Role of miR-200c/miR-141 in the regulation of epithelial-mesenchymal transition and migration in head and neck squamous cell carcinoma
Role of miR-200c/miR-141 in the regulation of epithelial-mesenchymal transition and migration in head and neck squamous cell carcinoma
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DOI：
10.3892/ijmm.2014.1625
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发表时间：
2014-04-01
影响因子：
5.4
通讯作者：
Yamanaka, Noboru
中科院分区：
文献类型：
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作者：
Tamagawa, Shunji;Beder, Levent Bekir;Yamanaka, Noboru
上皮间质转化（Epithelial-mesenchymal-transition，EMT）是肿瘤侵袭和转移的关键步骤，其命运主要由miR-200家族和ZEB转录因子的平衡表达决定。在这项研究中，我们观察到miR-200 c/mir-141和ZEB 1之间的相互关系，以及ZEB 2和E-cadherin在一组13个头颈部鳞状细胞癌（HNSCC）细胞系中的表达。我们还证实了miR-200 c和miR-141的强制表达显著降低了HNSCC细胞的迁移能力。因此，miR-200 c和mir-141的强制表达导致E-钙粘蛋白表达的显著上调，与3种细胞系（UTSCC-24 A、UTSCC-24 B和UTSCC-6A细胞）中ZEB 1表达的显著下调相反。另一对细胞系UTSCC-60 A和UTSCC-60 B在miR-200 c/miR-141的强制表达期间未能显示E-钙粘蛋白或ZEB 1/ZEB 2表达的显著变化。为了解决这个问题，我们集中在ZEB 1/2启动子的超甲基化状态，这两个都被证明包括广泛的CpG岛。我们观察到在两对UTSCC细胞系中用去甲基化剂处理后，ZEB 1和ZEB 2 mRNA表达显著上调。总之，我们的研究结果证实了miR-200家族和ZEB家族之间存在相互关系，并证明了miR-200家族在EMT中的作用，以及在HNSCC细胞的迁移和侵袭能力中的作用。此外，我们的数据表明，ZEB 1和ZEB 2的启动子超甲基化可能发挥重要作用，并可能掩盖了miR-200家族在癌变过程中调节EMT的作用。
Epithelial-mesenchymal-transition (EMT) is a critical step in tumor invasion and metastasis, while its fate is mainly defined by the balanced expression between the miR-200 family and ZEB transcription factors. In this study, we observed a reciprocal correlation between miR-200c/mir-141 and ZEB1, as well as between ZEB2 and E-cadherin expression in a panel of 13 head and neck squamous cell carcinoma (HNSCC) cell lines. We also confirmed that the enforced expression of miR-200c and miR-141 significantly reduced the migration capacity of HNSCC cells. Accordingly, the enforced expression of miR-200c and mir-141 resulted in a significant upregulation in E-cadherin expression, contrary to the significant downregulation in ZEB1 expression in 3 cell lines (UTSCC-24A, UTSCC-24B and UTSCC-6A cells). Another pair of cell lines, UTSCC-60A and UTSCC- 60B failed to show a significant change in the expression of E-cadherin or ZEB1/ZEB2 during the enforced expression of miR-200c/miR-141. To address the issue, we focused on the hypermethylation status of the ZEB1/2 promoters, which have both been shown to include wide CpG islands. We observed a marked upregulation in both ZEB1 and ZEB2 mRNA expression following treatment with a demethylating agent in both pairs of UTSCC cell lines. In conclusion, our findings confirm the existence of a reciprocal correlation between the mir-200 family and the ZEB family, and demonstrate the role of the miR-200 family in EMT, as well as in the migration and invasion ability of HNSCC cells. Furthermore, our data suggest that the promoter hypermethylation of ZEB1 and ZEB2 may play an essential role and may overshadow the effects of the miR-200 family in the regulation of EMT during carcinogenesis.