title: Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis.
abstract: E-cadherin is an important adhesion molecule whose loss is associated with progression and poor prognosis of liver cancer. However, it is unclear whether the 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 mice develop spontaneous periportal inflammation via an impaired intrahepatic biliary network, as well as 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, a few of the E-cadherin knockout mice developed spontaneous liver cancer. When knockout of E-cadherin is combined with Ras activation or chemical carcinogen administration, E-cadherin knockout mice display markedly accelerated carcinogenesis and an invasive phenotype associated with epithelial-mesenchymal transition, up-regulation of stem cell markers, and elevated ERK activation. Also in human hepatocellular carcinoma, E-cadherin loss correlates with increased expression of mesenchymal and stem cell markers, and silencing of E-cadherin in hepatocellular carcinoma cell lines causes epithelial-mesenchymal transition and increased invasiveness, suggesting that E-cadherin loss can be a causal factor of these phenotypes. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.
authors.affiliation: Department of Gastroenterology, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Joan
authors.initials: J
authors.lastname: Font-Burgada
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Umemura
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Kosuke
authors.initials: K
authors.lastname: Sakitani
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Hirano
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ikenoue
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ijichi
authors.forename: Debanjan
authors.initials: D
authors.lastname: Dhar
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Masao
authors.initials: M
authors.lastname: Akanuma
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D063646:Carcinogenesis; D002761:Cholangitis / Q000378:metabolism; D015209:Cholangitis, Sclerosing / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000166:cytology; D007249:Inflammation; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009362:Neoplasm Metastasis; D010641:Phenotype; D011379:Prognosis; D013234:Stem Cells / Q000166:cytology
chemical_list: D001426:Bacterial Proteins; D015820:Cadherins; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: cholangiocellular carcinoma; liver progenitor cell; mixed type tumor