The sonic hedgehog pathway as a treatment target for extrahepatic biliary tract cancer.

Abstract

Sonic hedgehog (SHh) signaling is essential for normal development of the human gastrointestinal (GI) tract and is reported to be aberrantly activated in GI cancers. However, the association between SHh signaling and extrahepatic biliary tract cancer is not clearly understood. In this study, we evaluated the activities of SHh family proteins and their downstream signals in extrahepatic biliary tract cancer. The activity of the SHh pathway was analyzed in established human extrahepatic biliary tract cell lines and human cancer tissues using RT-PCR and immunohistochemistry. We also evaluated the effects of suppressing the SHh pathway with cyclopamine and siRNA. The SHh, Smo and Gli-1 genes were overexpressed in extrahepatic biliary tract cancer cell lines and six extrahepatic biliary tract cancer tissues compared to the levels in normal biliary tract tissues. The degrees of SHh and Gli-1 expression were independent of tumor stage and cancer cell differentiation. SHh pathway suppression with cyclopamine or siRNA inhibited proliferation of extrahepatic biliary tract cancer cell lines. In conclusion, the SHh pathway is highly activated in extrahepatic biliary tract cancer and is a potential anticancer drug target.