SNHG16/miR-605-3p/TRAF6/NF-κB feedback loop regulates hepatocellular carcinoma metastasis
SNHG16/miR-605-3p/TRAF6/NF-κB feedback loop regulates hepatocellular carcinoma metastasis
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DOI：
10.1111/jcmm.15399
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发表时间：
2020-05-20
影响因子：
5.3
通讯作者：
Xue, Wan-Jiang
中科院分区：
文献类型：
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作者：
Hu, Yi-Lin;Feng, Ying;Xue, Wan-Jiang
miR-605- 3 p调控肝细胞癌（HCC）转移的机制尚未阐明。在这项研究中，我们发现miR-605- 3 p在HCC中下调，并且低miR-605- 3 p表达与肿瘤血栓和肿瘤卫星相关。低miR-605- 3 p表达的HCC患者手术后的总生存期和无病生存期较短。miR-605- 3 p过表达通过直接抑制TRAF 6的表达，通过NF-κ B B信号通路抑制HCC的上皮-间质转化和转移，而miR-605- 3 p沉默则具有相反的作用。我们还发现SNHG 16作为竞争性内源RNA直接结合miR-605- 3 p。SNHG 16的高表达促进了与miR-605- 3 p的结合并抑制了其活性，这导致TRAF 6的上调和NF-κ B通路的持续激活，进而促进了上皮-间质转化和HCC的转移。TRAF 6通过激活NF-κ B B增加SNHG 16启动子活性，从而促进SNHG 16的转录表达，形成加重HCC恶性程度的正反馈环。我们的研究结果揭示了SNHG 16/miR-605- 3 p/TRAF 6/NF-κ B反馈环在HCC中持续激活的机制，并为新的HCC治疗策略提供了潜在的靶点。
The mechanism by which miR-605-3p regulates hepatocellular carcinoma (HCC) metastasis has not been clarified. In this study, we found that miR-605-3p was down-regulated in HCC and that low miR-605-3p expression was associated with tumour thrombus and tumour satellites. HCC patients with low miR-605-3p expression showed shorter overall survival and disease-free survival after surgery. Overexpression of miR-605-3p inhibited epithelial-mesenchymal transition and metastasis of HCC through NF-kappa B signalling by directly inhibiting expression of TRAF6, while silencing of miR-605-3p had the opposite effect. We also found that SNHG16 directly bound to miR-605-3p as a competing endogenous RNA. Mechanistically, high expression of SNHG16 promoted binding to miR-605-3p and inhibited its activity, which led to up-regulation of TRAF6 and sustained activation of the NF-kappa B pathway, which in turn promoted epithelial-mesenchymal transition and metastasis of HCC. TRAF6 increased SNHG16 promoter activity by activating NF-kappa B, thereby promoting the transcriptional expression of SNHG16 and forming a positive feedback loop that aggravated HCC malignancy. Our findings reveal a mechanism for the sustained activation of the SNHG16/miR-605-3p/TRAF6/NF-kappa B feedback loop in HCC and provide a potential target for a new HCC treatment strategy.