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MiR-204-5p suppresses hepatocellular cancer proliferation by regulating homeoprotein SIX1 expression.

ABSTRACT: Fewer than 30% of patients with hepatocellular carcinoma (HCC) are eligible to receive curative therapies, and so a better understanding of the molecular mechanisms of HCC is needed to identify potential therapeutic targets. The role of microRNA (miRNA) in modulating tumour progression has been demonstrated, and therapies targeting miRNA appear promising. miR-204-5p has been shown to function in numerous types of cancer, but its role in HCC remains unclear. In this study, we found that miR-204-5p expression was downregulated in cancerous HCC tissues compared to nontumour tissues. Kaplan-Meier survival curve analysis also showed that low expression of miR-204-5p predicted worse outcomes of HCC patients. In addition, miR-204-5p expression was significantly lower in HCC cell lines. The function of miR-204-5p was also assessed both in vitro and in vivo. We demonstrated that ectopic expression of miR-204-5p in HCC cell lines inhibited HCC cell proliferation and clonogenicity using CCK8, BrdU and colony-forming assays, while the inhibition of miR-204-5p enhanced proliferation and clonogenicity. Further in vivo studies in mice further confirmed the proliferation capacity of miR-204-5p. We also identified sine oculis homeobox homologue 1 (SIX1) as a direct target of miR-204-5p and showed that it was inversely correlated with miR-204-5p in both human and mouse HCC tissues. Transfection of miR-204-5p mimics in BEL-7404 cells blocked the cell cycle by inhibiting the expression of cyclin-D1 and cyclin-A1, cell cycle-related factors regulated by SIX1. More importantly, overexpression of the 3'UTR mutant SIX1 but not the wild-type SIX1 abolished the suppressive effect of miR-204-5p, and downregulated SIX1 in BEL-7402 cells that transfected with miR-204 inhibitors could partly block the inhibitory effect of miR-204-5p on proliferation. Thus, we have demonstrated that miR-204-5p suppresses HCC proliferation by directly regulating SIX1 and its downstream factors.

SUBMITTER: Chu Y

PROVIDER: S-EPMC5794460 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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miR-204-5p suppresses hepatocellular cancer proliferation by regulating homeoprotein SIX1 expression.

Chu Yi Y Jiang Mingzuo M Du Feng F Chen Di D Ye Tao T Xu Bing B Li Xiaowei X Wang Weijie W Qiu Zhaoyan Z Liu Haiming H Nie Yongzhan Y Liang Jie J Fan Daiming D

FEBS open bio 20180115 2

Fewer than 30% of patients with hepatocellular carcinoma (HCC) are eligible to receive curative therapies, and so a better understanding of the molecular mechanisms of HCC is needed to identify potential therapeutic targets. The role of microRNA (miRNA) in modulating tumour progression has been demonstrated, and therapies targeting miRNA appear promising. miR-204-5p has been shown to function in numerous types of cancer, but its role in HCC remains unclear. In this study, we found that miR-204-5 ...[more]

PMID: 29435409

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Project description:Decreased level of miR-204-5p has been documented in various malignancies. However, the expression and clinical significance of miR-204-5p in hepatocellular carcinoma has not been investigated. The aim of this study is to examine the relationship between miR-204-5p expression and clinicopathological features in hepatocellular carcinoma (HCC) as well as to predict the relevant signaling pathways. The miR-204-5p expression level was detected in HCC and in matched paraneoplastic liver from 95 formalin-fixed paraffin-embedded tissues by the real-time reverse transcription polymerized chain reaction (qRT-PCR). The association of miR-204-5p expression with clinicopathological features as well as the prognosis of HCC was examined. Public data portals including the Gene Expression Omnibus and The Cancer Genome Atlas were used to retrieve the HCC-related data in order to perform a comprehensive meta-analysis. Meanwhile, protein-protein interaction (PPI) and enrichment analyses were performed using predicted target genes. The relative expression of miR-204-5p was remarkably reduced in HCC than that in paraneoplastic hepatic tissues. In HCC, the miR-204-5p expression was downregulated in the metastasis, vasoinvasion, and advanced stage (III and IV) subgroups compared with their counterparts. Furthermore, the meta-analysis based on qRT-PCR data demonstrated that miR-204-5p was markedly downregulated in HCC with a standardized mean difference of -5.19 (P?<?.001). However, no significant association was observed between miR-204-5p and survival outcomes. The potential target genes of miR-204-5p were significantly enriched in several pathways which might be associated with HCC, such as "cell proliferation" from GO terms and "pathways in cancer" from the KEGG analysis. A PPI network of miR-204-5p potential target genes identified prospective core genes potentially involved in the regulation of HCC oncogenesis and progression. Our findings suggested that miR-204-5p might act as a tumor-suppressive gene in the tumorigenesis and progression of HCC via vital signaling pathways and that miR-204-5p could be regarded as a protective factor in HCC.

Dataset Information

MiR-204-5p suppresses hepatocellular cancer proliferation by regulating homeoprotein SIX1 expression.

Publications

miR-204-5p suppresses hepatocellular cancer proliferation by regulating homeoprotein SIX1 expression.

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