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Carcinogenesis Advance Access published online on April 15, 2008
Carcinogenesis, doi:10.1093/carcin/bgn091
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Glypican-3-mediated oncogenesis involves the IGF signaling pathway

Wei Cheng1,2, Chia-Jen Tseng3,4, Tom TC Lin2, I Cheng2, Hung-Wei Pan5, Hey-Chi Hsu*,1,5 and Yu-May Lee*,3,4

1 Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
2 Department of Pathology, Kee-Lung General Hospital, Department of Health, The Executive Yuan, Kee-Lung, Taiwan
3 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
4 Institute of Biochemical Sciences, National Taiwan University
5 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

* Address reprint requests to: Yu-May Lee, Institute of Biological Chemistry Academia Sinica, Taipei, Taiwan. Tel: 886-2-27855696 ext 6120, Fax: 886-2-27889759, Email: YML6120{at}gate.sinica.edu.tw, or Hey-Chi Hsu, Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan. Tel: 886-2-23562154, Fax: 886-2-23934172, Email: heychi{at}ha.mc.ntu.edu.tw.

Glypican-3 (GPC3) is the gene responsible for Simpson-Golabi-Behmel overgrowth syndrome. Previously we have shown that GPC3 is overexpressed in hepatocellular carcinoma (HCC). In this study, we further demonstrated the mechanisms for GPC3-mediated oncogenesis. Firstly, GPC3 overexpression in NIH3T3 cells gave to cancer cell phenotypes including growing in serum-free medium and forming colonies in soft agar, or on the other way, GPC3 knockdown in HuH-7 cells decreased oncogenecity. We further demonstrated that GPC3 bound specifically through its N-terminal proline-rich region to both IGF-II and IGF-1R. GPC3 stimulated the phosphorylation of IGF-1R and the downstream signaling molecule ERK in an IGF-II-dependent way. Also, GPC3 knockdown in HCC cells decreased the phosphorylation of both IGF-1R and ERK. Therefore, GPC3 confers oncogenecity through the interaction between IGF-II and its receptor, and the subsequent activation of the IGF signaling pathway. This data is novel to the current understanding of the role of GPC3 in HCC, and will be important in future developments of cancer therapy.

Key Words: glypican-3 • oncogenesis • hepatocellular carcinoma • IGF-II • IGF-IR

First two authors contribute equally.

Received October 1, 2007; revised March 24, 2008; accepted March 26, 2008.


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