Burnat Grzegorz, Rau Tilman, Elshimi Esam, Hahn Eckhart Georg, Konturek Peter Christopher
First Department of Medicine, University Erlangen-Nuremberg, Erlangen, Germany.
Scand J Gastroenterol. 2007 Dec;42(12):1460-5. doi: 10.1080/00365520701452209.
OBJECTIVE: Barrett's esophagus (BE) is an acquired precancerous condition that develops from mucosal injury incurred after chronic gastroesophageal acid and bile reflux. The mechanism of progression of carcinogenesis in BE is still not fully understood. Recently, the role of bile acids and the homeobox gene transcription factor CDX-2 has been suggested in the pathogenesis of BE. The aims of the present study were 1) to compare the mRNA and protein expression of CDX-2 in biopsies obtained from patients with BE and normal squamous epithelium and 2) to study the effect of two different bile salts, ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA), on the mRNA expression of CDX-2 and vascular endothelial growth factor (VEGF) in Barrett's the adenocarcinoma cell line (OE-33). MATERIAL AND METHODS: CDX-2 expression was measured in Barrett's mucosa and normal esophageal mucosa obtained from 15 patients with BE histologically diagnosed by immunohistochemistry, Western blot, and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). In in vitro experiments, OE-33 cells were incubated with DCA (100 microM) and UDCA (100 microM) in neutral and shortly acidified media (pulse acidification). The expression of CDX-2 and VEGF was assessed by quantitative RT-PCR. RESULTS: Both mRNA and protein expression of CDX-2 were significantly up-regulated in Barrett's mucosa as compared to normal esophageal mucosa. In neutral medium, OE-33 cells showed an increase in CDX-2 expression after incubation with DCA or UDCA. After short acidification of the medium, expression of CDX-2 in OE-33 cells was significantly higher than that in cells incubated in neutral pH. The addition of DCA and UDCA did not cause any further alteration in CDX-2 expression. In neutral and acidified medium, VEGF mRNA expression was only significantly up-regulated by DCA, but not by UDCA. CONCLUSIONS: Bile acids, especially in acidic medium, increase expression of CDX-2. DCA appears to be a stronger stimulant of the expression of VEGF than UDCA in the Barrett's carcinoma cell line, indicating a stronger carcinogenic potential of this bile salt.
目的：巴雷特食管（BE）是一种后天性癌前病变，由慢性胃食管酸和胆汁反流引起的黏膜损伤发展而来。BE致癌进展的机制仍未完全明确。最近，胆汁酸和同源框基因转录因子CDX-2在BE发病机制中的作用已被提出。本研究的目的是：1）比较从BE患者和正常鳞状上皮患者获取的活检组织中CDX-2的mRNA和蛋白表达；2）研究两种不同的胆汁盐，熊去氧胆酸（UDCA）和脱氧胆酸（DCA），对巴雷特腺癌细胞系（OE-33）中CDX-2和血管内皮生长因子（VEGF）mRNA表达的影响。 材料与方法：通过免疫组织化学、蛋白质印迹和定量逆转录聚合酶链反应（RT-PCR），检测15例经组织学诊断为BE的患者的巴雷特黏膜和正常食管黏膜中CDX-2的表达。在体外实验中，将OE-33细胞在中性和短期酸化培养基（脉冲酸化）中与DCA（100微摩尔）和UDCA（100微摩尔）孵育。通过定量RT-PCR评估CDX-2和VEGF的表达。 结果：与正常食管黏膜相比，巴雷特黏膜中CDX-2的mRNA和蛋白表达均显著上调。在中性培养基中，OE-33细胞与DCA或UDCA孵育后，CDX-2表达增加。培养基短期酸化后，OE-33细胞中CDX-2的表达显著高于在中性pH下孵育的细胞。添加DCA和UDCA并未导致CDX-2表达的进一步改变。在中性和酸化培养基中，VEGF mRNA表达仅在DCA作用下显著上调，而UDCA无此作用。 结论：胆汁酸，尤其是在酸性介质中，可增加CDX-2的表达。在巴雷特癌细胞系中，DCA似乎比UDCA对VEGF表达的刺激更强，表明这种胆汁盐具有更强的致癌潜力。
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