Milano Francesca, van Baal Jantine W P M, Buttar Navtej S, Rygiel Agnieszka M, de Kort Floor, DeMars Cathrine J, Rosmolen Wilda D, Bergman Jacques J G H M, VAn Marle Jan, Wang Kenneth K, Peppelenbosch Maikel P, Krishnadath Kausilia K
Laboratory of Experimental Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
Gastroenterology. 2007 Jun;132(7):2412-21. doi: 10.1053/j.gastro.2007.03.026. Epub 2007 Mar 19.
BACKGROUND & AIMS: Barrett's esophagus (BE) is a metaplastic condition in which normal squamous esophageal epithelium is replaced by columnar epithelium. It is proposed that one of the possible mechanisms is dedifferentiation of squamous epithelium into columnar epithelium. The pathophysiology through which this metaplasia occurs is unknown. A recent study by serial analysis of gene expression showed that bone morphogenetic protein 4 (BMP-4) is uniquely expressed in BE. In this study, the role of the BMP pathway in the metaplastic transformation of normal squamous cells into columnar cells was examined.
Tissues from patients with esophagitis and BE and in an esophagitis-BE rat model were examined for the activation of the BMP pathway. Short-term cultures of primary normal squamous esophageal cells were treated with BMP-4, and cell biological changes were examined by Western blot analysis, immunohistochemistry, and microarrays.
In both human and rat tissues, the BMP pathway proved to be activated in esophagitis and BE. Upon incubation of squamous cell cultures with BMP-4, the cytokeratin expression pattern showed a shift that was consistent with columnar epithelium. Involvement of the BMP pathway was suggested by up-regulation of Phosphorylated-Smad 1/5/8 (P-Smad 1/5/8) that was effectively blocked by Noggin, a BMP antagonist. Comparison of the gene expression profiles of squamous cells, BMP-4-treated squamous cells, and BE cells showed a significant shift in the profile of the BMP-4-treated squamous cells toward that of the cultured BE cells.
These results suggest that the BMP pathway could play a role in the transformation of normal esophageal squamous cells into columnar cells.
巴雷特食管（BE）是一种化生状态，其中正常的鳞状食管上皮被柱状上皮取代。有人提出，一种可能的机制是鳞状上皮逆分化为柱状上皮。这种化生发生的病理生理学尚不清楚。最近一项通过基因表达序列分析的研究表明，骨形态发生蛋白4（BMP - 4）在BE中独特表达。在本研究中，检测了BMP信号通路在正常鳞状细胞向柱状细胞化生转化中的作用。
对食管炎和BE患者的组织以及食管炎 - BE大鼠模型进行BMP信号通路激活情况检测。用BMP - 4处理原代正常鳞状食管细胞的短期培养物，并通过蛋白质印迹分析、免疫组织化学和微阵列检测细胞生物学变化。
在人和大鼠组织中，BMP信号通路在食管炎和BE中均被激活。用BMP - 4孵育鳞状细胞培养物后，细胞角蛋白表达模式发生改变，与柱状上皮一致。磷酸化Smad 1/5/8（P - Smad 1/5/8）上调提示BMP信号通路参与其中，而BMP拮抗剂Noggin可有效阻断这种上调。鳞状细胞、经BMP - 4处理的鳞状细胞和BE细胞的基因表达谱比较显示，经BMP - 4处理的鳞状细胞的表达谱向培养的BE细胞的表达谱发生了显著转变。
这些结果表明，BMP信号通路可能在正常食管鳞状细胞向柱状细胞转化中起作用。
