Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice

J Clin Invest. 2006 Jul;116(7):1843-52. doi: 10.1172/JCI27282. Epub 2006 Jun 8.

Abstract

Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / metabolism*
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic / metabolism*
  • Bile Ducts, Intrahepatic / pathology
  • Cells, Cultured
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / metabolism*
  • Cholangiocarcinoma / pathology
  • Disease Models, Animal
  • Enzyme Inhibitors / metabolism
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Genotype
  • Humans
  • Liver / cytology
  • Liver / pathology
  • Liver / physiology
  • Mice
  • Mice, Knockout
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism*
  • TOR Serine-Threonine Kinases

Substances

  • Enzyme Inhibitors
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Smad4 Protein
  • Smad4 protein, mouse
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse