miR-137 regulates epithelial-mesenchymal transition in gastrointestinal stromal tumor
miR-137 regulates epithelial-mesenchymal transition in gastrointestinal stromal tumor
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DOI：
10.1007/s13277-014-2177-5
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发表时间：
2014-09-01
期刊：
影响因子：
--
通讯作者：
Wan, Guohui
中科院分区：
文献类型：
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作者：
Liu, Sheng;Cui, Juan;Wan, Guohui
上皮细胞向间质细胞转化（EMT）的激活赋予癌细胞非凡的侵袭能力，并且是胃肠道间质瘤（GIST）治疗失败和转移的原因;然而，控制GIST侵袭的分子机制在很大程度上仍不清楚。microRNAs（miRNAs）在细胞运动和侵袭中发挥重要作用，这促使我们研究miR-137在GIST EMT中的生物学功能。我们发现miR-137在GIST的临床标本中显著下调。使用计算机分析方法，Twist 1，EMT的关键调节基因，已被确定为miR-137的靶点。采用RT-PCT和Western blot方法检测miR-137对人胃肠道间质瘤GIST-H1细胞系Twist 1的作用。此外，发现miR-137增加E-钙粘蛋白和细胞角蛋白的表达，但抑制N-钙粘蛋白和波形蛋白的表达。体外实验表明，miR-137可增强上皮细胞形态，减少GIST细胞迁移，激活G1期细胞阻滞，诱导细胞凋亡。这些结果提示了miR-137通过下调Twist 1来调节EMT并抑制细胞迁移的新机制。因此，miR-137可能在GIST中起抗迁移和抗转移的作用，我们的研究为开发基于miR-137的GIST治疗策略提供了潜在的方法。
Activation of the epithelial-to-mesenchymal transition (EMT) endows extraordinary invasive capability of cancer cells and causes of treatment failure and metastasis in gastrointestinal stromal tumor (GIST); however, the molecular mechanisms governing GIST invasion remain largely unknown. MicroRNAs (miRNAs) have been shown to play critical roles in cell motility and invasion, which promotes us to study the biological functions of miR-137 in the EMT of GIST. We have found that miR-137 was dramatically downregulated in clinical specimen of GIST. Using an in silico analysis approach, Twist1, a key regulator gene of EMT, has been identified as the target of miR-137. Quantitative RT-PCT and western blot were used to confirm that miR-137 directly targeted on Twist1 and repressed Twist1 expression in GIST-H1 human gastrointestinal stromal tumor cell line. Further, miR-137 was found to increase expression of E-cadherin and cytokeratin, but suppress expression of N-cadherin and vimentin. In vitro experiments have shown that miR-137 enhanced the epithelial cell morphology, decreased GIST cell migration, activated G1 cell cycle arrest, and induced cell apoptosis. These results suggest a novel mechanism that miR-137 regulates EMT and inhibits cell migration via Twist1 downregulation. Therefore, miR-137 may function as anti-migration and anti-metastasis in GIST and our study provides a potential approach for developing miR-137-based therapeutic strategy for GIST.