Methylation-associated silencing of microRNA-129-3p promotes epithelial-mesenchymal transition, invasion and metastasis of hepatocelluar cancer by targeting Aurora-A.
Methylation-associated silencing of microRNA-129-3p promotes epithelial-mesenchymal transition, invasion and metastasis of hepatocelluar cancer by targeting Aurora-A.
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microRNA-129-3p 的甲基化相关沉默通过靶向 Aurora-A 促进肝细胞癌的上皮间质转化、侵袭和转移。
DOI：
10.18632/oncotarget.12870
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发表时间：
2016-11-22
期刊：
影响因子：
--
通讯作者：
Chen L
中科院分区：
文献类型：
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作者：
Cui S;Zhang K;Li C;Chen J;Pan Y;Feng B;Lu L;Zhu Z;Wang R;Chen L
转移复发已成为进一步提高肝细胞癌患者生存率的主要障碍之一。因此，阐明肝细胞癌转移的机制至关重要。本研究旨在探讨microRNA(MiR)-129-3p在肝癌转移中的作用及其可能的分子机制。通过芯片分析比较有无淋巴结转移的肝癌组织中miR-129-3p的表达水平，发现有淋巴结转移的肝癌组织中miR-129-3p的表达水平降低，这与其启动子甲基化有关，并与肿瘤转移、复发和预后不良有关。功能获得和功能丧失分析表明，miR-129-3p的重新表达可以逆转上皮-间充质转化，减少肝癌细胞的体外侵袭和体内转移。Aurora-A是一种丝氨酸/苏氨酸蛋白激酶，被认为是miR-129-3p的直接靶标。下调Aurora-A表型可观察miR-129-3p过表达对肝细胞癌转移的影响。此外，Aurora-A上调可部分挽救miR-129-3p的作用。我们进一步证明了PI3K/Akt和p38-MAPK信号通路的激活参与了miR-129-3p介导的肝细胞癌转移。这些结果表明，甲基化介导的miR-129-3p下调通过激活PI3K/Akt和p38-MAPK信号通路促进肝癌细胞的EMT、体外侵袭和体内转移，部分是通过靶向Aurora-A实现的。因此，miR-129-3p可能成为一种新的预测肝癌预后的生物标志物和潜在的治疗靶点。
Metastasis and recurrence has become one major obstacle for further improving the survival of hepatocelluar cancer (HCC) patients. Therefore, it is critical to elucidate the mechanisms involved in HCC metastasis. This study aimed to investigate the roles of microRNA (miR)-129-3p in HCC metastasis and its possible molecular mechanisms. By using microarray analysis to compare levels of different miRNAs in HCC tissues with or without lymph node metastasis (LNM), we showed that HCC tissues with LNM had reduced levels of miR-129-3p, which was related to its promoter hypermethylation and correlated with tumor metastasis, recurrence and poor prognosis. Gain - and loss - of - function assays indicated that re-expression of miR-129-3p could reverse epithelial-mesenchymal transition (EMT), and reduce in vitro invasion and in vivo metastasis of HCC cells. Aurora-A, a serine/threonine protein kinase, was identified as a direct target of miR-129-3p. Knockdown of Aurora-A phenocopied the effect of miR-129-3p overexpression on HCC metastasis. In addition, Aurora-A upregulation could partially rescue the effect of miR-129-3p. We further demonstrated that activation of PI3K/Akt and p38-MAPK signalings were involved in miR-129-3p-mediated HCC metastasis. These findings suggest that methylation-mediated miR-129-3p downregulation promotes EMT, in vitro invasion and in vivo metastasis of HCC cells via activation of PI3K/Akt and p38-MAPK signalings partially by targeting Aurora-A. Therefore, miR-129-3p may be a novel prognostic biomarker and potential therapeutic target for HCC.