Cell Cycle and Cervical Carcinoma Kanai et al. also found elevated cyclin B levels in SIL and invasive carcinomas and concomitantly elevated levels of cdc2, indicating that cyclin B plays an important role in cervical carcinoge- nesis.79 Contrary to the above results, Hashiguchi, et al. examined HPV status and cyclin B1 in CIN and invasive cancer by immunohistochemistry. This study showed that expression of cyclin B1 was 0% in CIN and 12.2% in invasive cancers, and the relationship between HPV type and cyclin B1 expression was not significant.111 Further experimental data are needed to confirm the role of cyclin B in malignant transformation of the cervix. CONCLUSION Cervical cancer, which plagues women all over the world, is still a major focus of oncological research. Infection with HPV has been implicated as an important etiological factor in the develop- ment of uterine cervical cancer. Moreover, even in cases where HPV infection persists, cervical can- cer most often does not appear until many years or more than a decade after infection. This long delay has supported the view that HPV infection may initiate, but not necessarily cause, progres- sion to cervical carcinoma, and that oncogenic influences by other factors such as environmental factors, specific aspects of lifestyle, or genetic alterations are necessary to fully establish an HPV-induced malignancy. Because cancer is a multi-etiological disease, the time lag between HPV infection and the diagnosis of cancer also indicates that multiple steps as well as multiple factors may be necessary for the development of cervical cancer. High-risk HPV types, specifically types 16 and 18, have been demonstrated to participate in cervical carcinogenesis through the expression of proteins, such as E6 and E7, interaction with different steroid hormones, and interaction with innate genetic susceptibilities to develop cervical cancer. The results from many studies showed aberrant alterations in the regulation of several cell cycle proteins, including cyclin D and E and p16, p21, and p27, to be characteristic features of HPV-infected and HPV E6/E7 oncogene-expres- sing cervical carcinomas and their precursors. These data suggest further that interactions of viral proteins with host cellular proteins, parti- cularly cell cycle proteins, are involved in activa- tion or repression of cell cycle progression in cervical carcinogenesis. REFERENCES 1. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999;49:33-64. 2. Zur Hausen H. Papillomaviruses causing cancer: eva- sion from host-cell control in early events in carcino- genesis. J Natl Cancer Inst 2000;92:690-8. 3. Clarke B, Chetty R. Cell cycle aberrations in the patho- genesis of squamous cell carcinoma of the uterine cervix. Gynecol Oncol 2001;82:238-46. 4. Milde-Langosch K, Riethdorf S. Role of cell-cycle regu- latory proteins in gynecological cancer. J Cell Physiol 2003;196:224-44. 5. Funk JO. Cancer cell cycle control. Anticancer Res 1999; 19:4772-80. 6. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501-12. 7. Semczuk A, Jakowicki JA. Alterations of pRb1-cyclin D1-cdk4/6-p16INK4A pathway in endometrial carcino- genesis. Cancer Lett 2004;203:1-12. 8. Murphy N, Heffron CC, King B, Ganuguapati UG, Ring M, McGuinness E, et al. p16INK4A positivity in benign, premalignant and malignant cervical glandular lesions: a potential diagnostic problem. Virchows Arch 2004; 445:610-5. 9. Kim JR, Kim SY, Kim MJ, Kim JH. Alterations of CDKN2 (MTS1/p16INK4A) gene in paraffin-embedded tumor tissues of human stomach, lung, cervix and liver cancers. Exp Mol Med 1998;30:109-14. 10. Dong SM, Kim HS, Rha SH, Sidransky D. Promoter hypermethylation of multiple genes in carcinoma of the uterine cervix. Clin Cancer Res 2001;7:1982-6. 11. Nuovo GJ, Plaia TW, Belinsky SA, Baylin SB, Herman JG. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc Natl Acad Sci USA 1999;96:12754-9. 12. Tsuda H, Hashiguchi Y, Nishimura S, Kawamura N, Inoue T, Yamamoto K. Relationship between HPV typing and abnormality of G1 cell cycle regulators in cervical neoplasm. Gynecol Oncol 2003;91:476-85. 13. Hirama T, Miller CW, Wilczynski SP, Koeffler HP. p16 (CDKN2/cyclin-dependent kinase-4 inhibitor/multiple tumor suppressor-1) gene is not altered in uterine cervi- cal carcinomas or cell lines. Mod Pathol 1996;9:26-31. 14. Kelley MJ, Otterson GA, Kaye FJ, Popescu NC, Johnson BE, Dipaolo JA. CDKN2 in HPV-positive and HPV- negative cervical-carcinoma cell lines. Int J Cancer 1995; Yonsei Med J Vol. 46, No. 5, 2005