Alterations of p16INK4a, p14ARF, p53, PCNA expressions and their relationship to HPV infection in the tumor progression of cervical cancer

JL Wang MD PhD^a, BY Zheng MD^a, M Lindstr, Ã

^aDepartment of Molecular Medicine, ^bDepartment of Oncology-Pathology; Karolinska Institute, Stockholm, Sweden

AIM: to evaluate the clinic significance of p16INK4a, p14ARF, p53 and PCNA expressions in tumor progression of cervical cancer. METHODS: 17 patients (40 samples) with consecutive cervical lesions from normal squamous epithelium/inflammatory of cervix to cervical intraepithelial neoplasm (CIN) and squamous cervical cancer (SCC) or from CIN to SCC were collected in this study. The expressions of p16INK4a, p14ARF, p53 and PCNA were detected by immunohistochemistry on paraffin embedded sections. In the same time, HPV DNA was detected with PCR and the type was determined by DNA sequence. RESULTS: The HPV type detected were 62.5% in normal/inflammatory biopsies, 80% in CIN and 100% in SCC. The main types of HPV were still HPV 16, 18, 31, 33 and 45. p16INK4a overexpression was significant higher in CIN (75.0%) and SCC (75.0%) than that in normal/inflammatory of cervix (12.5%) (p<0.01). The expression of p16INK4a and p14ARF were increased in 71.4% and 71.4% of cases with HPV infection from negative to positive, and in 60.0% and 70.0% of cases with HPV infection persistently (HPV + to +). However, p53 expression was increased in 57.1% of cases with HPV – to + and 30.0% of cases with HPV + to +. During the progression, cases with p16INK4a expression increasing had a shorter interval time (64.2±47.5 months) than that of p16INK4a expression stable (116.5±18.5 months) and decreasing (108.5±26.7 months). The interval time of Cases with p14ARF expression increasing in the progression was 78.8±35.4 months, with p14ARF expression decreasing or negative was 105.5±59.1 months. However, when the cases with p53 expression decreasing, the interval time was shortest (32.3±26.7 months). CONCLUSIONS: p16INK4a, p14ARF and PCNA overexpression relate to the progression of cervical lesions. P16INK4A, p14ARF expression increasing and p53 expression decreasing in the progression have a shorter interval time. It might suggest p16INK4a and p14ARF would be valuable markers to predict the progression of cervical disease.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 893 (Molecular pathology - Part I).