title: Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.
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.
authors.affiliation: Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Wenhui
authors.initials: W
authors.lastname: Qiao
authors.forename: Cuiling
authors.initials: C
authors.lastname: Li
authors.forename: Cuiying
authors.initials: C
authors.lastname: Xiao
authors.forename: Svetlana
authors.initials: S
authors.lastname: Radaeva
authors.forename: Bangyan
authors.initials: B
authors.lastname: Stiles
authors.forename: Rui-Hong
authors.initials: RH
authors.lastname: Wang
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ohara
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008099:Liver / Q000166:cytology / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
chemical_list: D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse