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. 2007 May 24:7:4.
doi: 10.1186/1472-6890-7-4.

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

Abeer A Bahnassy  1 , Abdel Rahman N Zekri, Maha Saleh, Mohammad Lotayef, Manar Moneir, Osama Shawki
Affiliations

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

Abeer A Bahnassy et al. BMC Clin Pathol. .

Abstract

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.

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Figures

Figure 1
Figure 1
a) Positive immunostaining for p27KIP1 in the nuclei of normal cervical tissue, b) positive immunostaining for p27KIP1 in CINI, c) lack of p27KIP1 immunostaining in a case of invasive squamous cell carcinoma, d) positive immunostaining for p16INK4A in a case of CINII, e) positive immunostaining for p16INK4A in a case of III, f) negative nuclear imminostaining for cyclinD1 in normal cervical tissue except in the parabasal cells, g) a strongly positive immunostaining for cyclinD1 in a case of invasive squamous cell carcinoma, h) positive nuclear immunostaining for Rb in parabasal and intermediate squamous cells in hyperplastic squamous epithelium, and i) focal and weak nuclear staining for Rb in a case of invasive squamous cell carcinoma.
Figure 2
Figure 2
Cases of invasive squamous cell carcinoma showing a) strong nuclear immunostaining for p53, b) diffuse nuclear staining for mdm2, c) positive nuclear immunostaining for p21WAF and, d) positive immunostaining for ki-67.
Figure 3
Figure 3
An ethidium bromide-stained 2% agarose gel for CDK4 gene amplification, lane 1: molecular weight marker (MW), lanes 2–7: cases of invasive squamous cell carcinoma, lanes 8–12: CIN cases, lanes 13–14: normal cervical tissue samples, lane 15: a negative control. Lanes 2, 3, 8 show CDK4 gene amplification.
Figure 4
Figure 4
An ethidium bromide-stained 2% agarose gel for cyclinD1 gene amplification, lane 1: MW, lanes 2–8: cases of invasive squamous cell carcinoma, lanes 9–14: CIN cases, lanes 15–16: normal cervical tissue samples. Lanes 2,4,6,8,10,12,14 show cyclinD1 gene amplification.
Figure 5
Figure 5
An ethidium bromide-stained 2% agarose gel for cyclinE gene amplification, lane 1: MW, lanes 2–4: normal cervical tissue samples, lanes 5–9: CIN cases, lanes 10–14: cases of invasive squamous cell carcinoma. Lanes 10, 13, 14 show cyclinE gene amplification.
Figure 6
Figure 6
An ethidium bromide-stained 4% agarose gel for Rb gene methylation lane 1: methylated control, lane 18: unmethylted control, lanes 8–12: cases of invasive squamous cell carcinoma, lanes 12–17: CIN cases.
Figure 7
Figure 7
A case of ISCC showing mutation in exon 7 of the p53 gene codon 247 by single stranded conformation polymorphism and sequence analysis.
Figure 8
Figure 8
The percentage of protein expression of different studied markers in the studied groups.
See this image and copyright information in PMC

References

    1. Klaes R, Woerner SM, Ridder R, Wentzensen N, Duerst M, Schneider A, Lotz B, Melsheimer P, Von Knebel Doeberitz M. Detection of high risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer res. 1999;59:6132–9616. - PubMed
    1. Clarke B, Chetty R. Cell cycle aberrations in the pathogenesis of squamous cell carcinoma of the uterine cervix. Gynecol Oncol. 2001;82:238–246. doi: 10.1006/gyno.2001.6306. - DOI - PubMed
    1. Howley PM, Scheffner M, Munger K. Oncoproteins encoded by the cancer-associated papillomavirus target the products of retinoblastoma and p53 tumor suppressor genes. Quant Biol. 1991;56:149–155. - PubMed
    1. Masumoto T, Fuji T, Ishikawa M, Saito M, Iwata T, Fukuchi T, Susumu N, Mukai M, Kubushiro K, Tsukazaki K, Nozawa S. p16 overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix. Hum Pathol. 2003;34:778–783. doi: 10.1016/S0046-8177(03)00284-3. - DOI - PubMed
    1. Spitokovsky D, Aengeneyndt F, Braspenning J, Doeberitz VK. P53-independent growth regulation of cervical cancer cells by the papillomvirus E6 oncogene. Ocogene. 1996;13:1027–1035. - PubMed