Increased expression of DNA methyltransferase 1 (DNMT1) protein in uterine cervix squamous cell carcinoma and its precursor lesion

Aberrant DNA methylation has been shown to play important roles during multistage carcinogenesis in various human organs. The aim of this study was to evaluate the significance of DNA methyltransferase 1 (DNMT1) protein expression during cervical carcinogenesis. We carried out an immunohistochemical examination for DNMT1 in 34 samples of histologically normal squamous epithelium, 36 samples of low-grade cervical intraepithelial neoplasia (CIN), 61 samples of higher-grade CIN and 30 samples of squamous cell carcinoma of the uterine cervix. The DNMT1 protein expression score, reflecting the intensity and incidence of DNMT1 nuclear immunoreactivity, was increased even in low-grade CIN (P < 0.0001) in comparison with histologically normal squamous epithelium and was further increased in higher-grade CIN (P < 0.0001 compared to low-grade CIN). The DNMT1 protein expression score remained at a plateau in microinvasive carcinoma (Stage IA, P = 0.0690 compared to higher-grade CIN) and then decreased with cancer invasion (Stage IB or more, P = 0.0176 compared to Stage IA), whereas the proliferating cell nuclear antigen (PCNA) labeling index did not decrease with cancer invasion (P = 0.8259 between Stage IA and Stage IB or more). Thus, the DNMT1 protein expression score and the PCNA labeling index were not mutually correlated in squamous cell carcinoma of the uterine cervix (P = 0.2304). These data suggest that progressively increasing expression of DNMT1 protein is not entirely a secondary result of increased cell proliferative activity, but is associated with an early step of multistage cervical carcinogenesis.