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- Title
Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.
- Authors
Xiaoling Xu; Shogo Kobayashi; Wenhui Qiao; Cuiling Li; Cuiying Xiao; Radaeva, Svetlana; Stiles, Bangyan; Rui-Hong Wang; Ohara, Nobuya; Yoshino, Tadashi; LeRoith, Derek; Torbenson, Michael S.; Gores, Gregory J.; Hong Wu; Bin Gao; Chu-Xia Deng
- 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-3β, 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.
- Subjects
CANCER; ONCOGENES; PROGNOSIS; CARCINOGENESIS; INTRAHEPATIC bile ducts; MICE; PHOSPHORYLATION
- Publication
Journal of Clinical Investigation, 2006, Vol 116, Issue 7, p1843
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI27282