Background and aims Gastric intestinal metaplasia 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.
背景及目的：胃肠上皮化生常见于慢性萎缩性胃炎患者的胃上皮。反流的胆汁酸能活化肠上皮化生组织内的CDX2，进而诱导慢性炎症。但是胆汁酸活化胃上皮的CDX2的潜在机制尚不明确。
Methods We performed microRNA and messenger RNA profiling using microarray in cells treated with bile acids. Data integration of the miRNA/mRNA profiles with gene ontology 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 situ hybridisation were used to detect the expression of selected miRNAs and their targets in IM tissue microarrays.
方法：我们通过微阵列技术对接受胆汁酸处理的细胞进行miRNA及mRNA表达谱分析。我们通过GO分析及生物信息学技术整合miRNA/mRNA表达谱数据，探索有意义的miRNA-mRNA调节通路。通过miRNA类似物及抑制剂转染胃癌细胞系，评估这些小分子对候选靶基因的表达过程及功能的影响。通过免疫组织化学染色及原位杂交检测选定的miRNAs及IM组织芯片上的相应的靶基因的表达水平。
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 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.
结果：我们发现了一条由胆汁酸激发的通路，该通路涉及miR-92a-1-5p表达上调及胃上皮细胞上的FOXD1的表达受抑制。首先，我们发现“胆汁酸能诱导IM组织内的miR-92a-1-5p表达上调”。此外，miR-92a-1-5p通过靶向FOXD1/FOXJ1轴及调节NF-kB通路的活化状态，活化CDX2及下游的肠道标志物。此外，这些相互作用与临床相关，因为miR-92a-1-5p的表达水平高与IM组织内的FOXD1表达水平低及CDX2表达水平高相关。
Conclusion 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.
结论：这些结果表明，miR-92a-1-5p/FOXD1/NF-KB-CDX2调节轴在胃肠上皮化生过程中发挥重要的作用。抑制miR-92a-1-5p表达及恢复FOXD1的表达水平也许是预防胆汁反流患者发生胃肠上皮化生的一种方法。
