleeping Beauty transposon-based insertional mutagenesis screen to identify novel oncogenes and tumor suppressors involved in HCC development and progression. This forward genetics approach identified a link between disruption of gene expression within the Dlk1-Dio3 imprinted domain and development of HCC in mice; over half of the induced HCCs contained transposon integrations within a ten kilobase region of this domain. Analysis of gene expression within the domain identified two consistent and significant events associated with transposon integration: activation of Delta-like 1 homolog (Dlk1) and inhibition of microRNA-370 (miR-370). These results led us to hypothesize that Dlk1 and miR-370 possess oncogenic and tumor suppressive functions, respectively, in HCC pathogenesis. The Dlk1 gene encodes a Notch receptor ligand. Overexpression has been documented in a subset of human HCC cases, and the effects of modulating expression level in cultured hepatocytes are consistent with a tumor-promoting role. To test Dlk1's oncogenic potential in vivo, we drove overexpression in adult mouse livers using a hydrodynamic gene delivery technique. Hepatic nodule formation was observed in ∼50% of mice, supporting our hypothesis that Dlk1 functions as an oncogene in HCC. miR-370 is a relatively uncharacterized microRNA, although it has been demonstrated to suppress proliferation of cultured cholangiocytes. Similarly, manipulation of miR-370 activity in cultured hepatocytes has proliferative consequences consistent with a tumor suppressor role. Efforts to examine the effect of modulating miR-370 activity in vivo are currently underway. 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 236.