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Geminin is an important molecule which plays a role in cell cycle regulation, and this has been considered to be a useful biomarker of cell proliferation. The purpose of this study was to evaluate the pathological and prognostic significance of geminin expression in small lung adenocarcinoma (AC). We performed Western blot analysis of five human lung AC cell lines and immunohistochemistry on 100 surgically resected specimens of lung AC with a diameter less than 3 cm. We counted the number of positively stained tumor cells, and calculated the labeling indices (LIs). Geminin proteins were variably detected in all five cell lines examined on Western blotting. The mean LIs for geminin, Ki-67, and MCM7 were 7.5%, 12.3%, and 18.5%, respectively. The geminin LIs were associated with some clinicopathological profiles including gender, histological grade, subtypes, N-status, p-factor, and tumor stage. A significantly worse prognosis was noted in the higher geminin LIs group than in the lower group (p < 0.01). Multivariate Cox regression analysis also confirmed that geminin LIs was an independent prognostic marker in stage IA lung AC patients. These results suggest that geminin is overexpressed in small lung ACs, and geminin LIs might be a useful prognostic indicator in patients with lung AC., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Minichromosome maintenance (MCM) proteins, essential molecules in the initiation and elongation of DNA replication, have been considered to be good indicators of cell proliferation. We examined the expressions of MCM7 and Ki-67 in lung adenocarcinomas (ACs) with a diameter less than 3cm (pT1), to clarify their pathobiological significance. Immunohistochemistry was conducted to obtain labeling indices (LIs%) for MCM7, MCM2 and Ki-67 in 100 surgically removed pT1 ACs. The LIs were compared with clinicopathological profiles and overall survival rates. The mean LIs of MCM7 and Ki-67 were 20.2+/-15.2% and 13.7+/-11.2%, the value being higher in the former than in the latter (P<0.01). MCM7 LIs were significantly correlated with sex, histological grade, histological subtype, tumor size, LIs of Ki-67, MCM2 and P53 (P<0.05). LIs of MCM7 and Ki-67 were significantly higher in the 84 non-bronchioloalveolar carcinomas than in the 16 bronchioloalveolar carcinomas (P<0.01). Kaplan-Meier survival curves showed that patients with higher MCM7 LIs had poorer prognosis in the 100 pT1 ACs as well as in the 73 stage I ACs. Multivariate Cox regression analysis confirmed that the LIs of MCM7, but not the LIs of MCM2 and Ki-67, was an independent prognostic marker in the 73 stage I ACs. These results suggest that MCM7 is an independent prognostic marker, being more reliable than MCM2 or Ki-67 in human pT1 ACs as well as in human stage I ACs.

Cyclooxygenase (Cox)-2 plays an important role in cell proliferation, carcinogenesis and tumor growth, in part through the synthesis of prostaglandin E2 (PGE2) as well as through other yet unknown routes. Epidermal growth factor receptor (EGFR) signaling regulates Cox-2 expression, which has not been thoroughly examined in bronchial carcinomas. The current study examined the expression of Cox-2, EGFR, P53 and proliferative marker Ki-67 immunoreactivities by immunohistochemistry in 71 surgically removed stage I bronchial adenocarcinomas. Furthermore, we evaluated the prognostic value of these molecules to elucidate the biological significance of Cox-2 expression. Higher Cox-2 expression (more than 10% immunoreactivities in tumor cells) was strongly associated with higher EGFR and P53 expression as well as a Ki-67 LI above 20% (P < 0.01). Cox-2 and EGFR immunoreactive tumor cells showed a similar distribution pattern. Five-year survival rate was 73% in 57 cases showing higher Cox-2 expression and 100% in 14 cases showing lower expression, indicating a significant difference in survival (P = 0.040). Higher Cox-2 expression might be associated with tumor progression and worse prognosis through EGFR signaling interaction in Stage I bronchial adenocarcinomas.