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The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma
  1. C Hellerbrand1,
  2. T Amann1,2,
  3. J Schlegel2,
  4. P Wild3,
  5. F Bataille3,
  6. T Spruss4,
  7. A Hartmann2,
  8. A-K Bosserhoff2
  1. 1
    Department of Internal Medicine I, University of Regensburg, Germany
  2. 2
    Institute of Pathology, University of Regensburg, Germany
  3. 3
    Department of Pathology, University of Zurich, Switzerland
  4. 4
    Institute of Pharmacy, University of Regensburg, Germany
  1. Dr Claus Hellerbrand, University of Regensburg, Department of Internal Medicine I, D-93042 Regensburg, Germany; claus.hellerbrand{at}klinik.uni-regensburg.de

Abstract

Background: Melanoma inhibitory activity 2 (MIA2) is a novel gene of the MIA gene family. The selective expression of MIA2 in hepatocytes is controlled by hepatocyte nuclear factor (HNF) 1 binding sites in the MIA2 promotor. In contrast, in most hepatocellular carcinomas (HCC) MIA2 expression is down-regulated or lost.

Aim: In this study we examined the regulation and functional role of MIA2 in hepatocancerogenesis.

Methods and results: In HCC cell lines and tissues HNF-1 expression was lower than in primary human hepatocytes (PHH) and corresponding non-tumorous tissue, respectively, and correlated significantly with the down-regulation of MIA2 expression. Re-expression of HNF-1 in HCC cells reinduced MIA2 in HCC cells to similar levels as found in PHH. Further, MIA2 was re-expressed in HCC cell lines by stable transfection, and the generated cell clones revealed a strongly reduced invasive potential and proliferation rate in vitro. In line with these findings treatment of HCC cells with recombinant MIA2 inhibited proliferation and invasion. In nude mice MIA2 re-expressing HCC cells grew significantly slower and revealed a less invasive growth pattern. Immunohistochemical analysis of a tissue microarray containing HCC and corresponding non-cancerous liver tissue of 85 patients confirmed reduced MIA2 expression in HCC. Furthermore, MIA2 negative HCC tissue showed a significantly higher Ki67 labelling index and loss of MIA2 expression correlated significantly with more advanced tumour stages.

Conclusion: This study presents MIA2 as an inhibitor of HCC growth and invasion both in vitro and in vivo, and consequently, as a tumour suppressor of HCC. Further, our findings indicate a novel mechanism, how loss of HNF-1 expression in HCC affects tumorigenicity via down-regulation of MIA2.

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Footnotes

  • Funding: The study was supported by grants from the German Research Association (DFG) to A.K.B., and the Medical Faculty of the University of Regensburg (ReForM) to C.H., A.H. and A.K.B.

  • Competing interests: None.

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