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

Abeer A Bahnassy,Maha Saleh,Manar Moneir,Osama Shawki,Mohammad Lotayef,Abdel Rahman N Zekri

doi:10.1186/1472-6890-7-4

Abstract

BackgroundHuman 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.MethodsWe investigated 43 invasive squamous cell carcinoma (ISCC), 38 CIN III, 11 CINII and 18 CINI for cyclin D1, cyclin E, CDK4, p53, mdm-2, p21waf, p27, p16INK4A, Rb and Ki-67 aberrations using immunohistochemistry and molecular techniques. Twenty samples of normal cervical tissues (NCT) were taken as a control.ResultsThere was a significant increase in the expression of Ki-67, cyclin E, CDK4, p16INK4A, Rb (p= 0.003, 0.001, 0.001, 0.01) and a significant decrease in p27KIP1 from NCT to ISCC (p = 0.003). Increased cyclin D1, p21waf, 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 p27KIP1 are significantly associated with reduced overall survival (OS) while on multivariate analysis; only FIGO stage, Ki-67, cyclin D1, p53 and p27KIP1 were significant.Conclusion1) Aberrations involving p27KIP1, cyclin E, CDK4, p16INK4A 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 p16INK4Aand cyclin E, could help in early diagnosis of cervical carcinoma. 3) Only FIGO stage p53, cyclin D1, p27KIP1 and Ki-67 are independent prognostic factors that might help in predicting outcome of cervical cancer patients.

Highlights

Human papillomavirus (HPV) 16 and 18 are associated with cervical carcinogenesis through an interaction between HPV oncogenic proteins and cell cycle regulatory genes
3) Only Federation of Gynecolology and Obstetrics (FIGO) stage p53, cyclin D1, p27KIP1 and Ki-67 are independent prognostic factors that might help in predicting outcome of cervical cancer patients
Expression of cyclins and cyclin dependent kinases (CDKs) Cyclin D1 overexpression was detected in CINIII and invasive squamous cell carcinoma (ISCC) cases only

Summary

Introduction

Human papillomavirus (HPV) 16 and 18 are associated with cervical carcinogenesis through an interaction between HPV oncogenic proteins and cell cycle regulatory genes. Undermining of pRb growth-inhibitory role with release of E2F transcription factors render the cells independent of mitogenic stimuli [5], whereas inactivation of the p53 precludes its role as one of the major factors controlling cell proliferation since it arrests the cell cycle in response to DNA damage or direct the damaged cell to an apoptotic pathway. This function is abolished via p53 degradation by the E6 protein of oncogenic HPV types or via cytoplasmic sequestration by complexing to mdm-2 protein [6]

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