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


CONCLUSIONS
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.
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Jyoti
J
Srivastava
Ayesha
A
Siddiq
Luni
L
Emdad
Prasanna Kumar
PK
Santhekadur
Dong
D
Chen
Rachel
R
Gredler
Xue-Ning
XN
Shen
Chadia L
CL
Robertson
Catherine I
CI
Dumur
Phillip B
PB
Hylemon
Nitai D
ND
Mukhopadhyay
Deepak
D
Bhere
Khalid
K
Shah
Rushdy
R
Ahmad
Shah
S
Giashuddin
Jillian
J
Stafflinger
Mark A
MA
Subler
Jolene J
JJ
Windle
Paul B
PB
Fisher
Devanand
D
Sarkar
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005174:Factor XII / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D005234:Fatty Liver / Q000235:genetics / Q000473:pathology; D005472:Fluorouracil / Q000494:pharmacology; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011132:Polyribosomes; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins
D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D005227:Fatty Acids; C483039:MTDH protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D004052:Diethylnitrosamine; D004317:Doxorubicin; D005174:Factor XII; D005472:Fluorouracil