MiR-425-5p promotes invasion and metastasis of hepatocellular carcinoma cells through SCAI-mediated dysregulation of multiple signaling pathways.
MiR-425-5p promotes invasion and metastasis of hepatocellular carcinoma cells through SCAI-mediated dysregulation of multiple signaling pathways.
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MiR-425-5p通过SCAI介导的多信号通路失调促进肝细胞癌细胞的侵袭和转移
DOI：
10.18632/oncotarget.15958
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发表时间：
2017-05-09
期刊：
影响因子：
--
通讯作者：
Xiong Q
中科院分区：
文献类型：
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作者：
Fang F;Song T;Zhang T;Cui Y;Zhang G;Xiong Q
微小RNA（miRNAs）在肝细胞癌（HCC）的进展中起着关键作用，并且是预后的关键决定因素。在这项研究中，我们发现miR-425- 5 p在HCC中升高，并与预后不良的临床病理特征和术后长期生存率低相关。多因素生存分析表明miR-425- 5 p表达是影响总生存期和无病生存期的独立危险因素。有趣的是，miR-425- 5 p在体外促进HCC细胞的侵袭和转移，但不促进HCC细胞的增殖或凋亡。SCAI和PTEN被确定为miR-425- 5 p的下游靶标。miR-425- 5 p介导的作用被SCAI的异位表达抑制，并且PTEN表现出较小的抑制作用。SCAI还抑制PTEN表达。此外，miR-425- 5 p促进上皮向间充质转化（EMT），这被SCAI拮抗。miR-425- 5 p还通过SCAI介导的整合素β1-Fak/Src-RhoA/CDC 42、PTEN-AKT和TIMP 2-MMP 2/MMP 9信号转导的失调促进HCC细胞侵袭和转移。最后，miR-425- 5 p在HCC的异种移植小鼠模型中促进转移。这些结果表明，miR-425- 5 p通过SCAI介导的多种信号通路的失调促进EMT和细胞外基质降解并促进HCC转移。因此，miR-425- 5 p是HCC中潜在的预后生物标志物和新的治疗靶点。
MicroRNAs (miRNAs) play critical roles in hepatocellular carcinoma (HCC) progression and are key determinants of prognosis. In this study, we found that miR-425-5p was elevated in HCC and correlated with poor prognostic clinicopathological features and low post-operative long-term survival. Multivariate survival analysis indicated that miR-425-5p expression was an independent risk factor for overall and disease-free survival. Interestingly, miR-425-5p promoted invasion and metastasis by HCC cells, but not HCC cell proliferation or apoptosis in vitro. SCAI and PTEN were determined to be downstream targets of miR-425-5p. miR-425-5p-mediated effects were inhibited by ectopic expression of SCAI, and PTEN exhibited a smaller inhibitory effect. SCAI also suppressed PTEN expression. In addition, miR-425-5p promoted epithelial-to-mesenchymal transition (EMT), which was antagonized by SCAI. miR-425-5p also promoted HCC cell invasion and metastasis via SCAI-mediated dysregulation of integrin β1-Fak/Src-RhoA/CDC42, PTEN-AKT, and TIMP2-MMP2/MMP9 signaling. Finally, miR-425-5p promoted metastasis in a xenograft mouse model of HCC. These results indicate that miR-425-5p facilitates EMT and extracellular matrix degradation and promotes HCC metastasis through SCAI-mediated dysregulation of multiple signaling pathways. MiR-425-5p is therefore a potential prognostic biomarker and novel therapeutic target in HCC.