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Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression
Byoung Kwon Yoo, … , Paul B. Fisher, Devanand Sarkar
Byoung Kwon Yoo, … , Paul B. Fisher, Devanand Sarkar
Published February 16, 2009
Citation Information: J Clin Invest. 2009;119(3):465-477. https://doi.org/10.1172/JCI36460.
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Research Article Oncology Article has an altmetric score of 9

Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression

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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/β-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-κB 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

Byoung Kwon Yoo, Luni Emdad, Zao-zhong Su, Augusto Villanueva, Derek Y. Chiang, Nitai D. Mukhopadhyay, Alan Scott Mills, Samuel Waxman, Robert A. Fisher, Josep M. Llovet, Paul B. Fisher, Devanand Sarkar

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Figure 3

Analysis of the tumors generated by Hep-AEG1-14 cells in athymic nude mice.

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AEG1 activates multiple signal transduction pathways.
(A) Expression of ...
Measurement of tumor volume (A) and tumor weight (B) at the end of the study at 3 weeks. Data represent mean ± SEM. (C) Hep-AEG1-14–induced tumor showing high vascularity. (D) H&E-stained section of Hep-AEG1-14–induced tumor showing nodular pattern. Arrows indicate the margins of the nodule. (E) Immunofluorescence analysis of AEG1 and CD31 in section of Hep-AEG1-14–induced tumor. Original magnification, ×100 (D); ×400 (E). (F) Photomicrograph of the lungs of nude mice after tail vein metastasis assay. Notice the knobby appearance of the lungs in Hep-AEG1-14 clones. (G) Human angiogenesis array. Molecules shown in red are upregulated in Hep-AEG1-14 clones compared with Hep-pc-4. Pos, positive control; Neg, negative control. Each item in the grid is represented in duplicate in the arrays.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 10 patents
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