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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.

SUBMITTER: Cui S

PROVIDER: S-EPMC5363640 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Cui Shiyun S Zhang Kai K Li Chen C Chen Jing J Pan Yan Y Feng Bing B Lu Lei L Zhu Ziman Z Wang Rui R Chen Longbang L

Oncotarget 20161101 47

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 ...[more]

PMID: 27793005

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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent common cancer worldwide with high mortality. Transforming growth factor-β (TGF-β) signaling pathway was reported dysregulated during liver cancer formation and progression. As a key component of TGF-β signaling, the role of SMAD2 and its regulatory mechanisms in HCC remain unclear.MethodsSMAD2 expression in paired HCC specimens were determined by western blot and immunohistochemistry (IHC). quantitative real-time PCR (qRT-PCR) was used to measure mRNA and microRNA (miRNA) expression level. Cell migration, invasion and proliferation ability were evaluated by transwell, CCK8 and EdU assay. In silico websites were used to manifest overall survival rates of HCC patients or to predict miRNAs targeting SMAD2. Dual luciferase reporter assay and anti-Ago2 immunoprecipitation assay were performed to confirm the binding between SMAD2 mRNA and miRNA-148a-3p (miR-148a). Tumorigenesis and lung metastasis mouse model were used to explore the role of miR-148a in vivo. In situ hybridization (ISH) was conducted to determine the expression of miR-148a in liver tissues.ResultsIn this study, we found that SMAD2 was highly expressed in HCC and elevated SMAD2 expression predicted shorter overall survival (OS) time for HCC patients. SMAD2 promoted mobility and proliferation of HCC cells in vitro. We further revealed that the expression of miR-148a was negatively correlated with SMAD2 and found that miR-148a repressed SMAD2 expression by downregulating its mRNA through binding with Argonaute 2 (Ago2) in HCC. Transwell, CCK8 and animal experiments exhibited miR-148a inhibited metastasis and proliferation of HCC in vitro and in vivo. Moreover, the phenotype changes caused by miR-148a manipulation were recovered by rescuing SMAD2 expression in HCC cells. ISH assay indicated miR-148a was downregulated in HCC and low expression of miR-148a associated with more aggressive clinic features and poor prognosis.ConclusionmiR-148a was identified as a repressor of HCC progression by downregulating SMAD2 in an Ago2 dependent manner.

Project description:MicroRNAs (miRNAs) are small non-coding RNAs that function as endogenous silencers of target genes, previous studies have shown that miR-335 play an important role in suppressing metastasis and migration in human cancer including gastric cancer (GC). However, the mechanisms which result in aberrant expression of miR-335 in GC are still unknown. Recent studies have shown that the silencing of some miRNAs is associated with DNA hypermethylation. In this study, we find the promoter of miR-335 we embedded in CpG island by accessing to bioinformatics data and the low expression of miR-335 in 5 gastric cell lines can be restored by 5-aza-2'-deoxycytidine (5-Aza-dC) treatment. So we postulated that the miR-335 genes undergo epigenetic inactivation in GC. Subsequently, in GC cells and tissues, we performed quantitative real-time PCR (RTQ-PCR) to assess the expression of miR-335, and methylation-specific PCR (MSP) and bisulfite sequence-PCR (BSP) to evaluate the DNA methylation status in the CpG islands upstream of MiR-335. The result showed that the expression of miR-335 was significantly reduce in gastric cancer cell lines and tumor tissues compared to matched normal gastric tissues, and cell lines, and which is inverse correlation with DNA hypermethylation of miR-335 both in GC cells lines and tissues, but not in normal tissues. In addition, we found that the lower miR-335 expression induced by abnormal methylation may be mainly involved in gastric cell invasion and metastasis in GC tissues. No statistical significance was found about miR-335 expression and methylation level between healthy individuals with and without H. pylori (HP) infection. Finally, we carry out miRNA transfection, RTQ-PCR and western blot assay to find the RAS p21 protein activator (GTPase activating protein) 1 (RASA1) may be the possible target genes which lead to the gastric cell invasion and metastasis, furthermore, the re-expression of endogenous miR-335 by 5-Aza-dC treatment can exert effects similar to exogenous miRNAs transfection. Taken together, our results suggest that miR-335 may be silenced by promoter hypermethylation and play important roles in gastric cell invasion and metastasis through its target genes, such as RASA1. Its methylation level might be a predictive epigenetic marker of GC and remodeling on the expression by demethylation can provided a potential therapeutic strategy.

Dataset Information

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

Publications

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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