Abstract 1324: Unraveling novel functions of the oncogene Astrocyte elevated gene-1 (AEG-1) contributing to hepatocarcinogenesis employing a transgenic mouse model

Abstract

Abstract In vitro tissue culture and nude mice xenograft models have firmly established the role of Astrocyte elevated gene-1 (AEG-1) as a positive regulator of tumorigenesis, including hepatocarcinogenesis. To better appreciate the role of AEG-1 in hepatocarcinogenesis and to dissect the underlying molecular mechanism, we have created a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG1). Wild-type (WT) and Alb/AEG-1 mice were challenged with a hepatocarcinogen, N-nitrosodiethylamine (DEN), at 2 weeks of age. At 28 weeks of age, Alb/AEG-1 mice, but not WT mice, developed multinodular HCC with steatotic features and highly elevated serum liver enzymes. Affymetrix microarray analyses identified modulation of expression of genes associated with invasion, metastasis, angiogenesis and fatty acid synthesis in DEN-treated Alb/AEG-1 mice versus their WT counterparts. Hepatocytes isolated from Alb/AEG-1 mice demonstrated profound chemoresistance and dramatically evaded reduction in cell viability upon growth factor deprivation, which was associated with activation of multiple pro-survival signaling pathways. Compared to the WT hepatocytes, Alb/AEG-1 hepatocytes demonstrated marked resistance towards senescence, which was associated with abrogation of activation of a DNA damage response. Conditioned media (CM) from Alb/AEG-1 hepatocytes, but not form WT hepatocytes, induced marked angiogenesis. Mass spectrometric analysis of CM revealed noticeable increases in coagulation factors by AEG-1, which are known to play a significant role in regulating tumor invasion, angiogenesis and metastasis. siRNA-mediated knockdown of coagulation factor XII resulted in profound inhibition of AEG-1-induced angiogenesis. Our studies reveal novel aspects of AEG-1 functions, such as induction of steatosis, inhibition of senescence, a known anti-cancer mechanism, and activation of coagulation pathway to augment an aggressive hepatocarcinogenic phenotype. The Alb/AEG-1 mouse will be a useful model to decipher AEG-1 function in the context of hepatocarcinogenesis and to evaluate the efficacy of novel therapeutic strategies directed towards HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1324. doi:1538-7445.AM2012-1324