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Carcinogenesis Advance Access originally published online on April 15, 2008
Carcinogenesis 2008 29(7):1319-1326; 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 Insulin-like growth factor-signaling pathway

Wei Cheng1,2,{dagger}, Chia-Jen Tseng3,4,{dagger}, Tom T.C. Lin2, I. Cheng5, Hung-Wei Pan6, Hey-Chi Hsu1,6 and Yu-May Lee3,4,*

1 Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
2 Department of Pathology, Kee-Lung General Hospital, Department of Health, The Executive Yuan, Kee-Lung 200, Taiwan
3 Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan
4 Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan
5 Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
6 Department of Pathology, National Taiwan University Hospital, Taipei 100, Taiwan

* To whom correspondence should be addressed. Tel: +886 2 27855696 ext. 6120; Fax: +886 2 27889759;, Email: yml6120{at}gate.sinica.edu.tw

Correspondence may also be addressed to Hey-Chi Hsu., Tel: +886 2 23562154; Fax: +886 2 23934172;, Email: heychi{at}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 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 Insulin-like growth factor (IGF)-II and IGF-1R. GPC3 stimulated the phosphorylation of IGF-1R and the downstream signaling molecule extracellular signal-regulated kinase (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 are novel to the current understanding of the role of GPC3 in HCC and will be important in future developments of cancer therapy.

Abbreviations: ERK, extracellular signal-regulated kinase; GFP, green fluorescence protein; GPC3, glypican-3; GST, glutathione S-transferase; HCC, hepatocellular carcinoma; IGF, insulin-like growth factor; shRNA, small hairpin RNA; siRNA, small interfering RNA; mRNA, messenger RNA

{dagger} These authors contributed equally to this work.

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


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