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.
背景及目的：胃腸上皮化生（IM）常見于慢性萎縮性胃炎患者的胃上皮。反流的膽汁酸能活化腸上皮化生組織內(nèi)的CDX2，進(jìn)而誘導(dǎo)慢性炎癥。但是膽汁酸活化胃上皮的CDX2的潛在機(jī)制尚不明確。
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 situ hybridisation were used to detect the expression of selected miRNAs and their targets in IM tissue microarrays.
方法：我們通過微陣列技術(shù)對(duì)接受膽汁酸處理的細(xì)胞進(jìn)行miRNA及mRNA表達(dá)譜分析。我們通過GO分析及生物信息學(xué)技術(shù)整合miRNA/mRNA表達(dá)譜數(shù)據(jù)，探索有意義的miRNA-mRNA調(diào)節(jié)通路。通過miRNA類似物及抑制劑轉(zhuǎn)染胃癌細(xì)胞系，評(píng)估這些小分子對(duì)候選靶基因的表達(dá)過程及功能的影響。通過免疫組織化學(xué)染色及原位雜交檢測(cè)選定的miRNAs及IM組織芯片上的相應(yīng)的靶基因的表達(dá)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 (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.
結(jié)果：我們發(fā)現(xiàn)了一條由膽汁酸激發(fā)的通路，該通路涉及miR-92a-1-5p表達(dá)上調(diào)及胃上皮細(xì)胞上的FOXD1（相應(yīng)的靶點(diǎn)）的表達(dá)受抑制。首先，我們發(fā)現(xiàn)“膽汁酸能誘導(dǎo)IM組織內(nèi)的miR-92a-1-5p表達(dá)上調(diào)”。此外，miR-92a-1-5p通過靶向FOXD1/FOXJ1軸及調(diào)節(jié)NF-kB通路的活化狀態(tài)，活化CDX2及下游的腸道標(biāo)志物。此外，這些相互作用與臨床相關(guān)，因?yàn)?/span>miR-92a-1-5p的表達(dá)水平高與IM組織內(nèi)的FOXD1表達(dá)水平低及CDX2表達(dá)水平高相關(guān)。
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.
結(jié)論：這些結(jié)果表明，miR-92a-1-5p/FOXD1/NF-KB-CDX2調(diào)節(jié)軸在胃腸上皮化生過程中發(fā)揮重要的作用。抑制miR-92a-1-5p表達(dá)及恢復(fù)FOXD1的表達(dá)水平也許是預(yù)防膽汁反流患者發(fā)生胃腸上皮化生的一種方法。
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