Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.
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.
Xu
Xiaoling
X
Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, Maryland 20892, USA.
Kobayashi
Shogo
S
Qiao
Wenhui
W
Li
Cuiling
C
Xiao
Cuiying
C
Radaeva
Svetlana
S
Stiles
Bangyan
B
Wang
Rui-Hong
RH
Ohara
Nobuya
N
Yoshino
Tadashi
T
LeRoith
Derek
D
Torbenson
Michael S
MS
Gores
Gregory J
GJ
Wu
Hong
H
Gao
Bin
B
Deng
Chu-Xia
CX
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
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