Role of microRNA-199a-5p and discoidin domain receptor 1 for human hepatocellular carcinoma invasion

Aims: Micro-ribonucleic acid (miRNA)-199a-5p has been reported to be down-regulated in hepatocellular carcinoma (HCC). Discoidin domain receptor-1 (DDR1) tyrosine kinase, involved in cell invasion-related signaling pathway, is predicted to be a potential target of miR-199a-5p by the use of miRNA target prediction algorithms. The aim of this study was to investigate the role of miR-199a-5p and DDR1 in HCC. Material and Methods: Mature miR-199a-5p and DDR1 expression were evaluated in tumor and adjacent non-tumor liver tissues from 23 patients with HCC undergoing liver resection and in five hepatoma cell lines by the use of TaqMan® real-time quantitative RT-PCR. The effect of aberrant miR-199a-5p expression on cell invasion was assessed in vitro using the HepG2 cell line. Luciferase reporter assay was employed to validate DDR1 as a putative miR-199a-5p target gene. Results: A significant down-regulation of miR-199a-5p was observed in 65% of HCC tissues and in four of five cell lines as compared to adjacent non-tumor tissues and normal hepatocytes, respectively. In contrast, DDR1 was significantly overexpressed in 52% of HCC samples and in two of five cell lines. High DDR1 expression in HCC was associated with advanced tumor stage. Enhanced miR-199a-5p expression inhibited invasion of HepG2 cells in vitro by directly reducing DDR1 mRNA and protein levels. Conclusions: Altered expression of miR-199a-5p contributes to increased cell invasion by functional deregulation of DDR1 activity in HCC. These findings may have significant translational relevance for development of new targeted therapies as well as prognostic prediction for patients with HCC. discoidin domain receptor 1 - hepatocellular carcinoma - microRNA