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首页> 外文期刊>Molecular and Cellular Biology >Downregulation of Thrombomodulin, a Novel Target of Snail, Induces Tumorigenesis through Epithelial-Mesenchymal Transition
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Downregulation of Thrombomodulin, a Novel Target of Snail, Induces Tumorigenesis through Epithelial-Mesenchymal Transition

机译：血栓调节蛋白的下调，一种新的蜗牛靶标，通过上皮-间质转化诱导肿瘤发生。

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The expression of thrombomodulin (TM), a calcium-dependent adhesion molecule, is frequently downregulated in various cancer types. However, the mechanism responsible for the low expression level of TM in tumorigenesis is unknown. Here, an inverse expression of TM and Snail was detected in different cancer cell lines. We further confirmed this inverse relation using the epithelial-mesenchymal transition cell model in HaCaT and A431 cells. We demonstrated that Snail suppressed TM expression by binding to E-box (CACCTG) in TM promoter. Moreover, TM knockdown by short hairpin RNA disrupted E-cadherin-mediated cell junctions and contributed to tumorigenesis. In the calcium switch assay, E-cadherin lost the ability to associate with β-catenin and accumulated in cytoplasm in TM knockdown cells. Meanwhile, wound healing and invasive assays showed that TM knockdown promoted cell motility. A subcutaneous injection of TM knockdown transfectants into immunocompromised mice induced squamous cell carcinoma-like tumors. Besides, forced expression of murine TM in TM knockdown cells made the cells reassume epithelium-like morphology and increased calcium-dependent association of E-cadherin and β-catenin. In conclusion, TM, a novel downstream target of Snail in epithelial-mesenchymal transition, is required for maintaining epithelial morphology and functions as a tumor suppressor.
机译：血栓调节蛋白（TM）（一种钙依赖性粘附分子）的表达在各种癌症类型中经常被下调。然而，导致肿瘤发生中TM低表达水平的机制尚不清楚。在此，在不同的癌细胞系中检测到TM和Snail的逆表达。我们在HaCaT和A431细胞中使用上皮-间质转化细胞模型进一步证实了这种反比关系。我们证明Snail通过与TM启动子中的E-box（CACCTG）结合来抑制TM表达。此外，短发夹RNA的TM敲低破坏了E-钙粘蛋白介导的细胞连接并促进了肿瘤的发生。在钙转换试验中，E-钙粘着蛋白失去了与β-catenin结合的能力，并累积在TM敲低细胞的细胞质中。同时，伤口愈合和侵袭性试验表明，TM抑制可促进细胞运动。向免疫功能低下的小鼠皮下注射TM组合转染子会诱发鳞状细胞癌样肿瘤。此外，鼠TM在TM敲除细胞中的强制表达使细胞恢复了上皮样形态并增强了钙依赖性钙黏着蛋白和β-连环蛋白的结合。总之，TM是Snail在上皮-间充质转化中的新型下游靶标，是维持上皮形态和发挥抑癌作用所必需的。

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