Reseach progress on human papilloma virus and its related carcinogenesis

20 6 2008 12 Chinese Bulletin of Life Sciences Vol. 20, No. 6 Dec., 2008 1004-0374(2008)06-0843-06 ( 200025) (human papilloma virus, HPV) HPV HPV HPV HPV R730.261; R737.33; R373.9 A Reseach progress on human papilloma virus and its related carcinogenesis LIANG De-guang, HE Zhi-heng, LAN Ke* (Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China) Abstract: Persistant infection of high risk HPV (human papilloma virus) is a critical factor to the onset of women cervical carcinoma. HPV can infect cervical epithelium and establish latent infection through down-regulation of host immune response. Viral proteins encoded by high risk HPV modulate multiple cellular functions during persistant infection, such as apoptosis, proliferation and cell cycle regulation. As a result, the morphology, genetic materials, and epigenetics of cervical epithelium can be changed dramatically. In some cases, HPV infected epithelium can be transformed and further developed to cervial cancer with the assistance of some cofactors. In a word, HPV plays an important role in cervical oncogenesis. This review will introduce recent research progress on the mechanisms by which HPV induces cervical cancer. Key words: human papilloma virus; carcinogenesis; cervical carcinoma (human papilloma virus, HPV) Harald zur Hausen 2008 HPV HPV 10 20 2008-12-02 * E-mail: lank@sibs.ac.cn 1 20 ( 1) DNA 7 200 8 000 bp (ORF) DNA (early region ER) (1ate region LR) E L 1 kb (upstream regulatory region URR) (1ong control region LCR)

844 [1,2] ( 2) E6 E7 HPV E6 151 E6 [3] E7 98 C N E7 HPV (16 18 31) E7 (HFK) [3, 4] 1 2 100 HPV 40 [5] HPV 10.5% 1 HPV ( Stephen C. Harrison ) 2 HPV ( John Doorbar, Clin Sci, 2006, 110: 525-41) 1 HPV ORF E1 ATP ATP E2 E1 DNA E5 T E4 L1 L2 HPV 50 100 HPV16 18 100 500 HPV ( II III ) HPV DNA 70% 90% I 20% 50% [6] HPV HPV DNA RNA DNA HPV HPV6 HPV11 HPV [7] HPV16 HPV18 [7, 8] 50% HPV16 20% HPV18 HPV [9] (cervical intraepithelial neoplasia CIN) 10 Dalstein HPV CIN HPV HPV CIN HPV

845 3 HPV 3.1 HPV HPV 12 18 HPV HPV 3.1.1 DNA 3.1.2 HPV16 NF-κB E6 E7 IFN E7 p48/ IRF-9 ISGF-3(IFN stimulated gene factor3) IFN-α E7 DNA IRF-1 IFN-β [10] E6 IRF3 IFN-α Tyk2 IFN STAT1 STAT2 STAT/JAK 3.1.3 II III T TH2 [11] E5 HPV Suprynowicz [12] E5 (23 40 )T caveolin-1/gm1 T E5 MHCII 3.2 HPV HPV E5 E6 E7 HPV E6 E6 E6-AP p53 P53 BCL-2 Bax E6-AP E6 E6-AP p53 E6-AP P53 [13] Hoppe- Seyler RNAi E6 RNAi Bax, E6 p53/puma/bax [14] HPV-16 E6 PDZ p52 p52 NF-κB ciap-2 TNF-α [15] HPV-16 E6 TNF-R1 TNF E6 [16] HPV E5 E7 E5 FAS-R TRAIL-R FAS-R TRAIL-R E5 FAS TRAIL [17] E7 TNF-α [18] 3.3 HPV G1/S G2/M HPV p53 p53 DNA HR-E6 E6-AP p53 DNA [13] E6 p53 CBP/P300 p53 G1/S S [19] Rb Rb E2F E2F S Cycline/CDK Rb E2F S S Rb M1/S HPV E7 Rb Cullin2 Rb E2F [20, 21] Rb HPV E7 E7 Mi2b HDACs,

846 E2F2 S [22] E7 cycline/cdk CDK2/ cyclina CDK2/cyclinE [23] prb E7 p27 p21, [24, 25] HPV-16 E7 Rb E2F6 E2F6 S E2F HPV-16 E7 E2F6 HPV S [26] E5 E5 EGFR E5 EGF E5 EGFR MAPK [27, 28] 3.4 HPV HPV HPV E6 htert E6 Myc Myc htert htert [29] E6/E6-AP NFX1-91, htert htert TERT [30] 3.5 HPV HPV HPV (LCR) E6 E7 ORF E2 E6 E7 E6 E7 E2 E6 E7 HPV 23% HPV [31] HPV HPV E6 Liu [32] E6 p53 p53 G1 E6 7(hMCM7) hmcm7 hmcm7 [33] E7 [34] E7 Fanconi Anemia(FA) [35] 3.6 HPV HPV HPV HPV HPV 11 HPV [36] HPV RARA p53 IL-10, WAF-1, HLA [37] HPV [37] HPV HPV HPV-16 E6 HPV [38] / / HPV

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