Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Cancer. 2011 Jun 1;117(11):2386-97. doi: 10.1002/cncr.25796. Epub 2010 Dec 14.
Bile reflux contributes to the development of esophageal injury and neoplasia. The mucin 5AC (MUC5AC) is absent in the normal squamous epithelium of the esophagus but is strongly expressed in Barrett esophagus (BE). The objective of this study was to determine whether and how bile acids influence the expression of MUC5AC in the esophagus.
MUC5AC expression was studied by immunohistochemistry and immunoblotting in human tissues, in tissues from a rat model of BE, and in SKGT-4 cultured esophageal epithelial cells. MUC5AC transcription was studied by real-time polymerase chain reaction and transient transfection assays.
MUC5AC was absent from normal squamous epithelium but was present in 100% of Barrett specimens and in 61.5% of human esophageal adenocarcinoma tissues that were examined. MUC5AC protein expression was induced to a greater degree by conjugated bile acids than by unconjugated bile acids, and this occurred at the transcriptional level. In the rat reflux model, MUC5AC mucin was expressed abundantly in tissues of BE stimulated by duodenoesophageal reflux. Conjugated bile acids induced AKT phosphorylation in SKGT-4 cells but had no effect on extracellular signal-regulated protein kinases 1 and 2, c-Jun N-terminal kinase, or protein-38 kinase phosphorylation. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and a dominant-negative protein kinase C (AKT) construct prevented the induction of MUC5AC by conjugated bile acids. Transactivation of AP-1 by conjugated bile acids coincided with MUC5AC induction, and cotransfection with a dominant-negative activator protein-1 (AP-1) vector decreased MUC5AC transcription and its induction.
Conjugated bile acids in the bile refluxate contribute to MUC5AC induction in the esophagus. This occurs at the level of transcription and involves activation of the PI3K/AKT/AP-1 pathway.
胆汁反流会导致食管损伤和肿瘤的发生。黏蛋白 5AC（MUC5AC）在正常食管鳞状上皮中不存在，但在 Barrett 食管（BE）中强烈表达。本研究旨在确定胆汁酸是否以及如何影响食管中 MUC5AC 的表达。
通过免疫组织化学和免疫印迹法在人组织、BE 大鼠模型组织和 SKGT-4 培养的食管上皮细胞中研究 MUC5AC 的表达。通过实时聚合酶链反应和瞬时转染测定研究 MUC5AC 的转录。
MUC5AC 不存在于正常的鳞状上皮中，但存在于 100%的 Barrett 标本和 61.5%的人食管腺癌组织中。与未结合的胆汁酸相比，结合胆汁酸更能诱导 MUC5AC 蛋白表达，并且这种作用发生在转录水平。在大鼠反流模型中，十二指肠-食管反流刺激的 BE 组织中大量表达 MUC5AC 粘蛋白。结合胆汁酸诱导 SKGT-4 细胞中 AKT 磷酸化，但对细胞外信号调节蛋白激酶 1 和 2、c-Jun N-末端激酶或蛋白激酶 38 的磷酸化没有影响。PI3K 抑制剂 LY294002 和蛋白激酶 C（AKT）显性失活构建体阻止了结合胆汁酸对 MUC5AC 的诱导。结合胆汁酸对 AP-1 的转导与 MUC5AC 的诱导同时发生，与显性失活的激活蛋白-1（AP-1）载体共转染可降低 MUC5AC 转录及其诱导。
胆汁反流中的结合胆汁酸有助于食管中 MUC5AC 的诱导。这发生在转录水平，并涉及 PI3K/AKT/AP-1 通路的激活。
