Clinicopathologic significance of mitotic arrest defective protein 2 overexpression in hepatocellular carcinoma.

ABSTRACT

Mitotic arrest defective protein 2 (MAD2) gene plays a central role in the mitotic checkpoint. Elevated MAD2 expression was observed in a number of human malignancies; its role in the development of hepatocellular carcinoma is still not understood and is controversial. The purpose of this study was to investigate the clinicopathologic significance of MAD2 expression in hepatocellular carcinoma. The MAD2 protein and its messenger RNA levels were measured in hepatocellular carcinomas, high-grade dysplastic nodules, and their paired nontumorous liver tissues by quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry. The results showed that MAD2 at both messenger RNA and protein levels was overexpressed in 8 of 9 high-grade dysplastic nodules and in 51 of 58 hepatocellular carcinomas, including 12 of 14 unifocal small hepatocellular carcinomas. There was a tendency for MAD2 expression to increase in the process of this multistep carcinogenesis. A significantly high tumor MAD2 immunostaining was associated with the progression of histologic grade and the overall low survival. In conclusion, MAD2 is overexpressed frequently in hepatocellular carcinoma, including high-grade dysplastic nodules and early-stage small hepatocellular carcinoma, indicating that overexpression of MAD2 plays a role in the development and progression of hepatocellular carcinoma. It may be an early event in hepatocarcinogenesis and could be used as a potential prognostic indicator.