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Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Xu, Xiaoling Kobayashi, Shogo Qiao, Wenhui Li, Cuiling Xiao, Cuiying Radaeva, Svetlana Wang, R. Ohara, Nobuya Yoshino, Tadashi Leroith, Derek Deng, Chu-Xia |
| Copyright Year | 2006 |
| 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. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://dm5migu4zj3pb.cloudfront.net/manuscripts/27000/27282/JCI0627282.pdf |
| Alternate Webpage(s) | https://www.jci.org/articles/view/27282/version/1/pdf/render |
| PubMed reference number | 16767220v1 |
| Volume Number | 116 |
| Issue Number | 7 |
| Journal | The Journal of clinical investigation |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Bile duct structure Bronchioloalveolar Adenocarcinoma Carcinogenesis Cholangiocarcinoma Duct (organ) structure Genes, Suppressor Hyperplasia Liver and Intrahepatic Biliary Tract Carcinoma Liver carcinoma Neoplasms Oncogenes Penetrance Proto-Oncogene Proteins c-akt SMAD4 gene Tumor Suppressor Genes glycogen synthase kinase 3 beta |
| Content Type | Text |
| Resource Type | Article |
