Prognostic value of p53 in non-small cell lung cancer: Relationship with proliferating cell nuclear antigen and cigarette smoking

doi:10.1016/S0046-8177(97)90112-X

Human Pathology

Volume 28, Issue 2, February 1997, Pages 233-237

https://doi.org/10.1016/S0046-8177(97)90112-X Get rights and content

Abstract

p53 mutations are among the most frequent genetic alterations reported in human lung cancer. Although the prognostic value of altered p53 expression is still debated, it is accepted widely that estimation of the proliferation rate has an important prognostic role. Moreover, an association between certain types of human lung cancers and tobacco use is well known. Drawing from this background, we investigated the immunohistochemical expression of mutant oncogenic p53 protein, and related it to the smoking history of 61 patients with non-small cell lung carcinoma (NSCLC) and to the expression pattern of proliferating cell nuclear antigen (PCNA), which is considered to be an important negative prognostic factor in several neoplasms. We found p53 overexpression in 22 (36.1%) specimens, including 16 squamous carcinomas (41%) and six (27.2%) adenocarcinomas. PCNA nuclear staining was detected in 98.4% of the specimens, and a significantly higher PCNA expression score was found in all of the p53-positive samples. When the patient survival time was compared, p53 accumulation had a statistically significant negative prognostic value (P < .001). This was supported by a KaplanMeier survival percentage plot of immunohistochemically p53-undetectable specimens and p53-detectable specimens. These latter patients had a greatly reduced survival time. A relationship was established between p53 immunohistochemical detection and the smoking history of the patients. None of the specimens from the nonsmoking patients expressed immunohistochemically detectable p53 protein. Altered p53 expression was detected in 40.7% of smoking patients. Our findings support the hypothesis of involvement of p53 mutations in tobacco-induced carcinogensis and indicate that altered p53 expression plays an important prognostic role in NSCLC in smokers.

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Cited by (53)

Effects of cigarette smoke extracts on cell cycle, cell migration and endocrine activity in human placental cells
2017, Reproductive Toxicology
Citation Excerpt :
However, the functions of cell cycle genes such as p21 and p53 or PCNA are reportedly altered by components of cigarette smoke [3,10]. PCNA is reportedly closely correlated with DNA replication and cell proliferation [11]. For example, Genbacev et al. (2000) demonstrated that nicotine, one of the major toxic components in cigarette smoke, contributed to inhibition of mitosis in cultured anchoring villi through decreased expression of cell proliferation markers, which was identified with decreased incorporation of BrdU [12].
Maternal smoking during pregnancy is known to be related to adverse pregnancy results associated with trophoblast proliferation and cell cycle progression. Moreover, many previous studies have shown that cigarette smoke is correlated with human chorionic gonadotropin beta (hCG-β) subunit produced from syncytiotrophoblasts during pregnancy. Thus, we further investigated whether cigarette smoke extract (CSE) affects the cell proliferation, migration and endocrine hormone activity of JEG-3 human placental cancer cells. JEG-3 cell proliferation was significantly reduced by all CSEs in a concentration-dependent manner. Moreover, CSEs decreased proliferating cell nuclear antigen (PCNA) levels in JEG-3 cells in Western blot. Increased migration or invasion ability of JEG-3 cells following CSE treatment was also confirmed by a scratch or fibronectin invasion assay in vitro. Additionally, protein levels of E-cadherin as an epithelial maker were down-regulated, while the mesenchymal markers N-cadherin, snail and slug were up-regulated in a time-dependent manner. The metastasis marker, cathepsin D, was also down-regulated by CSE. Finally, CSEs significantly reduced the expression of hCG-β protein in JEG-3 cells. Overall, these results indicate that exposure of placental cells to CSE deregulates the cell cycle by altering the expression of cell cycle-related proteins and stimulates cell metastatic ability by altering EMT markers and cathepsin D expression. CSE exposure may also decrease hCG-β production as an endocrine marker, implying that cigarette smoke has adverse effects during pregnancy.
Association between Smoking and p53 Mutation in Lung Cancer: A Meta-analysis
2014, Clinical Oncology
Citation Excerpt :
The p53 gene is located on the short arm of chromosome 17 and considered to be a tumour suppressor. The wild-type p53 inhibits cell proliferation by arresting cells in the G1 phase of the cell cycle, and loss of this activity can lead to neoplastic transformation [22]. Smoking is a major risk factor for lung cancer, and tobacco carcinogens have been shown to exert a direct mutagenic action of p53 in particular [37].
To carry out a meta-analysis on the relationship between smoking and p53 gene mutation in lung cancer patients.
PubMed, Web of Science, ProQest and Medline were searched by using the key words: ‘lung cancer or lung neoplasm or lung carcinoma’, ‘p53 mutation’ and ‘smoking’. According to the selection criteria, 15 articles were identified and methodologically analysed by stata 12.0 software package. Crude odds ratios with 95% confidence intervals calculated using the fixed-effects model were used to assess the strength of association between smoking and p53 mutation in lung cancer.
In total, 15 articles with 1770 lung cancer patients were identified; 69.6% of the patients were smokers, 30.4% were non-smokers. Overall, smokers with lung cancer had a 2.70-fold (95% confidence interval 2.04–3.59) higher risk for mutation than the non-smokers with lung cancer. In subgroup analyses, the increased risk of p53 mutation in smokers than in non-smokers was found in the non-small cell lung cancer (NSCLC) group (odds ratio = 2.38, 95% confidence interval = 1.71–3.32) and in the NSCLC and SCLC group (odds ratio = 3.82, 95% confidence interval = 2.19–6.69).
This meta-analysis strongly suggests that p53 mutation is associated with smoking-induced lung cancer. Smokers with lung cancer had a higher risk for p53 mutation than non-smokers.
The role of apoptosis-related genes in non-small-cell lung cancer
2002, Clinical Lung Cancer
Both intrinsic and acquired resistance to chemotherapeutic drugs are major obstacles in the treatment of non—small-cell lung cancer. Apart from classical drug resistance mechanisms, the failure of tumor cells to undergo apoptosis also plays an important role in drug resistance. Mutations and defects in the apoptotic pathway are, therefore, additional factors that determine drug resistance. The tumor suppressor gene p53, the retinoblastoma gene, and the bcl-2 family members are important factors in this pathway. Recently much attention has been drawn to different apoptotic pathways induced by naturally occurring death receptor ligands (such as tumor necrosis factor, Fas ligand, and tumor necrosis factor—related apoptosis-inducing ligand) or induced by drugs that affect the downstream pathway from the epidermal growth factor receptor. Insight regarding the proteins that determine sensitivity for chemotherapeutic drugs could provide new targets for cancer treatment, which may help to at least partly overcome drug resistance in non—smallcell lung cancer.
Prognostic relevance of proliferating cell nuclear antigen and p53 expression in non-small cell lung cancer
2002, Lung Cancer
Prognostic value of p53 and PCNA expression in non-small cell lung cancer (NSCLC) remains controversial. In this study we determined the relevance of these abnormalities in terms of overall survival and disease-free survival in 95 NSCLC patients who underwent curative pulmonary resection. Expression of p53 was found in 44 samples (45%), expression of PCNA—in 79 samples (83%), and expression of both markers—in 35 samples (36%). There was no relationship between expression of either protein and major clinicopathological characteristics. Median survival for patients with and without p53 expression was 36 and 33 months, respectively and 5-year survival probability—29 and 37%, respectively (P=0.73). Median survival for patients with and without PCNA expression was 36 and 27 months, respectively and 5-year survival probability—35 and 25%, respectively (P=0.60). There was no significant difference in overall survival between particular groups of patients with tumors carrying four possible p53/PCNA phenotypes. In multivariate analysis including patient age, sex, tumor stage, tumor type and differentiation, p53 and PCNA expression, the only variable important for survival was stage of disease. These results suggest the lack of prognostic relevance of p53 and PCNA expression in surgically treated NSCLC patients.
Molecular basis of lung carcinogenesis
2016, The Molecular Basis of Human Cancer
Meta-analysis on association between smoking and p53 gene mutation in patients with lung cancer
2014, Journal of Jilin University Medicine Edition

View all citing articles on Scopus

^☆: A.D.L. is supported by “Advanced fellowship NATO-CNR.” Supported in part by the Sbarro Institute for Cancer Research and Molecular Medicine, NIH grant RO1 CA60999-01A1, and from The Council for Tobacco Research to A.G.

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Original contributionPrognostic value of p53 in non-small cell lung cancer: Relationship with proliferating cell nuclear antigen and cigarette smoking☆

Abstract

Lancet

J Thorac Cardiovasc Surg

The biology of lung cancer

Semin Oncol

The roles of the tumor soppressors pRb and p53 in cell proliferation and cancer

Mol Cell Differ

p53 mutations in human cancers

Science

Normal e malignant growth control by p53

The tumor suppressor genes

Annu Rev Biochem

p53 expression in oat and non oat small cell lung carcinomas: Correlation with proliferating cell nuclear antigen

J Clin Pathol

p53 mutations in colorectal cancer

p53 protein accumulation and gene mutation in the progression of human prostate carcinoma

J Natl Cancer Inst

Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis

Cancer Res

Prognostic significance of p53 mutations and 3p deletions in primary resected non small-cell lung cancer

Cancer Res

The relationship of p53 immunostaining to survival in carcinoma of the lung

Br J Cancer

Accumulation of p53 protein correlates with a poor prognosis in human lung cancer

Cancer Res

Original contribution
Prognostic value of p53 in non-small cell lung cancer: Relationship with proliferating cell nuclear antigen and cigarette smoking☆