State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.
Gut. 2019 Oct;68(10):1751-1763. doi: 10.1136/gutjnl-2017-315318. Epub 2019 Jan 11.
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.
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.
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-κB) 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.
These findings suggest a miR-92a-1-5p/FOXD1/NF-κB/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.
胃肠上皮化生（IM）是慢性萎缩性胃炎患者胃上皮的常见病变。IM 中 CDX2 的激活是由胆汁反流和慢性炎症引起的。但胆汁酸如何在胃上皮细胞中激活 CDX2 的机制尚未完全阐明。
我们使用微阵列对胆汁酸处理的细胞进行 microRNA（miRNA）和信使 RNA（mRNA）谱分析。对 miRNA/mRNA 谱进行与基因本体论（GO）分析和生物信息学的整合，以检测潜在的 miRNA-mRNA 调控回路。通过转染 miRNA 模拟物和抑制剂，评估其对候选靶基因表达和功能的影响。免疫组织化学和原位杂交用于检测 IM 组织微阵列中选定 miRNA 及其靶基因的表达。
我们证明了一条胆汁酸触发的途径，涉及胃细胞中 miR-92a-1-5p 的上调和其靶基因 FOXD1 的下调。我们首先发现，在 IM 组织中 miR-92a-1-5p 增加，并受胆汁酸诱导。此外，miR-92a-1-5p 通过靶向 FOXD1/FOXJ1 轴并调节核因子 kappa B（NF-κB）途径的激活，被发现可激活 CDX2 和下游肠标记物。此外，这些作用具有临床相关性，因为在 IM 组织中，高 miR-92a-1-5p 水平与低 FOXD1 水平和高 CDX2 水平相关。
这些发现表明，miR-92a-1-5p/FOXD1/NF-κB/CDX2 调节轴在胃细胞产生 IM 表型中发挥关键作用。抑制 miR-92a-1-5p 和恢复 FOXD1 可能是胆汁反流患者胃 IM 的预防方法。
