Kazumori H, Ishihara S, Kinoshita Y
Department of Internal Medicine, Izumo City General Medical Center, 613 Nadabun-cho, Izumo, Shimane 691-0003, Japan.
Gut. 2009 May;58(5):620-8. doi: 10.1136/gut.2008.152975. Epub 2009 Jan 9.
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-kappaB) and stimulate production of Cdx2 protein in oesophageal keratinocytes with a resulting production of intestinal type mucin. In addition to Cdx2, Cdx1 may play an important role in the development of Barrett's oesophagus. Therefore, we studied the direct effects of bile acids on the expression of Cdx1 as well as the precise mechanisms of Cdx1 expression in cultured oesophageal squamous epithelial cells. Furthermore, we investigated the relationship between Cdx1 and Cdx2 expression in cultured oesophageal squamous epithelial cells.
A rat model of Barrett's oesophagus was produced by anastomosing the oesophagus and jejunum. The expression of Cdx1 was investigated by immunohistochemistry, while the response of that expression to bile acids was studied using a Cdx1 promoter luciferase assay. In addition, oesophageal squamous epithelial cells were transfected with a Cdx1 or Cdx2 expression vector, after which their possible transformation to intestinal-type epithelial cells was investigated.
In our Barrett's rat model, the metaplastic epithelium and adjoining squamous epithelium strongly expressed Cdx1. Further, the bile acids mixture dose-dependently increased Cdx1 promoter activity and Cdx1 protein in oesophageal epithelial cells. Transfection of the Cdx1 expression vector in cultured oesophageal epithelial cells induced production of Cdx2 protein.
Bile acid-induced sequential expression of Cdx1 followed by Cdx2 may have an important role in the development of Barrett's epithelium.
巴雷特食管向肠化生转变的机制尚未阐明。我们之前报道过，胆汁酸通过核因子κB（NF-κB）激活Cdx2启动子，并刺激食管角质形成细胞中Cdx2蛋白的产生，从而导致肠型黏蛋白的产生。除了Cdx2，Cdx1可能在巴雷特食管的发展中起重要作用。因此，我们研究了胆汁酸对Cdx1表达的直接影响，以及培养的食管鳞状上皮细胞中Cdx1表达的精确机制。此外，我们还研究了培养的食管鳞状上皮细胞中Cdx1与Cdx2表达之间的关系。
通过将食管与空肠吻合建立巴雷特食管大鼠模型。采用免疫组织化学法研究Cdx1的表达，同时使用Cdx1启动子荧光素酶测定法研究该表达对胆汁酸的反应。此外，用Cdx1或Cdx2表达载体转染食管鳞状上皮细胞，然后研究其向肠型上皮细胞转化的可能性。
在我们的巴雷特大鼠模型中，化生上皮和相邻的鳞状上皮强烈表达Cdx1。此外，胆汁酸混合物剂量依赖性地增加食管上皮细胞中Cdx1启动子活性和Cdx1蛋白。在培养的食管上皮细胞中转染Cdx1表达载体可诱导Cdx2蛋白的产生。
胆汁酸诱导的Cdx1随后Cdx2的顺序表达可能在巴雷特上皮的发展中起重要作用。
