Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression.
Hepatocellular carcinoma (HCC) is a highly aggressive vascular cancer characterized by diverse etiology, activation of multiple signal transduction pathways, and various gene mutations. Here, we have determined a specific role for astrocyte elevated gene-1 (AEG1) in HCC pathogenesis. Expression of AEG1 was extremely low in human hepatocytes, but its levels were significantly increased in human HCC. Stable overexpression of AEG1 converted nontumorigenic human HCC cells into highly aggressive vascular tumors, and inhibition of AEG1 abrogated tumorigenesis by aggressive HCC cells in a xenograft model of nude mice. In human HCC, AEG1 overexpression was associated with elevated copy numbers. Microarray analysis revealed that AEG1 modulated the expression of genes associated with invasion, metastasis, chemoresistance, angiogenesis, and senescence. AEG1 also was found to activate Wnt/beta-catenin signaling via ERK42/44 activation and upregulated lymphoid-enhancing factor 1/T cell factor 1 (LEF1/TCF1), the ultimate executor of the Wnt pathway, important for HCC progression. Inhibition studies further demonstrated that activation of Wnt signaling played a key role in mediating AEG1 function. AEG1 also activated the NF-kappaB pathway, which may play a role in the chronic inflammatory changes preceding HCC development. These data indicate that AEG1 plays a central role in regulating diverse aspects of HCC pathogenesis. Targeted inhibition of AEG1 might lead to the shutdown of key elemental characteristics of HCC and could lead to an effective therapeutic strategy for HCC.
Yoo
Byoung Kwon
BK
Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Emdad
Luni
L
Su
Zao-zhong
ZZ
Villanueva
Augusto
A
Chiang
Derek Y
DY
Mukhopadhyay
Nitai D
ND
Mills
Alan Scott
AS
Waxman
Samuel
S
Fisher
Robert A
RA
Llovet
Josep M
JM
Fisher
Paul B
PB
Sarkar
Devanand
D
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D016601:RNA-Binding Proteins; D012016:Reference Values; D014183:Transplantation, Heterologous
D015815:Cell Adhesion Molecules; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; C483039:MTDH protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins