Z Gastroenterol 2013; 51 - P_4_13
DOI: 10.1055/s-0032-1332058

miR-198 controls migration in hepatocellular carcinoma by regulation of Claudin 1

N Elfimova 1, A Noetel 1, M Kwiecinski 1, D Becker 2, P Nürnberg 3, A Teufel 2, HP Dienes 1, U Drebber 1, M Odenthal 1
  • 1University Hospital Cologne, Institute for Pathology, Cologne, Germany
  • 2University Hospital Mainz, I. Dept. of Internal Medicine, Mainz, Germany
  • 3University Cologne, Cologne Center for Genomics (CCG), Cologne, Germany

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths, worldwide. MicroRNAs, inhibiting gene expression by targeting various transcripts, are involved in genomic dysregulation during hepatocellular tumorigenesis. In previous studies, microRNA-198 (miR-198) was shown to be significantly downregulated in HCV-positive hepatocellular carcinoma (HCC). Herein, the function of miR-198 in hepatocellular carcinoma cell growth and gene expression was studied.

Methodology: The miR-198 expression level and the transcription levels of the liver-specific transcription factors HNF1α and HNF4α were quantified in different hepatoma cells by real-time PCR. Hepatoma cells were transfected with miR-198 and cell growth, proliferation, apoptosis and migration was determined. Gene expression profiling of Pop10 hepatoma cells, transfected with miR-198, was performed by microarray hybridization.

Principal Findings: In hepatoma cell-types with moderate HNF1α expression, indicating a low differentiation grade of the respective hepatoma cells, miR-198 expression was most downregulated. However, miR-198 treatment did not affect expression of the liver-specific transcription factors HNF1α and HNF4α. Importantly, overexpression of miR-198 in hepatoma cells markedly reduced cell growth. In agreement, gene expression profiling revealed that central signal transducers of proliferation pathways were downregulated by miR-198. However, in addition to interferon-induced genes, genes mediating cellular adherence were highly upregulated. Thus, we demonstrate that miR-198 abolished the low expression of E-cadherin and claudin-1, involved in cell adhesion and cell-cell contacts, in hepatoma cells. This definite induction of both proteins due to miR-198 overexpression was shown to be accompanied by a significantly impaired migration activity of hepatoma cells.

Conclusions: miR-198 acts as a tumor suppressor by repression of mitogenic and motogenic pathways diminishing cell growth and migration.