Hepatocellular carcinoma overexpressed Glypican-3-Mediated Oncogenesis Involves the Insulin-like Growth Factor Signaling Pathway

• Main Authors: Wei Cheng, 鄭威
• Other Authors: 許輝吉
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/69228426595934240114

博士 === 國立臺灣大學 === 病理學研究所 === 98 === Glypican-3 (gpc3) belongs to the glycosylphosphatidylinositol (GPI)-anchored glypican family and responsible for Simpson-Golabi-Behmel overgrowth syndrome, an X-linked condition characterized by pre-and postnatal overgrowth with visceral and skeletal anomalies. Previously, we have shown that GPC3 is overexpressed in more than 70% hepatocellular carcinoma (HCC) by Northern Blot analysis. In addition to HCC, GPC3 overexpression was also reported in certain types of human cancers, including Wilms'' tumor, hepatoblastoma, melanoma, and choriocarcinoma. GPC3 can promote the growth of cancer cells. GPC3 has been linked to Wnt, Hedgehog, BMPs and insulin-like growth factor (IGF) pathway, but the molecular mechanism remains unclear. In this study, we attempted to elucidate the mechanisms for GPC3-mediated oncogenesis. We demonstrated that ectopic overexpression of GPC3 in NIH3T3 cells led to cancer cell phenotypes including growth in serum-free medium, forming colonies in soft agar, and formation of in vivo malignant tumors in nude mice. GPC3-expressing PLC-PRF-5 cells enhanced cell growth in low serum. On the other hand, GPC3 knockdown decreased the oncogenic capability of HuH-7 cells. GPC3 stimulated the phosphorylation of IGF-1R and the downstream signaling molecule ERK in an IGF2-dependent fashion. Also, GPC3 knockdown in HCC HuH-7 cells decreased the phosphorylation of IGF-1R, IRS-1 and ERK. Therefore, we conclude that GPC3 confers oncogenecity through the interaction between IGF2 and its receptor, and the subsequent activation of the IGF-signaling pathway. 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. This proline-rich region was also important for the downstream ERK activation and AP-1 activity. GPC3 is a secretory protein. We demonstrated that the conditioned medium of MCF7 cells after transient transfection with GPC3 promoted colony growth of MCF7 and HA22T/VGH cells in soft agar. These findings are novel in the current understanding of the role of GPC3 in HCC and can be important in future developments of cancer therapy.