Geminin, Ki67, and minichromosome maintenance 2 in gastric hyperplastic polyps, adenomas, and intestinal-type carcinomas: pathobiological significance

Background Geminin negatively regulates Cdt1 and induces the formation of prereplicative complexes by loading mini-chromosome maintenance proteins (Mcm) onto chromatin and limiting DNA replication to once per cell cycle. Recent studies have suggested that geminin expression is a marker of the S/G2/M phase of the cell cycle and is associated with a poor prognosis in various human malignancies. This study aimed to clarify the pathobiological role of geminin in intestinal-type gastric carcinoma, and its relationships with minichromosome maintenance 2 (Mcm2) and Ki67 expression. Methods We performed western blot analysis of seven human gastric cancer cell lines, and immunohistochemical analysis of 72 gastric mucosal lesions and 128 surgically removed advanced intestinal-type gastric carcinomas. Double-labeling immuno-fluorescence was performed to identify the coexpression of geminin and Ki67. Results Geminin was detected in all cell lines. Geminin labeling indices (LIs) in hyperplastic polyps, low-grade adenomas, high-grade adenomas, and intestinal-type adenocarcinomas were 3.9%, 10.5%, 18.6%, and 27.2%, respectively. The equivalent LIs for Ki67 and Mcm2 were 17.7%, 42.2%, 52.6%, and 59.7%; and 26.7%, 70.0%, 67.8%, and 77.8%, respectively. Double-labeling immunofluorescence revealed coexpression of geminin and Ki67 in both normal and tumor cells. The LI for geminin was significantly correlated with N stage, International Union Against Cancer (UICC) stage, Mcm2 LI, and Ki67 LI. Patients in stages I-IV and stage III with higher LIs for geminin (>25%) had significantly worse prognoses (P < 0.05 and P < 0.04, respectively). Univariate Cox regression analysis indicated that the overall survival of stage I-IV tumors was significantly correlated with high geminin LIs (relative risk [RR] = 1.94; P = 0.04). Conclusions Geminin expression might reflect the biological nature of gastric intramucosal neoplasms and could be a possible prognostic marker in advanced intestinal-type gastric carcinomas.