Inhibition of SOX17 by MicroRNA 141 and Methylation Activates the WNT Signaling Pathway in Esophageal Cancer
Inhibition of SOX17 by MicroRNA 141 and Methylation Activates the WNT Signaling Pathway in Esophageal Cancer
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DOI：
10.1016/j.jmoldx.2012.06.004
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发表时间：
2012-11-01
影响因子：
4.1
通讯作者：
Guo, Mingzhou
中科院分区：
文献类型：
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作者：
Jia, Yan;Yang, Yunsheng;Guo, Mingzhou
本研究旨在探讨SOX 17基因启动子区甲基化作为食管癌检测标志物的可能性、SOX 17基因表达的调控以及SOX 17在食管癌WNT信号通路中的作用。包括8个食管癌细胞系、9个正常食管粘膜样品、60个不典型增生病例和169个癌组织样品。采用甲基化特异性PCR、半定量逆转录PCR、免疫组化、荧光素酶报告基因分析、克隆形成和Western blot分析等方法分析SOX 17在食管癌中的甲基化和功能。进行microRNA相关检测方法以评估microRNA对SOX 17的调控。SOX 17甲基化在正常粘膜中为0%，1级异型增生为39%，wades 2和3级异型增生为48%，原发性癌为65%，呈进展趋势。SOX 17甲基化与食管癌患者的饮酒史有关，并可能诱导β-连环蛋白的表达和再分布。SOX 17表达的缺失与启动子区域的高甲基化相关，并且在食管癌细胞系中通过5-氮杂-2 '-脱氧胞苷处理激活了重新表达。S 0X 17表达的恢复抑制TCF/β-连环蛋白依赖性转录和集落形成。MicroRNA 141还被发现下调SOX 17的表达并激活WNT信号通路。SOX 17在食管癌中频繁甲基化，并在食管癌发生过程中有进展趋势。S 0X 17的缺失消除了WNT信号传导的正常抑制并促进食管肿瘤发生。（J Mol Diagn 2012，14：577585; http：//dx.doLorg/10.1016/j.jmoldx.2012.06.004）
In this study, we explored the possibility of SOX17 promoter region methylation as an esophageal cancer detection marker, the regulation of SOX17 expression, and the function of SOX17 in the WNT signaling pathway in esophageal cancer. Eight esophageal cancer cell lines, 9 normal esophageal mucosa samples, 60 cases of dysplasia, and 169 cancer tissue samples were included. Methylation-specific PCR, semiquantitative reverse transcription PCR, immunohistochemistry, luciferase reporter assay, colony formation, and Western blot analysis were used to analyze methylation and function of SOX17 in esophageal cancer. MicroRNA-related detection methods were performed to evaluate microRNA regulation of SOX17. SOX17 methylation was found in progression tendency with 0% of normal mucosa, 39% of grade 1 dysplasia, 48% of wades 2 and 3 dysplasia, and 65% of primary cancer. SOX17 methylation is related to esophageal cancer patients' history of alcohol use and may induce beta-catenin expression and redistribution. Loss of SOX17 expression is correlated to promoter region hypermethylation, and re-expression was activated by 5-aza-2'-deoxycytidine treatment in esophageal cancer cell lines. Restoration of SOX17 expression suppresses TCF/beta-catenin dependent transcription and colony formation. MicroRNA 141 was also found to down-regulate SOX17 expression and activate the WNT signal pathway. SOX17 is frequently methylated in esophageal cancer and in a progression tendency during esophageal carcinogenesis. Loss of SOX17 removes the normal inhibition of WNT signaling and promotes esophageal tumorigenesis. (J Mol Diagn 2012, 14:577585; http://dx.doLorg/10.1016/j.jmoldx.2012.06.004)