(HPV) Advances of research on the carcinogenesis of human Papillomavirus. LIU Li-hong 1, WANG Kai 2, ZHANG Fu-chun 1, MA Zheng-hai 1 * (HPV )

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1 Chinese Bulletin of Life Sciences Vol. 20, No. 2 Apr., (2008) (HPV) ( ) (Human Papillomavirus HPV) HPV E2 E2 E5 EGFR E6 E7 E6 E7 p53 prb (htert) HPV HPV R373; R A Advances of research on the carcinogenesis of human Papillomavirus LIU Li-hong 1, WANG Kai 2, ZHANG Fu-chun 1, MA Zheng-hai 1 * (1 Key Laboratory of Molecular Biology, Key Laboratory of Xinjiang Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University,Urumqi , China; 2 Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai , China) Abstract: Human Papillomavirus(HPV) can be transmitted widely in human, which can cause human being's skin and mucosa of dysplasia. Some types of HPV are closely related with malignant genitalia disease. In the carcinogenic process of HPV, E2 gene normally integrates into the host cells, and resultes in the inactivation of E2 protein, which caused the over-expression of E6, E7 genes. Meanwhile, E5 gene sitimulates cell cycles via EGFR, which in turn raising the over-expression of E6, E7 genes. The activities of p53 gene and prb gene are inhibited by HPV16 E6 and E7 proteins respectively, resulting in the activation of the transcription of htert, and the inblance of cells, which could change the cells from the normal to the cancer. The carcinogenic process of HPV is a multi-factor and multi-step process, in which genetic and synergistic factors also play an important role. With the in-depth study, the carcinogenic mechanism of HPV has been drawn increased attention of the basic researchers and clinicians. The explorations of the carcinogenic mechanism of HPV has become the hotspot in the research. Key words: human Papillomavirus; carcinogenesis; synergistic factors HPV [1] 100 HPV 42 [2] HPV [3] (HPV ) ( ) * mzhxju@sohu.com

2 296 (HPV16 18) [4] ( ) [5] HPV HPV HPV HPV [6] HPV HPV 1 HPV HPV nm DNA 3 E1 E7 L1 L2 [7,8] 2 HPV HPV HPV L1 DNA HPV 50% HPV 100 HPV HPV L1 (BPV) [9] HPV HPV HPV HPV HPV HPV HPV HPV HPV16 HPV18, HPV16 HPV18 [10] 3 HPV (HPV) DNA HPV HPV HPV16 HPV16 HPV HPV HPV DNA 1 HPV16

3 (HPV) 297 E2 E6 E7 HPV DNA FRA3B 3p q14t [11] 13q14 prb prb HPV [12] HPV HPV E2 htert [13] Rahat [14] HPV 3.2 HPV HPV16 E2 E N C DNA E2 DNA HPV E2 E2 E2 E6 E7 [15] Goodwin DiMaio [16] E2 HPV18 HeLa E2 HPV18 E6 E7 P53 prb DNA E2 [17] HPV16 E5 E5 84 E5 E6 E7 p53 prb [18] E5 (EGFR) ATP EGFR EGFR EGF EGFR HPV16 E5 EGF MAP c-fos c-jun E5 MAP [19] HPV16 E6 E E6 E7 (HFK) E6 E6 AP p53 E6 p53 p53 E6 p53 HPV HPV E6 p53 E6 p53 p53 E6 p53 HPV [20] Shai [21] Snijders [22] HPV16E6 p53 CBP/p300 p53 HPV E6 p16 p27 G DNA (S ) HPV16 E7 E7 98 CR1 CR2 CR3 3 E7 C N CR1 CR2 E7 E7 HPV HPV ( ) E7 (HFK) E7 CR2 LXCXE Rb E2F DNA [23,24] E7 prb TGF-p p16 p21 p27 G/S HPV E7 p21 p21 p21 CyclinE CyclinA CDK2 p21 (proliferating cell nuclear antigen, PCNA) DNA p21 p21 prb E2F p21 E7 p53 E7 DNA E7 CyclinA CyclinA E2F [25,26] 3.3 HPV

4 298 HPV HPV -2 (HSV-2) (CT) (HCMV) De Villiers [27] Delvenne [28] HPV HPV (66.7%) (31.1%) HPV (PRE) (GRE) PRE/GRE HPV [27,28] 4 HPV HPV E6 E7 E6 E7 RNAi E6 E7 E6 E7 [1] Robertson C, Jayasuriya A, Allan PS. Sexually transmitted infections: where are we now? J R Soc Med, 2007, 100 (9): [2] Steben M, Duarte-Franco E. Human Papillomavirus infection: Epidemiology and pathophysiology. Gynecol Oncol, 2007, 107: S2-5 [3] Newall AT, Beutels P, Wood JG, et al. Cost-effectiveness analyses of human Papillomavirus vaccination.lancet Infect Dis, 2007, 7 (4): [4] Stanley M. Prevention strategies against the human Papillomavirus:The effectiveness of vaccination.gynecol Oncol, 2007, 107: S19-23 [5] Zimmerman RK. Ethical analysis of HPV vaccine policy options. Vaccine, 2006, 24 (22): [6] Weller SC, Stanberry LR. Estimating the population prevalence of HPV. JAMA, 2007, 297 (8): [7] Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent human Papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recommendations and Reports, 2007, 56 (RR-2): 1-24 [8] Wang Q, Griffin N, Southern S, et al. Functional analysis of the human Papillomavirus type 16 E1-E4 protein provides a mechanism for in vivo and in vitro keratin filament reorganization. J Virol, 2004, 78 (2): [9] Gravitt PE, van Doorn LJ, Quint W, et al. Human Papillomavirus (HPV) genotyping using paired exfoliated cervicovaginal cells and paraffin-embedded tissues to highlight difficulties in attributing HPV types to specific lesions. JCM, 2007, 45 (10): [10] Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10- year risk of cervical precancer and cancer in women with human Papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst, 2005, 97 (14): [11] Butler D, Mabruk M, Mabruk M. Deletion of the FHIT gene in neoplastic and invasive cervical lesions is related to high-risk HPV infection but is independent of histopathological features. J Pathol, 2000, 192: [12] Hopman AH, Smedts F. Transition of highgrade cervical intraepithelial neoplasia to micro-invasive carcinoma is characterized by chromosome abnormalities. J Pathol, 2004, 202 (1) : [13] Horikawa I, Barrett JC. Transcriptional regulation of the telomerase htert gene as a target for cellular and viral oncogenic mechanisms. Carcinogenesis, 2003, 24 (7): [14] Rahat MA, Lahat N, Sharon A, et al. Increased telomerase activity and decreased telomere length in genital condylomata acuminata. Int J STD AIDS, 1999, 10: [15] Parish JL, Kowalczyk A, Chen HT, et al. E2 proteins from high and low risk human Papillomavirus types differ in their ability to bind p53 and induce apoptotic cell death. J Virol, 2006, 80 (9): [16] Goodwin EC, DiMaio D. Repression of human Papillomavirus onoogenes in HeLa cervical carcinoma cells causes the orderly reaetivation of dormant tumor suppressor pathways. Proc Natl Acad Sci USA, 2000, 97 (23): [17] Demeret C, Garcia Carranca A, Thierry F. Transcription indepandent triggering of the extrinsic pathway of apoptosis by human Papillomavirus l8 E2 protein. Oneogene, 2003, 22 (2): [18] Disbrow GL, Hanover JA, Schlegel R. Endoplasmic reticulum-localized human Papillomavirus type 16 E5 protein alters endosomal ph but not trans-golgi ph. J Virol, 2005, 79 (9): [19] Maufort JP, Williams SM, Pitot HC, et al. Human Papillomavirus 16 E5 oncogene contributes to two stages of skin carcinogenesis. Cancer Res, 2007, 67 (13): [20] Zhang Y, Dasgupta J, Ma RZ, et al. Structures of a HPV-E6

5 (HPV) 299 polypeptide bound to MAGUK proteins: mechanisms of targeting tumor suppressors by a high-risk HPV oncoprotein. J Virol, 2007, 81 (7): [21] Shai A, Brake T, Somoza C, et al. The human Papillomavirus E6 oncogene dysregulates the cell cycle and contributes to cervical carcinogenesis through two independent activities. Cancer Res, 2007, 67 (4): [22] Snijders PJ, van Duin M, Walboomers JM, et al. Telomerase activity exclusively in cervical carcinomas and a subset of cervical intraepithelial neoplasia grade III lesions: strong association with elevated messenger RNA levels of its catalytic subunit and high-risk human Papillomavirus DNA. Cancer Res, 1998, 58 (17): [23] Boulet G, Horvath C, Broeck DV, et al. Human Papillomavirus: E6 and E7 oncogenes. Int J Biochem Cell Biol, 2007, 39: [24] Liu X, Clements A, Zhao KH, et al. Structure of the human Papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor. J Biol Chem, 2006, 281 (1): [25] Tamura G, Yin J, Wang S, et al. E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. J Natl Cancer Inst, 2000, 92: [26] Fields BN, Knipe DM, Howley PM, et al. Papillomaviridae: the viruses and their replication[m]. 3rd ed. Fields virology. Philadelphia:Lippincott Raven Publishers, 1996: [27] De Villiers. Relationship between steroid hormone contraceptives and HPV, cervical intraepithelial neoplasia and cervical carcinoma. Int J Cancer, 2003, 103 (6): [28] Delvenne P, Herman L, Kholod N, et al. Role of hormone cofactors in the human Papillomavirus induced carcinogenesis of the uterine cervix. Mol Cell Endocrinol, 2007, 264 (1-2) : 1-5 HIV HIV-1 mntrimcyp TRIM5α HIV-1 HIV/AIDS HIV/AIDS HIV AIDS HIV ( ) HIV/AIDS AIDS HIV/AIDS HIV-1 HIV-1 AIDS TRIM5α HIV-1 HIV-1 HIV-1 TRIM5α HIV-1 N-MLV EIAV TRIM5α (CypA) - CypA HIV-1 Gag HIV-1 HIV-1 TRIM5α-CypA HIV-1 HIV-1 TRIM5α HIV-1 CypA cdna TRIM5 TRIM5-CypA HIV-1 HIV-1 HIV-1 TRIM5α-CypA HIV-1 mntrimcyp HIV-1 TRIM5α CypA HIV-1 HIV AIDS mntrimcyp mntrimcyp TRIM5α CypA HIV (AIDS)