miR-4458 inhibits the epithelial–mesenchymal transition of hepatocellular carcinoma cells by suppressing the TGF-β signaling pathway via targeting TGFBR1
miR-4458 inhibits the epithelial–mesenchymal transition of hepatocellular carcinoma cells by suppressing the TGF-β signaling pathway via targeting TGFBR1
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miR-4458 通过靶向 TGFBR1 抑制 TGF-β 信号通路，从而抑制肝细胞癌细胞的上皮-间质转化
DOI：
10.1093/abbs/gmaa029
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发表时间：
2020
影响因子：
3.7
通讯作者：
Zhongjun Wu
中科院分区：
文献类型：
--
作者：
Yuke Zhang;Kun Shi;Hang Liu;Wei Chen;Yunhai Luo;Xufu Wei;Zhongjun Wu
肝细胞癌（HCC）是世界上最致命的癌症之一。microRNA在各种癌症的进展中起着关键作用。迄今为止，对miR-4458的关注很少。因此，本研究的目的是探讨miR-4458在肝癌中的作用及其分子机制。我们发现miR-4458在HCC组织和细胞系中的表达降低。miR-4458的强制过表达抑制HCC细胞的迁移、侵袭和上皮-间质转化（EMT），而miR-4458的下调促进侵袭表型。此外，通过双荧光素酶报告基因分析，证实TGF-β信号通路的调节因子转化生长因子β受体1（TGF-β R 1）是miR-4458的新靶基因。上调的miR-4458显著消除了TGF-β 1和p-Smad 2/3的表达，从而阻断了TGF-β信号通路。此外，TGFBR 1的恢复部分挽救了miR-4458介导的对HCC细胞迁移、侵袭和EMT的抑制作用，并重新激活了HCC细胞中的TGF-β信号通路。总之，我们的研究结果首次证明了miR-4458通过直接靶向TGFBR 1调节TGF-β信号通路在HCC细胞迁移、侵袭和EMT中的机制。
Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. MicroRNAs play a pivotal role in the progression of various cancers. To date, very little attention has been paid to miR-4458. Therefore, the aim of our study was to explore the function and underlying molecular mechanism of miR-4458 in HCC. We found that the expression of miR-4458 was reduced in HCC tissues and cell lines. Forced overexpression of miR-4458 inhibited the migration, invasion, and epithelial–mesenchymal transition (EMT) of HCC cells, while downregulation of miR-4458 promoted the aggressive phenotype. Furthermore, transforming growth factor beta receptor 1 (TGFBR1), the modulator of the TGF-β signaling pathway, was verified to be a novel target gene of miR-4458 by dual-luciferase reporter gene assay. Upregulated miR-4458 dramatically abolished TGFBR1 and p-Smad2/3 expression, thus blocking the TGF-β signaling pathway. Moreover, restoration of TGFBR1 partially rescued the miR-4458-mediated suppressive effect on the migration, invasion, and EMT and reactivated the TGF-β signaling pathway in HCC cells. In summary, our findings first demonstrated a mechanism of miR-4458 in HCC cell migration, invasion, and EMT by regulating the TGF-β signaling pathway via directly targeting TGFBR1.