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


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


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.


CONCLUSIONS
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.
Hellerbrand
C
C
University of Regensburg, Department of Internal Medicine I, D-93042 Regensburg, Germany. claus.hellerbrand@klinik.uni-regensburg.de
Amann
T
T
Schlegel
J
J
Wild
P
P
Bataille
F
F
Spruss
T
T
Hartmann
A
A
Bosserhoff
A-K
AK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor; D051537:Hepatocyte Nuclear Factor 1 / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000951:Antigens, Neoplasm; D016326:Extracellular Matrix Proteins; C090059:MIA protein, human; C109278:MIA2 protein, human; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; C569192:melanoma inhibitory activity protein 2, mouse; D051537:Hepatocyte Nuclear Factor 1