Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis

Hayato Nakagawa, Yohko Hikiba, Yoshihiro Hirata, Joan Font-Burgada, Kei Sakamoto, Yoku Hayakawa, Koji Taniguchi, Atsushi Umemura, Hiroto Kinoshita, Kosuke Sakitani, Yuji Nishikawa, Kenji Hirano, Tsuneo Ikenoue, Hideaki Ijichi, Debanjan Dhar, Wataru Shibata, Masao Akanuma, Kazuhiko Koike, Michael Karin, Shin Maeda

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57 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1090-1095
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number3
DOIs
Publication statusPublished - 2014 Jan 21

Keywords

  • Cholangiocellular carcinoma
  • Liver progenitor cell
  • Mixed type tumor

ASJC Scopus subject areas

  • General

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  • Cite this

    Nakagawa, H., Hikiba, Y., Hirata, Y., Font-Burgada, J., Sakamoto, K., Hayakawa, Y., Taniguchi, K., Umemura, A., Kinoshita, H., Sakitani, K., Nishikawa, Y., Hirano, K., Ikenoue, T., Ijichi, H., Dhar, D., Shibata, W., Akanuma, M., Koike, K., Karin, M., & Maeda, S. (2014). Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America, 111(3), 1090-1095. https://doi.org/10.1073/pnas.1322731111