Glypican-3-mediated oncogenesis involves the Insulin-like growth factor-signaling pathway.
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.
Cheng
Wei
W
Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Tseng
Chia-Jen
CJ
Lin
Tom T C
TT
Cheng
I
I
Pan
Hung-Wei
HW
Hsu
Hey-Chi
HC
Lee
Yu-May
YM
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D053673:Glypicans / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
C105937:GPC3 protein, human; D053673:Glypicans; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D048049:Extracellular Signal-Regulated MAP Kinases