期刊
MOLECULAR CARCINOGENESIS
卷 46, 期 1, 页码 60-70出版社
WILEY-LISS
DOI: 10.1002/mc.20253
关键词
AKR/J; aberrant crypt foci; beta-catenin; deoxycholic acid
资金
- NCI NIH HHS [CA 081428] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008607] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA081428] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008607] Funding Source: NIH RePORTER
AKR/J mice are resistant to the tumorigenic properties of the colon carcinogen, azoxymethane (AOM). Following AOM exposure, limited numbers of preneoplastic lesions, referred to as aberrant crypt foci (ACF), are formed in the colon, and their progression to tumors rarely occurs. To determine whether genetic resistance can be overcome by exposure to a dietary tumor promoter, AOM-exposed AKR/J mice were fed a diet containing 0.25% deoxycholic acid (DCA). DCA exposure was begun 1 wk prior to or 1 wk after tumor initiation with AOM. Mice placed on the DCA diet prior to AOM treatment developed a significantly higher multiplicity of ACF compared to AOM-exposed mice fed a control diet (15.50 +/- 0.96 vs. 6.17 +/- 0.48, respectively; P < 0.05). When DCA exposure was begun after AOM treatment (post-initiation), ACF formation was further enhanced (34.00 +/- 1.22). Interestingly, increased numbers of ACF were associated with the presence of nuclear beta-catenin, assessed by immunohistochemistry. While similar to 33% of ACF from mice exposed to DCA prior to AOM treatment contained positive nuclear beta-catenin staining, similar to 77% of ACF from mice fed DCA after AOM were positive. Accumulation of nuclear beta-catenin was not associated with a loss of beta-cadherin from the plasma membrane, although loss of APC staining was a consistent feature of most AOM-induced ACF, regardless of DCA exposure. These results demonstrate that exposure to DCA, an important digestive component, is sufficient to sensitize the resistant AKR/J colon to formation of high-grade dysplasia, and that nuclear translocation of beta-catenin may play an important role in this process. (c) 2006 Wiley-Liss, Inc.
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