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

Pathology Department, National Cancer Institute, Cairo University, 1st Kasr El-Aini st. Cairo, Egypt.
BMC Clinical Pathology 02/2007; 7(1):4. DOI: 10.1186/1472-6890-7-4
Source: PubMed


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.
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.
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.
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.

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    • "A high concentration of a cyclin D1 and CDK4 complex can result in the functional inactivation of retinoblastoma protein (pRb) and this pathway is commonly targeted in various malignancies (27). In cervical cancer, binding of HPV E7 protein to Rb leads to release of E2F transcription factor omitting the role of cyclin D1, and CDK4 has been shown a stepwise increase from normal to tumor tissues occurs, indicating an important role at an early stage of transformation of HPV infected cervical epithelium (28, 29). In this study, expression of CDK4 was up regulated in cervical cancer tissue and this finding suggests that CDK4 is closely correlated with carcinogenesis of cervical cancer. "
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    • "Recently, it has been proposed that p27 Kip1 protein works in a negative feedback loop regulating Grb2 in response to mitogen stimulation, inhibiting the Ras signal transduction pathway (Moeller et al., 2003). Other reports have shown that low levels of p27 Kip1 protein correlate with tumor progression and poor patient survival in many human cancers (Abukhdeir and Park 2008; Bahnassy et al., 2007; Catzavelos et al., 1997; Mori et al., 1997). On the other hand, during cancer development, it has been observed that viral oncoproteins from papillomavirus, adenovirus or SV40, target cell cycle proteins and manipulate the cell towards the transformed phenotype. "
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