Cancer Res Treat.  2008 Jun;40(2):45-52.

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

• Myong NH

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.

Keyword

Cyclin D1; Cyclin-dependent kinase inhibitor p16; Retinoblastoma protein; Non- small cell lung cancer; Long-term effects

MeSH Terms

Cell Cycle Proteins
Cell Transformation, Neoplastic
Cyclin D1
Cyclin-Dependent Kinase Inhibitor p16
Cyclins
G1 Phase Cell Cycle Checkpoints
Humans
Kaplan-Meier Estimate
Lung
Phosphorylation
Proteins
Retinoblastoma
Retinoblastoma Protein
Small Cell Lung Carcinoma
United Nations
Cell Cycle Proteins
Cyclin D1
Cyclin-Dependent Kinase Inhibitor p16
Cyclins
Proteins
Retinoblastoma Protein

Figure

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  Fig. 1 Cylin D1 overexpression in squamous cell carcinoma is characterized by the distinct nuclear immunoreactivity in most of the tumor cells, which is in contrast to the lack of immunostaining on the adjacent stromal cells (×200).

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  Fig. 2 Loss of p16, a cell cycle inhibitor protein, is observed in a few non-small cell carcinoma nests, which is contrast with the evident immunopositivity in the normal fibroblastic stromal cell nuclei (×200).

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  Fig. 3 Phosphorylated pRb protein is immunostained in a large proportion of the squamous carcinoma cell nuclei, which is also noted but less frequently in the adjacent activated stromal cell nuclei (×400).

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  Fig. 4 The Kaplan-Meier survival curves of the 115 non-small cell lung carcinoma patients, according to the solitary or combined immunoexpressions of cyclin D1, p16 and pRb proteins. (A) The cumulative survivals of the cyclin D1-positive and -negative cases were not significantly different during the overall follow-up period (p=0.368), but there was a tendency of the cyclin D1-positive cases to have markedly reduced survival rates after about 5 years (as indicated by a vertical line). (B) The p16-negative cases tended to survive for a shorter time than the p16-positive cases, not in the overall follow-up period, but after about 5 years of follow-up. (C~F) The cumulative survivals of the cyclin D1+/p16-, cyclin D1 +/p-pRb+, p16-/p-pRb+, and cyclin D1+/p16-/p-pRb- groups also revealed the tendency to have markedly reduced survival rates, especially after the postoperative 5th year.

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