Department of Head and Neck Surgery, the Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, China.
Cell Death Dis. 2019 Feb 27;10(3):195. doi: 10.1038/s41419-019-1444-1.
The incidence of papillary thyroid cancer (PTC) has been rapidly increasing in recent years. PTC is prone to lymph node metastasization, which further increases the recurrence rate and mortality of thyroid cancer. However, the underlying mechanisms of this process remain elusive. Several reports have shown that the microRNA miR-215 plays an important role in cancer metastasis. Here, we investigated, for the first time, the potential association between miR-215 and metastasis in PTC. The results of qPCR analysis demonstrated that miR-215 was downregulated in PTC cell lines and tissues, and lower levels of miR-215 correlated with lymph node metastasis of PTC. In vitro and in vivo assays revealed that restoration of miR-215 dramatically inhibited PTC cell proliferation and metastasis. We identified ADP ribosylation factor guanine nucleotide-exchange factor 1 (ARFGEF1) as the target, which mediated the function of miR-215. The expression of ARFGEF1 was inhibited by miR-215, and the effects of miR-215 were abrogated by re-expression of ARFGEF1. Moreover, we found that miR-215 suppressed PTC metastasis by modulating the epithelial-mesenchymal transition via the AKT/GSK-3β/Snail signaling. In summary, our study proves that miR-215 inhibits PTC proliferation and metastasis by targeting ARFGEF1 and indicates miR-215 as a biomarker for PTC prognosis.
近年来，甲状腺乳头状癌（PTC）的发病率迅速上升。PTC 易发生淋巴结转移，这进一步增加了甲状腺癌的复发率和死亡率。然而，这一过程的潜在机制仍不清楚。有几项报道表明，microRNA miR-215 在癌症转移中发挥重要作用。在这里，我们首次研究了 miR-215 与 PTC 转移之间的潜在关联。qPCR 分析结果表明，miR-215 在 PTC 细胞系和组织中下调，并且 miR-215 水平较低与 PTC 的淋巴结转移相关。体外和体内实验表明，恢复 miR-215 可显著抑制 PTC 细胞的增殖和转移。我们确定 ADP 核糖基化因子鸟嘌呤核苷酸交换因子 1（ARFGEF1）为靶标，该靶标介导了 miR-215 的功能。miR-215 抑制了 ARFGEF1 的表达，而 ARFGEF1 的再表达则消除了 miR-215 的作用。此外，我们发现 miR-215 通过调节 AKT/GSK-3β/Snail 信号通路抑制 EMT 来抑制 PTC 的转移。总之，我们的研究证明 miR-215 通过靶向 ARFGEF1 抑制 PTC 的增殖和转移，并表明 miR-215 可作为 PTC 预后的标志物。
