TY - JOUR
T1 - Astrocyte elevated gene-1 promotes hepatocarcinogenesis
T2 - Novel insights from a mouse model
AU - Srivastava, Jyoti
AU - Siddiq, Ayesha
AU - Emdad, Luni
AU - Santhekadur, Prasanna Kumar
AU - Chen, Dong
AU - Gredler, Rachel
AU - Shen, Xue Ning
AU - Robertson, Chadia L.
AU - Dumur, Catherine I.
AU - Hylemon, Phillip B.
AU - Mukhopadhyay, Nitai D.
AU - Bhere, Deepak
AU - Shah, Khalid
AU - Ahmad, Rushdy
AU - Giashuddin, Shah
AU - Stafflinger, Jillian
AU - Subler, Mark A.
AU - Windle, Jolene J.
AU - Fisher, Paul B.
AU - Sarkar, Devanand
PY - 2012/11
Y1 - 2012/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84868257532
U2 - 10.1002/hep.25868
DO - 10.1002/hep.25868
M3 - Article
C2 - 22689379
AN - SCOPUS:84868257532
SN - 0270-9139
VL - 56
SP - 1782
EP - 1791
JO - Hepatology
JF - Hepatology
IS - 5
ER -