Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development

Er Yea Wang, Shiou Hwei Yeh*, Ting Fen Tsai, Hsiang Po Huang, Yung Ming Jeng, Wei Hsiang Lin, Wei Chih Chen, Kun Huei Yeh, Pei Jer Chen, Ding Shinn Chen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Depletion of β-catenin impairs regeneration of the rapid turn-over gut epithelial cells, but appears dispensable for that of the slow turn-over mature hepatocytes in mice until 1 y of age. As the life span of mature murine hepatocytes is about 400 d, we studied conditional β-catenin knockout mice (Alb-Cre;Ctnnb1flx/flx) until 20 mo of age to determine the function of β-catenin in the postnatal liver. β-catenin was absent from the hepatocytes of β-catenin knockout mice 4 wk after delivery. From 9 mo of age, hepatocytes were gradually replaced by newly formed β-catenin-positive hepatocytes, which constituted about 90% of hepatocytes at 18-20 mo of age. This process was accompanied by active proliferation of bile duct/ductule cells. β-catenin-positive hepatocytes exhibited elevated proliferation activity and expression of progenitor cell markers, but lower albumin and Cre. This might explain their intact β-catenin protein, and suggest their origins from hepatic progenitor cells. Liver tumors arose spontaneously from β-catenin-positive cells, and tumorigenesis was accelerated by hepatitis B X protein. These results indicate β-catenin critical for the regeneration of mature hepatocytes. Failure to regenerate mature hepatocytes results in proliferation of hepatic progenitor cells that are able to maintain liver function but are predisposed to form liver tumors.

Original languageEnglish
Pages (from-to)18384-18389
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number45
DOIs
StatePublished - 8 Nov 2011

Keywords

  • HBx protein
  • Liver cancer
  • Postnatal liver regeneration

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