The role of p53, Bcl-2 and Ki-67 in premalignant cervical lesions and cervical cancer

Purpose: The aim of this study was to determine the role of p53, Bcl-2 and Ki-67 expression in the carcinogenesis of cervical carcinoma and aggressiveness of cervical intraepithelial neoplasia (CIN).

Methods: The pathology specimens of 63 patients with a diagnosis of normal squamous epithelium (22 cases), CIN I (14), CIN II (5), CIN III (8) and squamous cell carcinoma (14) were evaluated immunohistochemically for the expression of p53, Bcl-2 and Ki-67 in paraffin sections.

Results: The expression of p53 and Ki-67 increased proportionally to the grade of CIN and cervical cancer, but only the increase of p53 expression was statistically significant (p = 0.002). There was no significant correlation between Bcl-2 expression and premalignant and malignant cervical lesions.

Conclusion: p53 expression may have a role in the carcinogenesis of squamous cell cervical carcinoma whereas Bcl-2 expression has no role. Ki-67 expression can not be used in determining the aggressiveness of CIN lesions.

Cervical intraepithelial neoplasia; Cervical cancer; p53; Bcl-2; Ki-67

[1] Van Leeuwen A.M., Pieters W.J., Hollema H., Burger M.P.: "Atypical mitotic figures and the mitotic index in cervical intraepithelial neoplasia". Virchows Arch., 1995, 427,139.

[2] Schluter C., Duchrow M., Wohlenberg C., Becker M.H., Key G., Flad H.D. et al.: "The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins". J. Cell Biol., 1993, 123, 513.

[3] Kruse A.J., Baak J.P., de Bruin P.C., Jiwa M., Snijders W.P., Boodt P.J. et al.: "Ki-67 immunoquantitation in cervical intraepithelial neoplasia (CIN): a sensitive marker for grading". J Pathol., 2001, 193, 48.

[4] Bar J.K., Harlozinska A., Sedlaczek P., Kasiak J., Markowska J. "Relations between the expression of p53, c-erbB-2, Kl-67 and HPV infection in cervical carcinomas and cervical dysplasias". Anticancer Res., 2001, 21, 1001.

[5] Cheah P.L., Looi L.M.: "p53 immunohistochemical expression messages in cervical carcinogenesis". Pathology, 2002, 34, 326.

[6] Giarnieri E., Mancini R., Pisani T., Alderisio M., Vecchione A "Msh2, Mlhl , Fhit, p53, Bcl-2, and Bax expression in invasive and in situ squamous cell carcinoma of the uterine cervix". Clin. Cancer Res., 2000, 6, 3600.

[7] Dimtrakakis C., Kymionis G., Diakomanolis E., Papaspyrou I., Rodolakis A., Arzimanoglou I. et al.: "The possible role of p53 and bcl-2 expression in cervical carcinomas and their premalignant lesions". Gynecol. Oncol., 2000, 77, 129.

[8] Dellas A., Schultheiss E., Holzgreve W., Oberholzer M., Torhorst J., Gudat F.: "Investigation of the Bcl-2 and C-myc expression in relationship to the Ki-67 labelling index in cervical intraepithelial neoplasia". Int. J. Gynecol. Pathol., 1997, 16, 212.

[9] Hollstein M., Sidransky D., Vogelstein B., Harris C.C.: "p53 mutations in human cancers". Science, 1991, 253, 49.

[10] Vogelstein B.: "Cancer. A deadly inheritance". Nature, 1990, 348, 681.

[11] Hunt C.R., Hale R.J., Buckley C.H., Hunt J.: "p53 expression in carcinoma of the cervix". J. Clin. Pathol., 1996, 49,971.

[12] Ngan H.Y., Liu S.S., Yu H., Liu K.L., Cheung A.N.: "Proto-oncogenes and p53 protein expression in normal cervical stratified squamous epithelium and cervical intra epithelial neoplasia". Eur. J. Cancer, 1999, 35, 1546.

[13] Tjalma W.A., Weyler J.J.. Bogers J.J.. Polleflet C., Baay M., Goovaerts G.C. et al.: "The importance of biological factors (Bcl-2, bax, p53, PCNA, MI, HPV and angiogenesis) in invasive cervical cancer". Eur. J. Obstet. Gynecol. Reprod. Biol., 2001, 97, 223.

[14] Chen H.Y., Hsu C.T., Lin W.C., Tsai H.D., Chang W.C.: "Prognos tic value of p53 expression in Stage IB 1 cervical carcinoma" Gynecol. Obstet. Invest., 2000, 49, 266.

[15] Finlay C.A., Hinds P.W., Tan T.H., Eliyahu D., Oren M., Levine A.J.: "Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life". Mal. Cell. Biol., 1988, 8, 531.

[16] Kastan M.B., Onyekwere O., Sidransky D., Vogelstein B., Craig R.W.: "Participation of p53 protein in the cellular response to DNA damage". Cancer Res., 1991, 51, 6304.

[17] Prives C., Hall P.A.: "The p53 pathway". J. Pathol., 1999, 187, 112.

[18] Reed J.C.: "Bcl-2 and the regulation of programmed cell death" J. Cell. Biol., 1994, 124, 1.

[19] Cooper K., Haffajee Z., Taylor L.: "bcl-2 immunoreactivity, human papillomavirus DNA, and cervical intraepithelial neoplasia". Mod. Pathol., 1999, 12, 612.

[20] Kokawa K., Shikone T., Otani T., Nakano R.: "Apoptosis and the expression of Bax and Bcl-2 in squamous cell carcinoma and adenocarcinoma of the uterine cervix". Cancer, 1999, 85, 1799.

[21] Cheung T.H., Chung T.K., Lo KW., Yu M.Y., Krajewski S., Reed J.C. et al.: "Apotosis-related proteins in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix". Gynecol. Oncol., 2002, 86, 14.

[22] Chung T.K.H., Cheung T.H., Lo W.K., Yim S.F., Yu M.Y., Krajewski S. et al.: "Expression of apoptotic regulators and their significance in cervical cancer" (letters). Cancer, 2002, 180, 63.

[23] ter Harmsel B., Kuijpers J., Smedts F., Jeunink M., Trimbos B., Ramaekers F.: "Progressing imbalance between proliferation and apoptosis with increasing severity of cervical intraepithelial neoplasia". Int. J. Gynecol. Pathol., 1997, 16, 205.