Mariette Christophe, Piessen Guillaume, Leteurtre Emmanuelle, Hémon Brigitte, Triboulet Jean-Pierre, Van Seuningen Isabelle
Inserm Unit 837, and Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Lille Cedex, France.
Surgery. 2008 Jan;143(1):58-71. doi: 10.1016/j.surg.2007.07.043.
In esophageal adenocarcinoma, MUC1 mucin expression increases in early stages of the carcinogenetic sequence, during which bile reflux has been identified as a major carcinogen. However, no link between MUC1 overexpression and the presence of bile acids in the reflux has been established so far, and molecular mechanisms regulating MUC1 expression during esophageal carcinogenetic sequence are unknown. Our aim was to identify (1) the bile acids able to upregulate MUC1 expression in esophageal cancer cells and mucosal samples, (2) the regulatory regions in MUC1 promoter responsive to bile acids, and (3) the signaling pathway(s) involved in this regulation.
MUC1 mRNA and mucin expression were studied by the means of real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry, both in the human esophageal OE33 adenocarcinoma cell line and in an ex vivo explant model. MUC1 promoter was cloned and transcription regulation was studied by transient cell transfection to identify the bile acid-responsive regions. Signaling pathways involved were identified using specific pharmacologic inhibitors and siRNA approach.
Taurocholic, taurodeoxycholic, taurochenodeoxycholic, glycocholic, sodium glycocholate, and deoxycholic bile acids upregulated MUC1 mRNA and protein expression. The highest induction was obtained with deoxycholic and taurocholic acids in both cellular and explant models. The bile acid-mediated upregulation of MUC1 transcription occurs at the promoter level, with responsive elements located in the -1472/-234 region of the promoter, and involves the phosphatidylinositol 3-kinase signaling pathway.
Bile acids induce MUC1 mucin overexpression in human esophageal adenocarcinoma cells and tissues by activating its transcription through a process involving phosphatidylinositol 3-kinase.
在食管腺癌中，MUC1粘蛋白表达在致癌序列的早期阶段增加，在此期间胆汁反流已被确定为主要致癌物。然而，到目前为止，尚未确定MUC1过表达与反流中胆汁酸的存在之间的联系，并且食管致癌序列中调节MUC1表达的分子机制尚不清楚。我们的目的是确定：（1）能够上调食管癌细胞和黏膜样本中MUC1表达的胆汁酸；（2）MUC1启动子中对胆汁酸有反应的调控区域；（3）参与该调控的信号通路。
通过实时逆转录聚合酶链反应（RT-PCR）和免疫组织化学方法，在人食管OE33腺癌细胞系和离体组织外植体模型中研究MUC1 mRNA和粘蛋白表达。克隆MUC1启动子并通过瞬时细胞转染研究转录调控，以确定胆汁酸反应区域。使用特异性药理抑制剂和小干扰RNA（siRNA）方法确定参与的信号通路。
牛磺胆酸、牛磺脱氧胆酸、牛磺鹅脱氧胆酸、甘胆酸、甘氨胆酸钠和脱氧胆酸上调MUC1 mRNA和蛋白表达。在细胞和组织外植体模型中，脱氧胆酸和牛磺胆酸诱导作用最强。胆汁酸介导的MUC1转录上调发生在启动子水平，反应元件位于启动子的-1472/-234区域，并且涉及磷脂酰肌醇3-激酶信号通路。
胆汁酸通过磷脂酰肌醇3-激酶激活转录，从而诱导人食管腺癌细胞和组织中MUC1粘蛋白过表达。
