State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Cell Death Dis. 2017 Oct 12;8(10):e3101. doi: 10.1038/cddis.2017.493.
Metastasis is a major clinical obstacle responsible for the high mortality and poor prognosis of gastric cancer (GC). MicroRNAs (miRNAs) are critical mediators of metastasis that act by modulating their target genes. In this study, we found that miR-143 and miR-145 act via a common target gene, MYO6, to regulate the epithelial-mesenchymal transition (EMT) and inhibit metastasis. We determined that miR-143 and miR-145 were downregulated in GC, and the ectopic expression of miR-143 and/or miR-145 inhibited GC cell migration and metastasis. Furthermore, MYO6 was identified as a direct common target of miR-143 and miR-145 and was elevated in GC. Silencing of MYO6 resulted in a metastasis-suppressive activity similar to that of miR-143 and miR-145, while restoring MYO6 attenuated the anti-metastatic or anti-EMT effects caused by miR-143 and miR-145. Clinically, an inverse correlation was observed between miR-143/145 levels and MYO6 levels in GC tissues, and either miR-143/145 downregulation or MYO6 upregulation was associated with more malignant phenotypes in patients with GC. In conclusion, miR-143 and miR-145 suppress GC cell migration and metastasis by inhibiting MYO6 expression and the EMT, which provides a novel mechanism and promising therapeutic target for the treatment of GC metastasis.
转移是导致胃癌（GC）高死亡率和预后不良的主要临床障碍。miRNAs（miRNAs）是转移的关键介质，通过调节其靶基因发挥作用。在这项研究中，我们发现 miR-143 和 miR-145 通过共同的靶基因 MYO6 发挥作用，调节上皮-间充质转化（EMT）并抑制转移。我们确定 miR-143 和 miR-145 在 GC 中下调，miR-143 和/或 miR-145 的异位表达抑制 GC 细胞迁移和转移。此外，MYO6 被鉴定为 miR-143 和 miR-145 的直接共同靶基因，在 GC 中上调。沉默 MYO6 导致类似于 miR-143 和 miR-145 的转移抑制活性，而恢复 MYO6 则减弱了 miR-143 和 miR-145 引起的抗转移或抗 EMT 作用。临床上，在 GC 组织中观察到 miR-143/145 水平与 MYO6 水平之间存在反相关，miR-143/145 的下调或 MYO6 的上调与 GC 患者更恶性的表型相关。总之，miR-143 和 miR-145 通过抑制 MYO6 表达和 EMT 抑制 GC 细胞迁移和转移，为 GC 转移的治疗提供了新的机制和有前途的治疗靶点。
