Activation of FXR promotes intestinal metaplasia of gastric cells via SHP-dependent upregulation of the expression of CDX2.
Activation of FXR promotes intestinal metaplasia of gastric cells via SHP-dependent upregulation of the expression of CDX2.
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FXR 激活通过 SHP 依赖性 CDX2 表达上调促进胃细胞肠化生
DOI：
10.3892/ol.2018.8342
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发表时间：
2018-05
期刊：
影响因子：
2.9
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
Zhou H;Ni Z;Li T;Su L;Zhang L;Liu N;Shi Y
胆汁酸诱导的胃肠上皮化生(IM)是胃腺癌的癌前病变，与尾端相关同源盒2(CDX2)的表达有关。本研究探讨了法尼醇X受体(FXR)对胃细胞CDX2表达的调节作用，并探讨了其分子机制。用鹅去氧胆酸(CDCA)或FXR激动剂GW4064处理人胃癌细胞株。在有或没有FXR拮抗剂或FXR siRNA转染的情况下，用CDCA处理细胞。接下来，在有或没有SHP siRNA的情况下，用CDCA处理细胞，用逆转录-定量聚合酶链式反应和Western印迹分析检测FXR、CDX2和SHP的mRNA和蛋白水平。采用染色质免疫沉淀法检测FXR与SHP的关系，免疫组织化学方法检测FXR、CDX2在胃炎及肠化组织中的表达。结果表明，CDCA能诱导CDX2的表达，其表达可被FXR的抑制或敲除所阻断。在机制上，FXR直接诱导小分子异二聚体(SHP)的表达。SHP基因敲除可显著降低CDCA诱导的CDX2表达。芯片结果表明，FXR能直接与SHP启动子结合，促进SHP表达。免疫组织化学结果显示CDX2和FXR在人IM皮损中的表达水平明显高于胃炎皮损，且呈正相关。这些结果表明，胆汁酸诱导的胃IM病变中CDX2的表达与FXR的激活和SHP的顺序直接转录诱导有关。
Gastric intestinal metaplasia (IM) induced by bile acid is a precancerous lesion of gastric adenocarcinoma and is associated with the expression of caudal-related homeobox 2 (CDX2). In the present study, the role of farnesoid X receptor (FXR) on the regulation of CDX2 in gastric cells was investigated and the underlying molecular mechanisms were examined. Human gastric cell lines were treated with chenodeoxycholic acid (CDCA) or FXR agonist GW4064. Cells were treated with CDCA in the presence or absence of the FXR antagonist or FXR siRNA transfection. Next, cells were treated with CDCA in the presence or absence of SHP siRNA transfection and FXR, CDX2 and SHP mRNA and protein levels were determined by reverse transcription-quantitative polymerase chain reaction and western blot analysis. A chromatin immunoprecipitation assay was performed to examine the relationship between FXR and SHP and the expressions of FXR and CDX2 in gastritis and IM tissues were detected using immunohistochemistry. The results revealed that CDCA was able to induce CDX2 expression, which could be blocked by inhibition or knockdown of FXR. Mechanistically, FXR directly induced the expression of small heterodimer partner (SHP). SHP knockdown significantly decreased CDCA-induced CDX2 expression. ChIP results indicated that FXR could directly bind SHP promoter and promote SHP expression. Finally, immunohistochemistry results demonstrated that the expression levels of CDX2 and FXR in human IM lesions were significantly higher, compared with those in gastritis lesions, and were positively correlated. Collectively, these results revealed that the activation of FXR and sequential direct transcriptional induction of SHP were involved in the expression of CDX2 induced by bile acid in gastric IM lesions.
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