期刊
GASTROENTEROLOGY
卷 142, 期 3, 页码 562-U228出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2011.11.026
关键词
Colon Cancer; Mouse Model; Intestinal Epithelium; Signal Transduction; Carcinoma
资金
- Vanderbilt-Ingram Cancer Center [CA068485]
- GI Cancer SPORE [CA095103]
- Vanderbilt Digestive Diseases Center [DK058404]
- Clinical and Translational Science Award [UL1 RR024975]
- Society of University Surgeons
- Vanderbilt Ingram Cancer Center
- Vanderbilt Vision Center [P30 EY08126]
- Vanderbilt Digestive Disease Research Center
- [CA069457]
- [T32 GM07347]
- [T32 CA106183]
- [CA084239]
- [DK052334]
- [GM088822]
- [TL1 RR024978]
- [CA112215]
- [P50CA095103]
BACKGROUND & AIMS: Mutational inactivation of adenomatous polyposis coli (APC) is an early event in colorectal cancer (CRC) progression that affects the stability and increases the activity of beta-catenin, a mediator of Wnt signaling. Progression of CRC also involves inactivation of signaling via transforming growth factor beta and bone morphogenetic protein (BMP), which are tumor suppressors. However, the interactions between these pathways are not clear. We investigated the effects of loss of the transcription factor Smad4 on levels of beta-catenin messenger RNA (mRNA) and Wnt signaling. METHODS: We used microarray analysis to associate levels of Smad4 and beta-catenin mRNA in colorectal tumor samples from 250 patients. We performed oligonucleotide-mediated knockdown of Smad4 in human embryonic kidney (HEK293T) and in HCT116 colon cancer cells and transgenically expressed Smad4 in SW480 colon cancer cells. We analyzed adenomas from (APC(Delta 1638/+)) and (APC(Delta 1638/+)) x (K19Cre(ERT2)Smad4(lox/lox)) mice by using laser capture microdissection. RESULTS: In human CRC samples, reduced levels of Smad4 correlated with increased levels of beta-catenin mRNA. In Smad4-depleted cell lines, levels of beta-catenin mRNA and Wnt signaling increased. Inhibition of BMP or depletion of Smad4 in HEK293T cells increased binding of RNA polymerase II to the beta-catenin gene. Expression of Smad4 in SW480 cells reduced Wnt signaling and levels of beta-catenin mRNA. In mice with heterozygous disruption of Apc(APC(Delta 1638/+)), Smad4-deficient intestinal adenomas had increased levels of beta-catenin mRNA and expression of Wnt target genes compared with adenomas from APC(Delta 1638/+) mice that expressed Smad4. CONCLUSIONS: Transcription of beta-catenin is inhibited by BMP signaling to Smad4. These findings provide important information about the interaction among transforming growth factor beta, BMP, and Wnt signaling pathways in progression of CRC.
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