Abstract
BackgroundMicroRNA-139-5p (miR-139) has been shown to play important roles in hepatocellular carcinoma (HCC) development. However, the exact mechanism of miR-139 in HCC remains largely unknown.MethodsWe investigated the function in human cell lines and patient tissue samples by experimental techniques in molecular biology including Co-IP assay, cell viability assay, quantitative real-time-PCR, et al. In addition, datasets were used to verify the results by database analysis. Statistical analysis was performed by using the GraphPad Prism 6 (GraphPad Software Inc., USA). A P value < 0.05 was defined as statistically significant.ResultsIn this study, we found that miR-139 was significantly down-regulated in HCC. MiR-139 level was negatively associated with the stage of HCC, and HCC patients with higher miR-139 level had longer overall survival (OS) than these having lower miR-139 expression. Overexpression of miR-139 led to reduced cell viability, elevated apoptosis, and decreased colony forming, migratory and invasive capacities in HCC cells, while down-regulation of miR-139 led to opposite phenotypes. MiR-139 also inhibited HCC growth in a xenograft mouse model. We identified karyopherin alpha 2 (KPNA2) as a direct target of miR-139. KPNA2 is up-regulated in HCC and higher KPNA2 level is associated with poor patient prognosis. Silencing of KPNA2 expression led to similar phenotypic changes as miR-139 overexpression. Restoration of KPNA2 attenuated the suppressive effects of miR-139 overexpression on cell viability, apoptosis, colony formation, migration and invasion. In addition, miR-139 overexpression and KPNA2 depletion led to decreased nucleus level of POU class 5 homeobox 1 (POU5F1) and c-myc, two well-known pro-oncogenes.ConclusionIn together, these data revealed the essential roles of the miR-139/KPNA2 axis in HCC.
Highlights
MicroRNA-139-5p has been shown to play important roles in hepatocellular carcinoma (HCC) development
The liver hepatocellular carcinoma (LIHC) dataset in The Cancer Genome Atlas (TCGA) that has a larger cohort of patients indicated that mir-139 expression was down-regulated in HCC tissues compared to non-cancerous tissues (Fig. 1c)
The results indicated that inhibition of histone deacetylase activity led to significant up-regulation of miR-139 level, but 5-AZA did not result in significant change in miR-139 level, suggesting that miR-139 is under-expressed in HCC due to lowered histone acetylation (Fig. 1e and f )
Summary
MicroRNA-139-5p (miR-139) has been shown to play important roles in hepatocellular carcinoma (HCC) development. The exact mechanism of miR-139 in HCC remains largely unknown. A large body of evidence has revealed that deregulated microRNAs (miRNAs) play important roles in cancer. MiRNAs belong to a class of endogenous non-coding small RNAs that regulate gene expression post-transcriptionally. They bind to the 3′ untranslated region (UTR) of target messenger RNAs (mRNAs) to promote mRNA degradation and/or translational repression. Through down-regulating the expression of target genes, miRNAs play pivotal roles in a number of physiological and pathological processes, such as cell differentiation, proliferation, apoptosis, migration and carcinogenesis [5].
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