The possible role of cell cycle regulators in multistep process of HPV-associated cervical carcinoma

BACKGROUND Human papillomavirus (HPV) 16 and 18 are associated with cervical carcinogenesis through an interaction between HPV oncogenic proteins and cell cycle regulatory genes. However, the exact pathogenetic mechanisms are not determined yet. METHODS We investigated 43 invasive squamous cell carcinoma (ISCC), 38 CIN III, 11 CINII and 18 CINI for cyclin D1, cyclin E, CDK4, p53, mdm-2, p21(waf), p27, p16(INK4A), Rb and Ki-67 aberrations using immunohistochemistry and molecular techniques. Twenty samples of normal cervical tissues (NCT) were taken as a control. RESULTS There was a significant increase in the expression of Ki-67, cyclin E, CDK4, p16(INK4A), Rb (p= 0.003, 0.001, 0.001, 0.01) and a significant decrease in p27(KIP1) from NCT to ISCC (p = 0.003). Increased cyclin D1, p21(waf), p53, mdm-2 expression, homozygous deletion (HZD) and promoter methylation (PM) of the Rb were detected in CINIII and ISCC only. On univariate analysis; tumor size, differentiation, lymph node status, FIGO stage, Ki-67, cyclin D1, p53 and p27(KIP1) are significantly associated with reduced overall survival (OS) while on multivariate analysis; only FIGO stage, Ki-67, cyclin D1, p53 and p27(KIP1) were significant. CONCLUSION 1) Aberrations involving p27(KIP1), cyclin E, CDK4, p16(INK4A) are considered early events in HPV 16 and 18-associated cervical carcinoma, whereas cyclin D1 and p53 pathway abnormalities are considered late events. 2) Immunohistochemical tests for p16(INK4A) and cyclin E, could help in early diagnosis of cervical carcinoma. 3) Only FIGO stage p53, cyclin D1, p27(KIP1) and Ki-67 are independent prognostic factors that might help in predicting outcome of cervical cancer patients.