Hellerbrand C et al. (2008) The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma. Gut 57: 243–251

MIA2 (melanoma inhibitory activity 2) is a newly discovered gene expressed solely in hepatocytes. Expression of MIA2 is reduced in hepatocellular carcinoma (HCC) cell lines and excised HCC tissue, which suggests a role for this gene in development and/or proliferation of HCC. Hellerbrand and colleagues, therefore, studied the regulation and functional role of MIA2 in hepatocarcinogenesis.

Expression of HNF1A (hepatic nuclear factor 1 homeobox A), which regulates MIA2 expression, was lower in HCC cell lines and HCC tissue than in primary human hepatocytes; this reduction correlated significantly with MIA2 downregulation in HCC tissue. In HCC cell lines transfected with an HNF1A-containing plasmid, MIA2 expression reverted to levels similar to those in primary hepatocytes, suggesting that loss of HNF1A expression in HCC reduces MIA2 levels.

HCC cells transfected with an MIA2-expressing plasmid showed impaired proliferation and reduced invasiveness in vitro; the same inhibitory effects were observed in HCC cell lines treated with recombinant MIA2 protein. Compared with control mice (injected with nontransfected or mock-transfected HCC cells), mice injected with MIA2-expressing HCC cells developed fewer and significantly smaller tumors, suggesting that reduced MIA2 expression influences tumorigenicity. MIA2 expression was also reduced in HCC tissue compared with noncancerous liver tissue from patients. Reduced MIA2 expression was significantly associated with advanced tumor stage in these patients.

The authors conclude that MIA2 functions as a tumor suppressor in HCC, and represents not only a marker of HCC prognosis but also a possible therapeutic target.