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

Xiaoling Xu, Shogo Kobayashi, Wenhui Qiao, Cuiling Li, Cuiying Xiao, Svetlana Radaeva, Bangyan Stiles, Rui Hong Wang, Nobuya Ohara, Tadashi Yoshino, Derek LeRoith, Michael S. Torbenson, Gregory J. Gores, Hong Wu, Bin Gao, Chu Xia Deng

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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.

Original languageEnglish
Pages (from-to)1843-1852
Number of pages10
JournalJournal of Clinical Investigation
Volume116
Issue number7
DOIs
Publication statusPublished - Jul 3 2006

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Cholangiocarcinoma
Liver
Glycogen Synthase Kinase 3
Penetrance
Cyclin D1
Liver Neoplasms
Bile Ducts
Tumor Suppressor Genes
Oncogenes
Neoplasms
Carcinogenesis

ASJC Scopus subject areas

  • Medicine(all)

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Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. / Xu, Xiaoling; Kobayashi, Shogo; Qiao, Wenhui; Li, Cuiling; Xiao, Cuiying; Radaeva, Svetlana; Stiles, Bangyan; Wang, Rui Hong; Ohara, Nobuya; Yoshino, Tadashi; LeRoith, Derek; Torbenson, Michael S.; Gores, Gregory J.; Wu, Hong; Gao, Bin; Deng, Chu Xia.

In: Journal of Clinical Investigation, Vol. 116, No. 7, 03.07.2006, p. 1843-1852.

Research output: Contribution to journalArticle

Xu, X, Kobayashi, S, Qiao, W, Li, C, Xiao, C, Radaeva, S, Stiles, B, Wang, RH, Ohara, N, Yoshino, T, LeRoith, D, Torbenson, MS, Gores, GJ, Wu, H, Gao, B & Deng, CX 2006, 'Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice', Journal of Clinical Investigation, vol. 116, no. 7, pp. 1843-1852. https://doi.org/10.1172/JCI27282
Xu, Xiaoling ; Kobayashi, Shogo ; Qiao, Wenhui ; Li, Cuiling ; Xiao, Cuiying ; Radaeva, Svetlana ; Stiles, Bangyan ; Wang, Rui Hong ; Ohara, Nobuya ; Yoshino, Tadashi ; LeRoith, Derek ; Torbenson, Michael S. ; Gores, Gregory J. ; Wu, Hong ; Gao, Bin ; Deng, Chu Xia. / Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 7. pp. 1843-1852.
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AU - Xiao, Cuiying

AU - Radaeva, Svetlana

AU - Stiles, Bangyan

AU - Wang, Rui Hong

AU - Ohara, Nobuya

AU - Yoshino, Tadashi

AU - LeRoith, Derek

AU - Torbenson, Michael S.

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AU - Wu, Hong

AU - Gao, Bin

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AB - 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.

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