Oncotarget

Research Papers:

Methylation-associated silencing of microRNA-129-3p promotes epithelial-mesenchymal transition, invasion and metastasis of hepatocelluar cancer by targeting Aurora-A

Shiyun Cui, Kai Zhang, Chen Li, Jing Chen, Yan Pan, Bing Feng, Lei Lu, Ziman Zhu, Rui Wang _ and Longbang Chen

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Oncotarget. 2016; 7:78009-78028. https://doi.org/10.18632/oncotarget.12870

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Abstract

Shiyun Cui1,*, Kai Zhang1,*, Chen Li1, Jing Chen1, Yan Pan1, Bing Feng1, Lei Lu2, Ziman Zhu3, Rui Wang1, Longbang Chen1

1Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, PR China

2Liver Disease Center of PLA, The 81th Hospital of PLA, Nanjing 210002, Jiangsu, PR China

3Department of Hepatobiliary Surgery, First Hospital Affiliated to the Chinese PLA General Hospital, Haidian District, Beijing 100048, PR China

*These authors have contributed equally to this work

Correspondence to:

Rui Wang, email: [email protected]

Longbang Chen, email: [email protected]

Keywords: hepatocelluar cancer, miR-129-3p, Aurora-A, epithelial-mesenchymal transition, metastasis

Received: July 26, 2016    Accepted: October 14, 2016    Published: October 25, 2016

ABSTRACT

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.


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