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Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice
Xu X.1; Kobayashi S.2; Qiao W.1; Li C.1; Xiao C.1; Radaeva S.3; Stiles B.6; Wang R.-H.1; Ohara N.4; Yoshino T.4; LeRoith D.1; Torbenson M.S.7; Gores G.J.2; Wu H.6; Gao B.3; Deng C.-X.1
2006-07-03
Source PublicationJournal of Clinical Investigation
ISSN00219738 15588238
Volume116Issue:7Pages:1843-1852
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.

DOI10.1172/JCI27282
URLView the original
Indexed BySCI
Language英语
WOS Research AreaResearch & Experimental Medicine
WOS SubjectMedicine, Research & Experimental
WOS IDWOS:000238924900018
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Cited Times [WOS]:123   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorDeng C.-X.
Affiliation1.National Institute of Diabetes and Digestive and Kidney Diseases
2.Mayo Medical School
3.National Institute on Alcohol Abuse and Alcoholism
4.Okayama University
5.National Institutes of Health, Bethesda
6.David Geffen School of Medicine at UCLA
7.The Johns Hopkins School of Medicine
Recommended Citation
GB/T 7714
Xu X.,Kobayashi S.,Qiao W.,et al. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice[J]. Journal of Clinical Investigation,2006,116(7):1843-1852.
APA Xu X..,Kobayashi S..,Qiao W..,Li C..,Xiao C..,...&Deng C.-X..(2006).Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.Journal of Clinical Investigation,116(7),1843-1852.
MLA Xu X.,et al."Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice".Journal of Clinical Investigation 116.7(2006):1843-1852.
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