Deoxycholic acid promotes the growth of colonic aberrant crypt foci
Deoxycholic acid promotes the growth of colonic aberrant crypt foci
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DOI：
10.1002/mc.20253
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发表时间：
2007-01-01
影响因子：
4.6
通讯作者：
Rosenberg, Daniel W.
中科院分区：
文献类型：
--
作者：
Flynn, Christopher;Montrose, David C.;Rosenberg, Daniel W.
AKR/J小鼠对结肠致癌物氧化偶氮甲烷（AOM）的致瘤特性具有抗性。AOM暴露后，在结肠中形成有限数量的肿瘤前病变，称为异常隐窝病灶（ACF），并且很少发生其进展为肿瘤。为了确定遗传抗性是否可以通过暴露于饮食肿瘤促进剂来克服，AOM暴露的AKR/J小鼠喂食含有0.25%脱氧胆酸（DCA）的饮食。DCA暴露开始前1周或肿瘤开始后1周与AOM。与喂食对照饮食的AOM暴露小鼠相比，在AOM处理之前喂食DCA饮食的小鼠产生了显著更高的ACF多样性（分别为15.50 +/- 0.96对6.17 +/- 0.48; P < 0.05）。当在AOM处理后开始DCA暴露时（开始后），ACF形成进一步增强（34.00 +/- 1.22）。有趣的是，通过免疫组织化学评估，ACF数量的增加与细胞核β-连环蛋白的存在相关。虽然在AOM处理前暴露于DCA的小鼠的ACF中有33%含有阳性细胞核β-连环蛋白染色，但在AOM处理后喂食DCA的小鼠的ACF中有77%呈阳性。细胞核β-连环蛋白的积累与细胞膜β-钙粘蛋白的丢失无关，尽管APC染色的丢失是大多数AOM诱导的ACF的一致特征，而与DCA暴露无关。这些结果表明，暴露于DCA，一种重要的消化成分，足以使耐药的AKR/J结肠对高度异型增生的形成敏感，并且β-连环蛋白的核转位可能在此过程中起重要作用。(c)2006威利-利斯公司
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.