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

Qingli Shen15, Vito R Cicinnati12*, Xiaoyong Zhang3, Speranta Iacob14, Frank Weber2, Georgios C Sotiropoulos2, Arnold Radtke2, Mengji Lu3, Andreas Paul2, Guido Gerken1 and Susanne Beckebaum12

Author Affiliations

1 Department of Gastroenterology and Hepatology, University Hospital Essen, 55 Hufeland Street, Essen, 45122, Germany

2 Department of General, Visceral and Transplantation Surgery, University Hospital Essen, 55 Hufeland Street, Essen, 45122, Germany

3 Institute of Virology, University Hospital Essen, 55 Hufeland Street, Essen, 45122, Germany

4 Gastroenterology and Hepatology Center, Fundeni Clinical Institute, 258 Fundeni Street, Bucharest, 22338, Romania

5 Department of Gynecology & Obstetrics, Guangzhou Women and Childrens Medical Center, Guangzhou, China

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Molecular Cancer 2010, 9:227  doi:10.1186/1476-4598-9-227

Published: 27 August 2010

Abstract

Background

Micro-ribonucleic acid (miRNA)-199a-5p has been reported to be decreased in hepatocellular carcinoma (HCC) compared to normal tissue. Discoidin domain receptor-1 (DDR1) tyrosine kinase, involved in cell invasion-related signaling pathway, was 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 invasion.

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 five hepatoma cell lines by the use of real-time quantitative RT-PCR (qRT-PCR) analysis. The effect of aberrant miR-199a-5p expression on cell invasion was assessed in vitro using HepG2 and SNU-182 hepatoma cell lines. Luciferase reporter assay was employed to validate DDR1 as a putative miR-199a-5p target gene. Regulation of DDR1 expression by miR-199a-5p was assessed by the use qRT-PCR and western blotting analysis.

Results

A significant down-regulation of miR-199a-5p was observed in 65.2% of HCC tissues and in four of five cell lines. In contrast, DDR1 expression was significantly increased in 52.2% of HCC samples and in two of five cell lines. Increased DDR1 expression in HCC was associated with advanced tumor stage. DDR1 was shown to be a direct target of miR-199a-5p by luciferase reporter assay. Transfection of miR-199a-5p inhibited invasion of HepG2 but not SNU-182 hepatoma cells.

Conclusions

Decreased expression of miR-199a-5p contributes to increased cell invasion by functional deregulation of DDR1 activity in HCC. However, the effect of miR-199a-5p on DDR1 varies among individuals and hepatoma cell lines. These findings may have significant translational relevance for development of new targeted therapies as well as prognostic prediction for patients with HCC.