Hepatology

The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma

C Hellerbrand¹, T Amann^1,2, J Schlegel², P Wild³, F Bataille³, T Spruss⁴, A Hartmann², A-K Bosserhoff²

¹ Department of Internal Medicine I, University of Regensburg, Germany
² Institute of Pathology, University of Regensburg, Germany
³ Department of Pathology, University of Zurich, Switzerland
⁴ Institute of Pharmacy, University of Regensburg, Germany

Dr Claus Hellerbrand, University of Regensburg, Department of Internal Medicine I, D-93042 Regensburg, Germany; claus.hellerbrand{at}klinik.uni-regensburg.de

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Digest

Robin Spiller and Magnus Simren
Gut 2008 57: 1-2. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Amann, T., Maegdefrau, U., Hartmann, A., Agaimy, A., Marienhagen, J., Weiss, T. S., Stoeltzing, O., Warnecke, C., Scholmerich, J., Oefner, P. J., Kreutz, M., Bosserhoff, A. K., Hellerbrand, C. (2009). GLUT1 Expression Is Increased in Hepatocellular Carcinoma and Promotes Tumorigenesis. Am. J. Pathol. 174: 1544-1552 [Abstract] [Full Text]