MAD1 (mitotic arrest deficiency 1) is a candidate for a tumor suppressor gene in human stomach

Mitotic arrest deficiency 1 (MAD1) is a component of the spindle checkpoint factors that monitor fidelity of chromosomal segregation. We previously confirmed that the level of MAD1 protein was decreased in gastric carcinoma compared with non-tumoral mucosa by conducting proteome-based analyses (Nishigaki R, Osaki M, Hiratsuka M, Toda T, Murakami K, Jeang KT, Ito H, Inoue T, Oshimura M, Proteomics 5:3205–3213, 29). In this study, an immunohistochemical analysis was performed to examine MAD1 expression histologically in gastric mucosa and tumor. MAD1 was detected in the supranuclear portion of normal epithelial, intestinal metaplasia, and adenoma cells, but its expression was not restricted to any specific area in carcinoma cells. Lower levels of expression were noted in 16 (47.1%) of 34 adenomas and in 52 (60.5%) of 86 carcinomas, whereas all normal mucosae and intestinal metaplasias were grouped into cases with higher level of expression. Moreover, the expression of MAD1 was significantly lower in advanced carcinomas than early carcinomas and in intestinal than diffuse type, respectively (P < 0.05). Exogenous expression of wild-type MAD1, but not the mutant MAD1, inhibited cell proliferation and resulted in G2/M accumulation in MKN-1, a gastric carcinoma cell line. Taken together, our findings suggest that the MAD1 gene could be a candidate tumor suppressor gene and that down-regulation of MAD1 expression contribute to tumorigenesis in human stomach.