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Astrocyte elevated gene‐1 promotes hepatocarcinogenesis: Novel insights from a mouse model
Author(s) -
Srivastava Jyoti,
Siddiq Ayesha,
Emdad Luni,
Santhekadur Prasanna Kumar,
Chen Dong,
Gredler Rachel,
Shen XueNing,
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
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25868
Subject(s) - angiogenesis , gene knockdown , biology , small interfering rna , cancer research , astrocyte , hepatocyte , genetically modified mouse , transgene , microbiology and biotechnology , gene , endocrinology , rna , biochemistry , in vitro , central nervous system
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 RNA–mediated 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. (H EPATOLOGY 2012;56:1782–1791)