title: Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression.
abstract: 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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Yoo
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Zao-zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Derek Y
authors.initials: DY
authors.lastname: Chiang
authors.forename: Nitai D
authors.initials: ND
authors.lastname: Mukhopadhyay
authors.forename: Alan Scott
authors.initials: AS
authors.lastname: Mills
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fisher
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: 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
chemical_list: 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