Glypican-3-mediated oncogenesis involves the Insulin-like growth factor-signaling pathway

• Published in: Carcinogenesis (New York) Vol. 29; no. 7; pp. 1319 - 1326
• Main Authors: Cheng, Wei, Tseng, Chia-Jen, Lin, Tom T.C., Cheng, I., Pan, Hung-Wei, Hsu, Hey-Chi, Lee, Yu-May
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2008; Oxford Publishing Limited (England)
• Subjects: Animals; Biological and medical sciences; Cancer Biology; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Extracellular Signal-Regulated MAP Kinases - metabolism; Glypicans - biosynthesis; Glypicans - genetics; Glypicans - metabolism; HeLa Cells; Humans; Insulin-Like Growth Factor II - metabolism; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Medical sciences; Mice; NIH 3T3 Cells; Phosphorylation; Receptor, IGF Type 1 - metabolism; Signal Transduction; Transfection; Tumors; Proteoglycan; Insulin like growth factor; Glypican 3; Signaling pathway; Carcinogenesis
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgn091

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.