title: Methylation-associated silencing of microRNA-129-3p promotes epithelial-mesenchymal transition, invasion and metastasis of hepatocelluar cancer by targeting Aurora-A.
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.
authors: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, PR China.
authors: Shiyun
authors: S
authors: Cui
authors: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, PR China.
authors: Kai
authors: K
authors: Zhang
authors: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, PR China.
authors: Chen
authors: C
authors: Li
authors: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, PR China.
authors: Jing
authors: J
authors: Chen
authors: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, PR China.
authors: Yan
authors: Y
authors: Pan
authors: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, PR China.
authors: Bing
authors: B
authors: Feng
authors: Liver Disease Center of PLA, The 81th Hospital of PLA, Nanjing 210002, Jiangsu, PR China.
authors: Lei
authors: L
authors: Lu
authors: Department of Hepatobiliary Surgery, First Hospital Affiliated to the Chinese PLA General Hospital, Haidian District, Beijing 100048, PR China.
authors: Ziman
authors: Z
authors: Zhu
authors: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, PR China.
authors: Rui
authors: R
authors: Wang
authors: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, Jiangsu, PR China.
authors: Longbang
authors: L
authors: Chen
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis
chemical_list: D035683:MicroRNAs; C541915:Mirn129 microRNA, human; D019869:Phosphatidylinositol 3-Kinases; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: Aurora-A; epithelial-mesenchymal transition; hepatocelluar cancer; metastasis; miR-129-3p