Pillai M R, Halabi S, McKalip A, Jayaprakash P G, Rajalekshmi T N, Nair M K, Herman B
Department of Cell Biology and Anatomy, School of Medicine, University of North Carolina at Chapel Hill, 27599-7090, USA.
Cancer Epidemiol Biomarkers Prev. 1996 May;5(5):329-35.
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.
宫颈癌是全球女性癌症死亡的第二大主要原因，最近的流行病学研究有力地表明，性传播的人乳头瘤病毒（HPV）是致病因素。高危型HPV促成恶性进展的能力似乎取决于病毒E6和E7癌基因的表达。E6癌蛋白与细胞肿瘤抑制蛋白p53形成复合物，导致p53通过泛素依赖性蛋白水解作用而降解。因此，E6的表达导致细胞中p53功能丧失，包括刺激细胞凋亡和抑制抗凋亡蛋白bcl-2的表达。最近，我们发现在含有突变型或E6失活型p53的宫颈癌细胞系中，bcl-2表达增加（X.L.梁、S.蒙加尔、A.艾斯克、J.D.迈斯纳、P.沃迪茨基、G.戈登、S.洛克特和B.赫尔曼。《细胞生物化学杂志》，57:509 - 520，1995年）。基于这些发现，我们使用免疫荧光显微镜检查了94名患有不同程度宫颈疾病的女性的巴氏涂片，以检测p53、HPV - 16/18 E6和bcl-2蛋白的有无。我们的研究结果表明，p53的存在与浸润性宫颈疾病之间存在统计学上显著的负相关[比值比（OR），0.3；95%置信区间（CI），0.1 - 0.7]。此外，与E6和bcl-2呈阴性的女性相比，E6蛋白呈阳性的女性被诊断为宫颈癌浸润期的几率高3.7倍（95% CI，1.6 - 8.8），bcl-2蛋白呈阳性的女性被诊断为宫颈癌浸润期的几率高17倍（95% CI，5.5 - 58.3）。患有浸润性宫颈癌的女性检测出一种以上标志物呈阳性的可能性也高4.59倍（95% CI，1.8 - 11.8）。卡方分析表明E6和bcl-2的存在之间存在强关联（P < 0.001）以及E6或bcl-2的存在与诊断之间存在强关联（分别为P = 0.015和< 0.001）。在多变量分析中，bcl-2的存在（OR，18.8；95% CI，5.5 - 67.8）和诊断时的年龄（≥50岁；OR，7.8；95% CI，2.5 - 24.5）与浸润性宫颈疾病显示出显著关联。这些发现表明：（a）bcl-2蛋白的存在与浸润性宫颈疾病的发生密切相关；（b）高危型HPV - E6、p53和bcl-2蛋白的存在模式可能有助于识别浸润性宫颈癌发生风险增加的女性；（c）细胞凋亡缺陷可能是宫颈癌发生的部分原因。
