Abstract
Growing evidence indicates that miR-146a is involved in carcinogenesis and tumor progression in several human malignancies. However, the molecular details underlying miR-146a mediated regulation of its target genes and its precise biological function in cancer, especially in hepatocellular carcinoma (HCC) remains unclear.MethodsThe expression levels of genes including miR-146a, APC, VEGF and HAb18G were examined in HCC cell lines and patient specimens were compared with control levels using quantitative reverse transcription-PCR. The functions of miR-146a and HAb18G in migration/invasion and liver metastasis formation were determined by transwell and spleen injection assays, respectively. miR-146a related genes were determined by PCR array. The potential regulatory targets of miR-146a were determined by bioinformatics and prediction tools, correlation with target protein expression, and luciferase reporter assay. DNA methylation status of miR-146a promoter were performed by PCR analysis of bisulfite-modified genomic DNA.ResultsWe demonstrated that miR-146a expression was markedly downregulated in hepatoma cells and hepatoma tissues compared to immortalized normal liver epithelial cells and normal hepatic tissues. DNA methylation of miR-146a promoter correlated with its downexpression and with liver cancer metastasis. The restoration of miR-146a dramatically suppressed HCC cell invasion and metastasis by repressing VEGF expression through upregulating APC, which inhibits β-catenin accumulation in nucleus, and downregulating NF-κB p65 by targeting HAb18G. In human HCC, miR-146a expression was negative correlated with increased HAb18G, VEGF, NF-κB p65 and beneficial prognosis.ConclusionThis study identified a novel target of miR-146a and defined miR-146a as a crucial tumor suppressor in human HCC that acts through multiple pathways and mechanisms to suppress HCC invasion or metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-14-5) contains supplementary material, which is available to authorized users.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and one of the leading causes of cancer-related death worldwide [1,2]
As post-transcriptional regulators of gene expression, these small non-coding RNAs complementarily bind to the 3′ untranslated region (3′-UTR) of their target messenger RNAs, leading to either the degradation of mRNAs or the inhibition of protein translation. miRNAs are involved in the regulation of most cellular processes, including cell proliferation, migration, and apoptosis [10]
MiR-146a is frequently down-regulated in HCC and associated with tumor invasion and metastasis In attempt to explore that miR-146a expression levels differ between tumor and non-tumor tissues, we examined the expression in 11 pairs of HCC tissues and matched tumor adjacent tissues
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies and one of the leading causes of cancer-related death worldwide [1,2]. Numerous studies have shown that aberrant expression of miRNAs is associated with the development and progression of various types of cancer, including HCC [10], and some of these miRNAs function as tumor suppressor genes or oncogenes [11,12]. MiR-146a is located on human chromosome 5q34, which is a region that is often deleted in human tumors [13], and has been reported to be aberrantly expressed in several cancers. MiR-146a has been shown to inhibit cancer cell metastasis by targeting IRAK-1 [17,18,19] It remains unknown whether miR-146a is involved in the regulation of HCC cell invasion and how this miRNA mediates invasive inhibition
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