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Cyclin D1 Overexpression, p16 Loss, and pRb Inactivation Play a Key Role in Pulmonary Carcinogenesis and have a Prognostic Implication for the Long-term Survival in Non-small Cell Lung Carcinoma Patients

Abstract

Purpose: We investigated the immunoexpressions of cyclin D1, cyclin-dependent kinase inhibitor p16 and phosphorylated retinoblastoma (p-pRb) proteins in non- small cell lung carcinoma (NSCLC) to demonstrate their key roles in tumorigenesis, their relationship with the clinicopathologic factors, and their prognostic influences on the long-term survival. Materials and Methods: 115 surgically resected NSCLCs were immunohistochemically stained for the G₁/S cell cycle proteins, with using a tissue microarray. The correlation between their immunoexpressions and the clinicopathologic prognostic factors, their inter-relationships and their single or combined effects on the long-term survival (over 5 years) were statistically analyzed by SPSS15.0. Results: Loss of p16 was found in 75% of the cases and cyclin D1 overexpression and phosphorylated pRb (p-pRb) were found in 64% and 46%, respectively. Cyclin D1 overexpression was correlated with the p16 loss and pRb inactivation by phosphorylation. The p16 loss was tightly associated with p-pRb. The Kaplan-Meier survival curves disclosed that the cyclin D1-positive group and the p16-negative group showed a rapid decline of survival at the point of about 5 years after surgery and thereafter. The combined actions of cyclin D1 overexpression, loss of p16 and pRb inactivation tended to have an adverse influence on the prolonged survival. Conclusions: The observation that cyclin D1 overexpression, p16 loss and pRb inactivation were largely found in NSCLCs suggests that they play an important role in pulmonary carcinogenesis. Also, their inverse or positive correlations indicate that the G₁/S cell cycle proteins may act alternatively or synergistically on the mechanisms by which tumor cells escape the G₁ restriction point. Finally, their solitary or combined actions might have a long-term effect on the survival.

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