Journal
MOLECULAR CANCER
Volume 14, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/1476-4598-14-5
Keywords
Hepatocellular carcinoma; MicroRNA-146a; VEGF; HAb18G/CD147; Invasion; Metastasis
Categories
Funding
- National Natural Science Foundation of China [81101569]
- National Science and Technology Major Project [2013ZX09301301]
- National Basic Research Program (973 Program) [2009CB521705]
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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. Methods: The 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. Results: We 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 beta-catenin accumulation in nucleus, and downregulating NF-kappa B p65 by targeting HAb18G. In human HCC, miR-146a expression was negative correlated with increased HAb18G, VEGF, NF-kappa B p65 and beneficial prognosis. Conclusion: This 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.
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