The presence of human papillomavirus-16/-18 E6, p53, and Bcl-2 protein in cervicovaginal smears from patients with invasive cervical cancer

• Published in: Cancer epidemiology, biomarkers & prevention biomarkers & prevention, 1996-05, Vol.5 (5), p.329-335
• Main Authors: Pillai, M R, Halabi, S, McKalip, A, Jayaprakash, P G, Rajalekshmi, T N, Nair, M K, Herman, B
• Format: Article
• Language: English
• Subjects: Adult; Aged; Apoptosis - genetics; Carcinoma - genetics; Carcinoma - pathology; Carcinoma - virology; Cause of Death; Cell Transformation, Neoplastic - pathology; Disease Progression; DNA-Binding Proteins; Female; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Humans; Microscopy, Fluorescence; Middle Aged; Mutation - genetics; Neoplasm Invasiveness; Oncogene Proteins, Viral - analysis; Oncogenes - genetics; Papanicolaou Test; Papillomaviridae - genetics; Papillomavirus Infections; Protein-Tyrosine Kinases - analysis; Proto-Oncogene Proteins c-bcl-2 - analysis; Repressor Proteins - analysis; Tumor Suppressor Protein p53 - analysis; Tumor Virus Infections; Ubiquitins - genetics; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology; Vaginal Smears
• ISSN: 1055-9965; 1538-7755

Cervical cancer is the second leading cause of death from cancer in women worldwide, and recent epidemiological studies have strongly implicated the sexually transmitted human papillomavirus (HPV) as a causative agent. The ability of high-risk HPVs to contribute to malignant progression seems to depend on expression of the viral E6 and E7 oncogenes. The E6 oncoprotein forms a complex with the cellular tumor suppressor protein p53, leading to degradation of p53 via ubiquitin-dependent proteolysis. Thus, E6 expression results in the loss of p53 function in cells, including stimulation of apoptosis and inhibition of the expression of the antiapoptotic protein bcl-2. Recently, we found increased bcl-2 expression in cervical carcinoma cell lines containing mutated or E6-inactivated p53 (X. L. Liang, S. Mungal, A. Ayscue, J. D. Meissner, P. Wodnicki, G. Gordon, S. Lockett, and B. Herman. J. Cell. Biochem., 57: 509-520, 1995). Based on these findings, we examined Papanicolaou smears from 94 women with varying degrees of cervical disease for the presence or absence of p53, HPV-16/18 E6, and bcl-2 proteins using immunofluorescence microscopy. Our findings indicate that there is a statistically significant, inverse association between the presence of p53 and invasive cervical disease [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.7]. Moreover, the odds of being diagnosed with an invasive stage of cervical cancer were 3.7 times higher (95% CI, 1.6-8.8) for women positive for the E6 protein and 17 times higher (95% CI, 5.5-58.3) for women positive for the bcl-2 protein compared with women negative for E6 and bcl-2. Women with invasive cervical cancer were also 4.59 times more likely to test positive for the presence of more than one marker (95% CI, 1.8-11.8). Chi(2) analysis demonstrated a strong association between the presence of E6 and bcl-2 (P < 0.001) as well as between the presence of E6 of bcl-2 and diagnosis (P = 0.015 and < 0.001, respectively). In the multivariate analysis, the presence of bcl-2 (OR, 18.8; 95% CI, 5.5-67.8) and age at diagnosis (> or = 50 years; OR, 7.8; 95% CI, 2.5-24.5) showed significant association with Invasive cervical disease. These findings indicate that: (a) the presence of the bcl-2 protein is strongly associated with the development of invasive cervical disease: (b) the pattern of the presence of high-risk HPV-E6, p53, and bcl-2 proteins may be useful for identifying women at increased risk for the development of invas