Cholangiocarcinoma (CCA), a malignant tumor of the bile duct epithelium, is one of the major of cancers in Northeast Thailand. This disease is difficult to diagnose and has a high mortality rate, thus posing an important public health problem in this region. Generally, cancer arises from dysregulation of tumor suppressor genes and oncogenes. c-Met, hepatocyte growth factor (HGF) receptor, and its ligand, HGF, regulate diverse biological responses including proliferation, migration and invasion, key features of metastatic cancer. Overexpression of c-Met has frequently been found in cholangiocarcinoma especially of well-differentiated type suggesting the role of c-Met in cholangiocarcinogenesis. In this study the role of HGF in invasiveness of cholangiocarcinoma was investigated using the human CCA cell line, KKU-213, in which c- Met expression is high when compare to immortalized cholangiocyte, H-69. Activation of c-Met by HGF induced KKU-213 cell proliferation, invasion and motility. Furthermore, we have addressed the significant of PI3-kinase in regulation of HGF-induced invasiveness by blocking PI3-kinase activity using PI3-kinase inhibitor, LY294002. We showed that LY294002 markedly inhibited HGF-stimulated KKU-213 cells invasion, demonstrating that PI3-kinase is necessary for HGF-induced cell invasiveness. These findings provide evidence that HGF induces KKU-213 cell motility and invasion via PI3 kinase/Akt pathway. Our study shows that HGF activates both proliferation and invasion machinery in cholangiocarcinoma cells, suggesting that HGF might promote their malignant behavior by concomitant activation of different biological functions.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]