Involvement of c-Met/hepatocyte growth factor pathway in cholangiocarcinoma cell invasion and its therapeutic inhibition with small interfering RNA specific for c-Met.
BACKGROUND
Hepatocyte growth factor receptor (c-Met) plays an important role in many functions of cancer cells. We examined the roles of c-Met and its downstream signaling molecules in cholangiocarcinoma cell lines RMCCA1 and HuCCA1.


METHODS
The expression of c-Met and their signaling cascades were determined in RMCCA1 and HuCCA1 cholangiocarcinoma cell lines by Western blotting. Small interfering RNA (siRNA) specific for c-Met was used to suppress the expression of c-Met. The proliferation, migration and invasion assay were tested in these cholangiocarcinoma cells treated with hepatocyte growth factor (HGF).


RESULTS
Activation of c-Met with HGF triggered the signaling via the ERK cascade mediated by sequential phosphorylation of MEK1/2 and MAPK and induction of cholangiocarcinoma cell invasion. The expression of c-Met in cholangiocarcinoma cells was suppressed by treatment with small interfering RNA (siRNA) specific for c-Met, and resulted in decrease in phosphorylation of MEK1/2. Furthermore, treatment with siRNA specific for c-Met or MEK inhibitor U0126 inhibited cholangiocarcinoma cell invasion induced by HGF.


CONCLUSIONS
These results indicated that HGF and c-Met involved in the mechanism of cholangiocarcinoma cell invasion. It implies a potential role for the inhibition of c-Met in the treatment of cholangiocarcinoma.
Leelawat
Kawin
K
Department of Surgery, Rajavithi Hospital, Bangkok, Thailand. kawin_leelawat@hotmail.com
Leelawat
Surang
S
Tepaksorn
Panada
P
Rattanasinganchan
Panthip
P
Leungchaweng
Anicha
A
Tohtong
Rutaiwan
R
Sobhon
Prasert
P
D008841:Actin Cytoskeleton / Q000378:metabolism; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology*
D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; D017228:Hepatocyte Growth Factor; C482128:MAP2K2 protein, human; D019859:Proto-Oncogene Proteins c-met; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human