Immunohistochemical expression of geminin in colorectal cancer: Implication of prognostic significance

Abstract

DNA should be duplicated precisely once per cell cycle to maintain genome integrity. After DNA replication, geminin binding to Cdt1 inhibits uploading of the minichromosome maintenance (MCM) complex as DNA helicase onto chromatin and prevents DNA re-replication in the same cell cycle. Expression of geminin indicates poor prognosis in some malignancies, such as breast and renal cell carcinoma. We evaluated the expression of geminin to clarify its pathobiological and prognostic significance in colorectal cancer, compared with expression of MCM7 and Ki-67. We performed Western blot analyses of 5 human colorectal cancer cell lines and immunohistochemistry on 191 surgically removed specimens of Dukes' B and C stage colorectal cancer. Double-labeling immunofluorescence was also carried out to identify co-expression of geminin, MCM7 and Ki-67. Geminin proteins were detected in all the 5 cell lines examined. Geminin, MCM7 and Ki-67 were co-expressed and cells that stained only for geminin were not detected. Mean labeling indices (LIs) for geminin, MCM7 and Ki-67 were 26.3, 58.2 and 40.8%, respectively. Patients with high geminin LIs had significantly unfavorable prognosis in stage II and III colorectal cancer (P=0.04). Patients with a tumor with a higher proliferating nature (i.e. high LIs for three markers) showed significantly unfavorable prognosis in multivariate Cox analysis. Our results indicate that assessment of geminin, MCM7 and Ki-67 may be useful for predicting prognosis in patients with colorectal cancer.