Roles of Kruppel-like factor 4 in oesophageal epithelial cells in Barrett's epithelium development
Roles of Kruppel-like factor 4 in oesophageal epithelial cells in Barrett's epithelium development
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DOI：
10.1136/gut.2010.221648
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发表时间：
2011-05-01
期刊：
影响因子：
24.5
通讯作者：
Kinoshita, Yoshikazu
中科院分区：
文献类型：
--
作者：
Kazumori, Hideaki;Ishihara, Shunji;Kinoshita, Yoshikazu
目的Barrett食管向肠上皮化生转化的机制尚不清楚。我们以前报道过胆汁酸通过核因子κ B（NF-κ B B）激活Cdx 2启动子并刺激食管角化细胞中Cdx 2蛋白的产生，从而导致唾液酸型粘蛋白的产生。Kruppel样因子4（KLF 4）是肠粘膜发育中的重要转录因子，与Cdx 2具有相似的功能。在本研究中，我们研究了胆汁酸对KLF 4表达的直接影响以及在培养的食管鳞状上皮cells.Methods中表达的精确机制，我们研究了KLF 4在大鼠和人Barrett上皮标本中的表达，同时使用KLF 4启动子荧光素酶测定研究了该表达对胆汁酸的反应。此外，食管鳞状上皮细胞转染的KLF 4表达载体，之后，他们可能转化为pneuminal-type上皮cells的investigated.Results在大鼠和人体组织中，巴雷特上皮强烈表达KLF 4。此外，胆汁酸混合物增加KLF 4启动子活性，mRNA和蛋白质表达在食管上皮细胞。KLF 4启动子的突变分析结果表明，NF-kB结合位点负责胆汁酸诱导的KLF 4启动子的激活。结论胆汁酸诱导KLF 4表达和MUC 2表达的顺序性过程可能在Barrett上皮细胞的发育过程中起重要作用。
Objectives The mechanism of transformation to intestinal metaplasia in Barrett's oesophagus has not been clarified. We previously reported that bile acids activate the Cdx2 promoter via nuclear factor kappa B (NF-kappa B) and stimulate production of Cdx2 protein in oesophageal keratinocytes, resulting in production of intestinal-type mucin. Kruppel-like factor 4 (KLF4) is an important transcription factor in the development of intestinal mucosa and has similar functions as Cdx2. In the present study, we investigated the direct effects of bile acids on KLF4 expression as well as the precise mechanisms of expression in cultured oesophageal squamous epithelial cells.Methods We investigated the expression of KLF4 in rat and human Barrett's epithelium specimens, while the response of that expression to bile acids was studied using a KLF4 promoter luciferase assay. In addition, oesophageal squamous epithelial cells were transfected with a KLF4 expression vector, after which their possible transformation into intestinal-type epithelial cells was investigated.Results In both rat and human tissues, Barrett's epithelium strongly expressed KLF4. Furthermore, a bile acids mixture increased KLF4 promoter activity, and mRNA and protein expression in oesophageal epithelial cells. Results from mutation analysis of the KLF4 promoter suggested that the NF-kB binding site is responsible for bile acid-induced activation of the KLF4 promoter. In addition, KLF4 and Cdx2 stimulated each other by directly binding to the promoter of the other, while transfection of the KLF4 expression vector in oesophageal epithelial cells induced production of MUC2 protein.Conclusion Bile acid-induced sequential expression of KLF4 followed by MUC2 production may have an important role in the development of Barrett's epithelium.