Induction of Intrahepatic Cholangiocellular Carcinoma by Liver-specific Disruption of Smad4 and Pten in Mice.
From: Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, Maryland 20892, USA.
The Journal of clinical investigation
- Publish Date: Jul 2006
- ISSN: 0021-9738
- Volume: 116
- Issue: 7
- Pages: 1843-52
- Medium: Print
- Language: English
- Citation (JAMA): Xu Xiaoling, Kobayashi Shogo, Qiao Wenhui, et al. Induction of Intrahepatic Cholangiocellular Carcinoma by Liver-specific Disruption of Smad4 and Pten in Mice.. J. Clin. Invest. Jul 2006;116:1843-52
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.
Mesh Headings (Keywords): Animals, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Cells, Cultured, Cholangiocarcinoma, Disease Models, Animal, Enzyme Inhibitors, Forkhead Transcription Factors, Gene Expression Regulation, Genotype, Humans, Liver, Mice, Mice, Knockout, PTEN Phosphohydrolase, Protein Kinases, Proto-Oncogene Proteins c-akt, Smad4 Protein
Check for Full Text / PubMed Unique Identifier (PMID): 16767220
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