Graduate Training Program in Cellular and Molecular Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Gastroenterology. 2010 May;138(5):1810-22. doi: 10.1053/j.gastro.2010.01.048. Epub 2010 Feb 4.
BACKGROUND & AIMS: The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium.
Immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice.
Marked up-regulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of Deleted in Malignant Brain Tumors 1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9, and columnar cytokeratins.
Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype.
巴雷特食管中上皮细胞化生的分子机制尚不清楚。我们认识到 Hedgehog 信号通路在食管早期发育中是必需的，因此，我们试图确定 Hedgehog 通路是否在巴雷特食管中被重新激活，以及该通路下游的基因是否可以促进食管上皮的柱状分化。
采用免疫组织化学、免疫荧光和实时定量聚合酶链反应分析临床标本、人食管细胞系和小鼠食管。对人食管鳞状上皮（HET-1A）和腺癌细胞（OE33）进行酸处理，并进行转染实验。使用胆汁反流损伤的外科手术模型的瑞士 Webster 小鼠。利用 Sonic hedgehog 转基因小鼠的食管上皮，创建体内移植培养系统。
Hedgehog 配体表达的显著上调经常发生在巴雷特食管中，可由酸或胆汁暴露诱导，与 Hedgehog 靶基因 PTCH1 和 BMP4 的基质表达相关。BMP4 信号诱导肠隐窝转录因子 Sox9 的表达，Sox9 在巴雷特上皮中高度表达。我们进一步表明，人类同源物 Hensin 的柱状细胞因子 Deleted in Malignant Brain Tumors 1 的表达发生在巴雷特上皮中，并由 Sox9 诱导。最后，Sonic hedgehog 在小鼠食管上皮中的转基因表达诱导基质 Bmp4、上皮 Sox9 和柱状细胞角蛋白的表达。
上皮 Hedgehog 配体的表达可能通过诱导基质 BMP4 来促进巴雷特食管的发生，从而促使食管上皮向柱状表型重编程。
