MicroRNA-92a-1-5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia
MicroRNA-92a-1-5p increases CDX2 by targeting FOXD1 in bile acids-induced gastric intestinal metaplasia
复制标题
MicroRNA-92a-1-5p 通过靶向胆汁酸诱导的胃肠化生中的 FOXD1 增加 CDX2
DOI：
10.1136/gutjnl-2017-315318
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发表时间：
2019-10-01
期刊：
影响因子：
24.5
通讯作者：
Shi, Yongquan
中科院分区：
文献类型：
--
作者：
Li, Ting;Guo, Hanqing;Shi, Yongquan
背景与目的胃肠上皮化生在慢性萎缩性胃炎患者的胃上皮细胞中十分常见。在IM中，CDX2的激活是由胆汁酸的反流和慢性炎症引起的。但胆汁酸激活胃上皮细胞CDX2的机制尚未完全阐明。方法采用基因芯片技术对胆汁酸处理的细胞进行microRNA(MiRNA)和信使RNA(MRNAs)的表达谱分析。将miRNA/mRNA图谱与基因本体论(GO)分析和生物信息学进行数据集成，以检测潜在的miRNA-mRNA调控电路。用miRNA模拟物和抑制剂转染胃癌细胞，观察它们对候选靶点和功能表达的影响。结果在胃黏膜细胞中发现了胆汁酸触发的miR-92a-1-5p表达上调和靶向FOXD1抑制的途径。我们首次发现在IM组织中miR-92a-1-5p的表达增加，并被胆汁酸诱导。此外，miR-92a-1-5p通过靶向FOXD1/FOXJ1轴和调节核因子-kappa B(NF-kappa B)途径激活CDX2及其下游肠道标志物。结论miR-92a-1-5p/FOXD1/FOXD1/NF-kappa B/CDX2调节轴在胃细胞IM表型的形成中起关键作用。抑制miR-92a-1-5p和恢复FOXD1可能是胆汁反流患者胃IM的一种预防措施。
Background and aims Gastric intestinal metaplasia (IM) is common in the gastric epithelium of patients with chronic atrophic gastritis. CDX2 activation in IM is driven by reflux of bile acids and following chronic inflammation. But the mechanism underlying how bile acids activate CDX2 in gastric epithelium has not been fully explored.Methods We performed microRNA (miRNA) and messenger RNA (mRNA) profiling using microarray in cells treated with bile acids. Data integration of the miRNA/mRNA profiles with gene ontology (GO) analysis and bioinformatics was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with miRNA mimics and inhibitors was used to evaluate their effects on the expression of candidate targets and functions. Immunohistochemistry and in situhybridisation were used to detect the expression of selected miRNAs and their targets in IM tissue microarrays.Results We demonstrate a bile acids-triggered pathway involving upregulation of miR-92a-1-5p and suppression of its target FOXD1 in gastric cells. We first found that miR-92a-1-5p was increased in IM tissues and induced by bile acids. Moreover, miR-92a-1-5p was found to activate CDX2 and downstream intestinal markers by targeting FOXD1/FOXJ1 axis and modulating activation of nuclear factor kappa B (NF-kappa B) pathway. Furthermore, these effects were found to be clinical relevant, as high miR-92a-1-5p levels were correlated with low FOXD1 levels and high CDX2 levels in IM tissues.Conclusion These findings suggest a miR-92a-1-5p/FOXD1/NF-kappa B/CDX2 regulatory axis plays key roles in the generation of IM phenotype from gastric cells. Suppression of miR-92a-1-5p and restoration of FOXD1 may be a preventive approach for gastric IM in patients with bile regurgitation.