Transcriptional Inactivation of p53, Bax, Bcl-2 and Mdm2 Correlates with Malignant Transformation of the Uterine Cervix

Abstract

Deregulation of the apoptotic machinery plays a major role in cell death, cellular transformation and cancer. p53, Bcl-2, Bcl-XL, Bax and Mdm2 mRNA expression patterns were evaluated in tissue samples with cervical intraepithelial neoplasia (CIN) and cervical cancer compared to those of normal cervical tissues, and correlated with the underlying cervical lesions. Transcript levels of the above genes were assessed by RT-PCR analysis in a total of 44 cervical specimens. p53, Bcl-2, Bax and Mdm2 transcript levels were significantly different in the normal, CIN and cancer specimen groups (p=0.003, p=0.009, p=0.040 and p=0.001, respectively). Specifically, p53, Bax and Bcl-2 exhibited substantially lower transcript levels in CIN lesions compared to controls, whereas Bax mRNA levels showed a significant decrease in cancer compared to normal specimens. Mdm2 mRNA expression was considerably lower in cancer than in CIN lesions or normal cervix. High-grade squamous intraepithelial lesions exhibited lower p53 and Bcl-2 mRNA levels than controls (p=0.002, p=0.016). Coexpression analysis revealed more correlations between the above apoptosis-related molecules in normal tissues compared to CIN or cancer specimens. p53 showed significant coexpression with Bax, Bcl-2 and Mdm2 (p=0.040, p=0.013 and p=0.015, respectively) in normal cervical specimens. Bax and Bcl-XL mRNA expression was negatively correlated. Mdm2 transcriptional levels correlated significantly with those of Bax, Bcl-XL and Bcl-2. Our findings show that p53, Bax, Bcl-2 and Mdm2 mRNA expression levels correlate with the malignant transformation of the uterine cervix. mRNA coexpression patterns of the members of the pro- and anti-apoptotic family examined in cervical carcinogenesis were found to be disrupted in CIN and cancer, as already demonstrated at the protein level.