title: The presence of human papillomavirus-16/-18 E6, p53, and Bcl-2 protein in cervicovaginal smears from patients with invasive cervical cancer.
abstract: 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 invasive cervical cancer; and (c) a defect in apoptosis may partially underlie the development of cervical cancer.
authors.affiliation: Department of Cell Biology and Anatomy, School of Medicine, University of North Carolina at Chapel Hill, 27599-7090, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Pillai
authors.forename: S
authors.initials: S
authors.lastname: Halabi
authors.forename: A
authors.initials: A
authors.lastname: McKalip
authors.forename: P G
authors.initials: PG
authors.lastname: Jayaprakash
authors.forename: T N
authors.initials: TN
authors.lastname: Rajalekshmi
authors.forename: M K
authors.initials: MK
authors.lastname: Nair
authors.forename: B
authors.initials: B
authors.lastname: Herman
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics / Q000473:pathology* / Q000821:virology; D002423:Cause of Death; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D004268:DNA-Binding Proteins; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006801:Humans; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D009856:Oncogene Proteins, Viral / Q000032:analysis*; D009857:Oncogenes / Q000235:genetics; D065006:Papanicolaou Test; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections; D011505:Protein-Tyrosine Kinases / Q000032:analysis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D012097:Repressor Proteins / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D014412:Tumor Virus Infections; D014452:Ubiquitins / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology; D014626:Vaginal Smears
chemical_list: D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D011505:Protein-Tyrosine Kinases