Our preliminary analysis on the mutant mice has revealed distinct functions of SMAD genes in multiple biological processes. We showed that SMAD2 and SMAD4 are needed for gastrulation, SMAD5 for angiogenesis, and SMAD3 for establishment of the mucosal immune response and proper development of the skeleton. Our recent effort is focused on SMAD4, which is a common mediator of TGF-beta signals. SMAD4 is also called DPC4 (deleted in pancreastic cancer locus 4). Mutatons of SMAD4 has been detected in pancreatic cancer, colon cancer, cholangiocellular carcinoma, gastric polyposis, and adenocarcinomas. Our study indicates that SMAD4 is essential for embryonic development in mice, as loss of SMAD4 results in lethality at E67 due to impaired extraembryonic membrane formation and decreased epiblast proliferation. SMAD4-heterozygous mice developed gastric polyposis and cancer due to haploinsufficiency. Using SMAD4-Co mice, we have demonstrated that SMAD4 deficiency could cause tumor formation in mammary tissue, skin, liver, forestomach, and colon. Deletion of SMAD4 in hepatic cells also results in iron accumulation, a disease mimicking human hemochromatosis.? ? In the past year, we focused on studying SMAD4 in cholangiocellular carcinoma (CC). CC is the second most common primary liver cancer, and 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.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2008
Total Cost
$240,057
Indirect Cost
City
State
Country
United States
Zip Code
Pan, Dejing; Schomber, Tibor; Kalberer, Christian P et al. (2007) Normal erythropoiesis but severe polyposis and bleeding anemia in Smad4-deficient mice. Blood 110:3049-55
Anthoni, Minna; Wang, Guoying; Deng, Chuxia et al. (2007) Smad3 signal transducer regulates skin inflammation and specific IgE response in murine model of atopic dermatitis. J Invest Dermatol 127:1923-9
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Song, Lanying; Yan, Wensheng; Chen, Xinbin et al. (2007) Myocardial smad4 is essential for cardiogenesis in mouse embryos. Circ Res 101:277-85
Izeradjene, Kamel; Combs, Chelsea; Best, Melissa et al. (2007) Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 11:229-43
Katuri, V; Tang, Y; Li, C et al. (2006) Critical interactions between TGF-beta signaling/ELF, and E-cadherin/beta-catenin mediated tumor suppression. Oncogene 25:1871-86
Qiao, W; Li, A G; Owens, P et al. (2006) Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin. Oncogene 25:207-17
Kim, Byung-Gyu; Li, Cuiling; Qiao, Wenhui et al. (2006) Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441:1015-9
Xu, Xiaoling; Kobayashi, Shogo; Qiao, Wenhui et al. (2006) Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. J Clin Invest 116:1843-52
Park, Changwon; Lavine, Kory; Mishina, Yuji et al. (2006) Bone morphogenetic protein receptor 1A signaling is dispensable for hematopoietic development but essential for vessel and atrioventricular endocardial cushion formation. Development 133:3473-84

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