Comparative effects of diet and carcinogen on microRNA expression in the stem cell niche of the mouse colonic crypt.
Comparative effects of diet and carcinogen on microRNA expression in the stem cell niche of the mouse colonic crypt.
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DOI：
10.1016/j.bbadis.2015.10.012
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Chapkin RS
中科院分区：
文献类型：
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作者：
Shah MS;Kim E;Davidson LA;Knight JM;Zoh RS;Goldsby JS;Callaway ES;Zhou B;Ivanov I;Chapkin RS
越来越多的证据表明，非编码microRNA（miRNA）是由选择的化学保护饮食剂调节。例如，最近我们证明了膳食鱼油（含有n-3脂肪酸）加果胶（在结肠中发酵成丁酸盐）（FPA）的独特组合与对照（玉米油加纤维素（CCA））饮食相比，上调肠粘膜中推定的肿瘤抑制miRNA的子集，并下调致癌物暴露后其预测的靶基因。为了进一步阐明饮食和致癌物调节的miR在结肠中的生物学效应，我们验证了miR-26 b和miR-203分别直接靶向PDE 4 B和TCF 4。由于成体干细胞动力学的扰动通常被认为代表结肠肿瘤发生的早期步骤，并且为了更好地理解结肠干细胞群体如何响应环境因素如饮食和致癌物，我们另外确定了化学保护性FPA饮食对从Lgr 5-EGFP-IRES-creERT 2敲入小鼠获得的结肠干细胞中的miRNA和mRNA的影响。在总体miRNA谱分析后，26个miRNA（P <0.05）在Lgr 5高干细胞中与Lgr 5阴性分化细胞相比差异表达。与CCA相比，FPA处理在Lgr 5 high细胞中特异性上调miR-19 b、miR-26 b和miR-203表达。相反，在Lgr 5阴性细胞中，FPA饮食仅调节miR-19 b及其间接靶点PTK 2B。这些数据首次表明，选择饮食线索可以影响干细胞调控网络，部分是通过调节miRNA的稳态水平。据我们所知，这是第一项利用Lgr 5+报告小鼠来确定饮食和致癌物对结肠干细胞及其后代中miRNA表达的影响的研究。
There is mounting evidence that noncoding microRNAs (miRNA) are modulated by select chemoprotective dietary agents. For example, recently we demonstrated that the unique combination of dietary fish oil (containing n-3 fatty acids) plus pectin (fermented to butyrate in the colon) (FPA) up-regulates a subset of putative tumor suppressor miRNAs in intestinal mucosa, and down-regulates their predicted target genes following carcinogen exposure as compared to control (corn oil plus cellulose (CCA)) diet. To further elucidate the biological effects of diet and carcinogen modulated miR’s in the colon, we verified that miR-26b and miR-203 directly target PDE4B and TCF4, respectively. Since perturbations in adult stem cell dynamics are generally believed to represent an early step in colon tumorigenesis and to better understand how the colonic stem cell population responds to environmental factors such as diet and carcinogen, we additionally determined the effects of the chemoprotective FPA diet on miRNAs and mRNAs in colonic stem cells obtained from Lgr5-EGFP-IRES-creERT2 knock-in mice. Following global miRNA profiling, 26 miRNAs (P <0.05) were differentially expressed in Lgr5high stem cells as compared to Lgr5negative differentiated cells. FPA treatment up-regulated miR-19b, miR-26b and miR-203 expression as compared to CCA specifically in Lgr5high cells. In contrast, in Lgr5negative cells, only miR-19b and its indirect target PTK2B were modulated by the FPA diet. These data indicate for the first time that select dietary cues can impact stem cell regulatory networks, in part, by modulating the steady-state levels of miRNAs. To our knowledge, this is the first study to utilize Lgr5+ reporter mice to determine the impact of diet and carcinogen on miRNA expression in colonic stem cells and their progeny.