| 抄録 |
Loss of E-cadherin is associated with progression and poor prognosis of various cancers, including hepatocellular carcinoma（HCC）and cholangiocellular carcinoma（CCC）. However, it is unclear whether loss of E-cadherin is a real culprit or a bystander in liver cancer progression. In addition, the precise role of E-cadherin in maintaining liver homeostasis is also still unknown, especially in vivo. Here, we demonstrate that liver-specific E-cadherin knockout（CDH1-LKO）mice developed spontaneous periportal inflammation via an impaired intrahepatic biliary network, and subsequent periductal fibrosis which resembles primary sclerosing cholangitis. Inducible gene knockout studies identified E-cadherin loss in biliary epithelial cells as a causal factor of cholangitis induction. Furthermore, although spontaneous liver cancer rarely develop in CDH1-LKO mice, when crossed with active KRas knock-in mice（KRas/CDH1-LKO）or chemical carcinogen administration, E-cadherin loss markedly accelerated carcinogenesis and induced an invasive phenotype associated with epithelial-mesenchymal transition（EMT）, gain of stem cell property, and elevated ERK activation. Of note, although tumors arising in KRas/CDH1-LKO mice were mostly HCC, KRas/CDH1-LKO revealed tremendous ductalar reaction and developed CCC and mixed-type HCC/CCC tumors. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver. In addition, this mouse model could be a useful tool for investigating the pathogenesis of PSC-mediated hepatocarcinogenesis in humans.
Key words：E-cadherin, sclerosing cholangitis, hepatocarcinogenesis, EMT |
