Analysis of cell cycle regulator proteins in non-small cell lung cancer.

Third Division of Infective Diseases, D. Cotugno Hospital, Naples 80100, Italy.
Journal of Clinical Pathology (Impact Factor: 2.92). 02/2004; 57(1):58-63.
Source: PubMed

ABSTRACT Abnormalities of the proteins involved in cell cycle checkpoints are extremely common among almost all neoplasms. This study aimed to investigate the expression of four components of the cell cycle machinery-p21, p16, p53, and proliferating cell nuclear antigen (PCNA)-in non-small cell lung cancer (NSCLC).
The expression of p21, p16, p53, and PCNA was examined in 68 well characterised NSCLC specimens using immunohistochemistry. The coregulation of these proteins and their influence on survival were analysed using both univariate and multivariate analyses.
By univariate analysis, the expression of all the proteins examined, except for PCNA, was significantly correlated with survival. In multivariate analysis, the only immunohistochemical parameter able to influence overall survival was p16, confirming the hypothesis that the RB-p16 tumour suppressor pathway is inactivated in most lung cancer samples. Finally, the group of patients with NSCLC who were negative for both p21 and p16 had a significantly shorter overall survival.
These results suggest that loss of control of cell cycle checkpoints is a common occurrence in lung cancers, and support the idea that functional cooperation between different cell cycle inhibitor proteins constitutes another level of regulation in cell growth control and tumour suppression.

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Available from: Alfonso Baldi, Sep 28, 2015
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    • "One of the most important checkpoints involved in oncogenesis is the restriction point in the late G1 stage. Defects in G1 regulatory proteins, particularly deregulation of the P53–MDM2/4(Greenblatt et al. 1994; Esposito et al. 2004) and cyclin D/CDK 4-CDKN2A (p16)-retinoblastoma (RB) protein pathways (Yoshida et al. 2004; Cheng et al. 2003), seem to be essential for the development of lung cancer. The product of the Cdkn2a gene is an inhibitor of CDK 4/6, which phosphorylates the serine/threonine residues of the tumour suppressor RB and plays an important role in inhibiting cell cycle progression (WIKENHEISER-BROKAMP, 2006). "
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    ABSTRACT: Radon exposure has been linked to lung carcinogenesis in both human and animal studies. The identification of sequential changes in DNA methylation during tumour progression and the elucidation of their interplay with genetic changes will broaden our molecular understanding of this disease. Rats were exposed to 120 or 400 working level months (WLM) of radon, lung pathological changes were examined by haematoxylin and eosin staining, lung single cell suspension cell cycles were detected by flow cytometry, lung cell cycle regulated gene (Cdkn2a, P53, Cdk4/2, Mdm4/2 and Rb1 genes) expression was quantified by real-time PCR and methylation of CpG islands in the promoters of cell cycle-regulated genes were detected by bisulfite sequencing PCR. The alveolar walls of rat lungs after exposured to radon exhibited papillae and the lung bronchial epithelial cells stained positively for proliferating cell nuclear antigen. The bronchial epithelial cells displayed some hyperplasia after challenged by 400 WLM of radon. Moreover, G1 arrest decreased; Rb1, Mdm2/4, and Cdk2/4 expression decreased and Cdk2 was demethylated at the second and sixth CpG loci from base pairs 3092704 to 3092953 of chromosome 7. Cdk2 demethylation may be applicable as a biomarker of early lung damage that was induced by radon and other environmental carcinogens.
    Genes & genomics 12/2014; 36(6):763-770. DOI:10.1007/s13258-014-0210-0 · 0.60 Impact Factor
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    • "While several of the factors involved in regulating cell-cycle control have been investigated in lung cancer, few studies have examined multiple factors in the same tumor series. Our research group recently sets up a study to evaluate the expression of p53, p21, p16, and PCNA proteins in a large series of non-small-cell lung cancers (NSCLCs) to assess the integrity of cell-cycle checkpoints in these tumors, to evaluate the coexpression of these proteins, and, finally, to examine the relationship between these cell-cycle regulators and the clinicopathological features of NSCLCs, including their ability to predict survival in NSCLC patients [127]. When we looked at the correlation between clinicopathological data and expression of cell-cycle proteins, we found a negative correlation between lymph nodes status and p21, and p16 expression, suggesting a possible role for these two proteins in the progression of the disease. "
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    ABSTRACT: The cell cycle is the cascade of events that allows a growing cell to duplicate all its components and split into two daughter cells. Cell cycle progression is mediated by the activation of a highly conserved family of protein kinases, the cyclin-dependent kinases (CDKs). CDKs are also regulated by related proteins called cdk inhibitors grouped into two families: the INK4 inhibitors (p16, p15, p19, and p18) and the Cip/Kip inhibitors (p21, p27, and p53). Several studies report the importance of cell-cycle proteins in the pathogenesis and the prognosis of lung cancer. This paper will review the most recent data from the literature about the regulation of cell cycle. Finally, based essentially on the data generated in our laboratory, the expression, the diagnostic, and prognostic significance of cell-cycle molecules in lung cancer will be examined.
    Pathology Research International 10/2011; 2011:605042. DOI:10.4061/2011/605042
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    • "Only p16 had a direct impact on the 5-yr survival in patients with NSCLC. This is in agreement with the results of the study by Esposito et al. (8). In their multivariate analysis on cell cycle regulator proteins, the only immunohistochemical parameter that influenced overall survival was p16. "
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    ABSTRACT: Non-small cell lung cancers (NSCLC) vary in their biologic behavior. Recurrence and tumor-related mortality may be attributable to molecular abnormalities in primary tumors. This study evaluated such immunophenotypes with regard to cell cycle regulation and proliferation, apoptosis, and angiogenesis, to determine their significance for patient outcome. Core biopsies from 219 patients with NSCLC were assembled on tissue microarrays, and the expressions of p16, p21, p27, cyclin B1, cyclin E, Ki-67, caspase-3, survivin, bcl-2, VEGF, and endostatin were evaluated by immunohistochemistry. Despite previously described prognostic relevance of some of the investigated molecules, many of those markers were not directly associated with recurrence or survival. However, there was a trend for p16 immunoreactivity to be associated with a good prognosis (57% vs. 42% in 5-yr survival) (p=0.071). bcl-2 expression was strongly correlated with a better outcome (65% vs. 45% in 5-yr survival) (p=0.029), and the hazard of death for bcl-2 positive patients was 0.42 times of that for bcl-2 negative patients (p=0.047). A multivariate analysis with Cox proportional hazards model confirmed that the lymph node status (p=0.043) and stage (p=0.003) were other independent prognostic factors. Our results suggest that p16 and bcl-2 provide prognostic information independent of the TNM stage in NSCLC.
    Journal of Korean Medical Science 05/2007; 22(2):318-25. DOI:10.3346/jkms.2007.22.2.318 · 1.27 Impact Factor
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