Astrocyte elevated gene-1 promotes hepatocarcinogenesis: Novel insights from a mouse model

作者：Srivastava Jyoti; Siddiq Ayesha; Emdad Luni; Santhekadur Prasanna Kumar; Chen Dong; Gredler Rachel; Shen Xue Ning; Robertson Chadia L; Dumur Catherine I; Hylemon Phillip B; Mukhopadhyay Nitai D; Bhere Deepak; Shah Khalid; Ahmad Rushdy; Giashuddin Shah; Stafflinger Jillian; Subler Mark A; Windle Jolene J; Fisher Paul B; Sarkar Devanand^*

来源：Hepatology, 2012, 56(5): 1782-1791.

DOI：10.1002/hep.25868

Astrocyte elevated gene-1 (AEG-1) is a key contributor to hepatocellular carcinoma (HCC) development and progression. To enhance our understanding of the role of AEG-1 in hepatocarcinogenesis, a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG1) was developed. Treating Alb/AEG-1, but not wild-type (WT) mice, with N-nitrosodiethylamine resulted in multinodular HCC with steatotic features and associated modulation of expression of genes regulating invasion, metastasis, angiogenesis, and fatty acid synthesis. Hepatocytes isolated from Alb/AEG-1 mice displayed profound resistance to chemotherapeutics and growth factor deprivation with activation of prosurvival signaling pathways. Alb/AEG-1 hepatocytes also exhibited marked resistance toward senescence, which correlated with abrogation of activation of a DNA damage response. Conditioned media from Alb/AEG-1 hepatocytes induced marked angiogenesis with elevation in several coagulation factors. Among these factors, AEG-1 facilitated the association of factor XII (FXII) messenger RNA with polysomes, resulting in increased translation. Short interfering RNAmediated knockdown of FXII resulted in profound inhibition of AEG-1-induced angiogenesis. Conclusion: We uncovered novel aspects of AEG-1 functions, including induction of steatosis, inhibition of senescence, and activation of the coagulation pathway to augment aggressive hepatocarcinogenesis. The Alb/AEG-1 mouse provides an appropriate model to scrutinize the molecular mechanism of hepatocarcinogenesis and to evaluate the efficacy of novel therapeutic strategies targeting HCC. (HEPATOLOGY 2012;56:17821791)

• 出版日期2012-11