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The use of a human papillomavirus 18 promoter for tissue-specific expression in cervical carcinoma cells
Cellular & Molecular Biology Letters volume 16, pages 477–492 (2011)
Abstract
The use of tissue-specific promoter elements in the treatment of cervical cancer has been explored in this paper. The P105 promoter of human papillomavirus 18 (HPV18) was utilised to direct tissue-specific expression in a number of cell types. Expression was examined in three cervical carcinoma cell lines: HeLa (HPV18 positive), SiHa (HPV16 positive), and C33A cells (HPV negative); the epithelial cell line, H1299; and the foetal fibroblast cell line, MRC5, utilising a luciferase expression vector. Expression was highest in the cervical cell lines by a factor of at least 80. The effect of a number of mutations in the P105 promoter on expression levels was examined. Three deletion constructs of the long control region (LCR) were investigated: an 800 bp fragment (LCR800), a 400 bp fragment (LCR400), and a 200 bp fragment (LCR200), as well as the full length product LCR of HPV18 (LCR1000). The LCR800 construct of the HPV18 P105 promoter had the highest level of expression in the cervical cell lines and was also highest in the HPV18-positive HeLa cell line. Site-directed mutagenesis was then employed on the LCR800 construct to create four further constructs that each had inactivating mutations in one of the four E2 binding sites (E2BSs). Overall, this study indicated that the LCR800 construct of the HPV18 P105 promoter could be utilised as a tissuerestricted promoter in cervical cancer cells.
Abbreviations
- E2BS:
-
E2-binding site
- LCR:
-
long control region
- ORF:
-
opening reading frame
References
Jo, H. and Kim, J.W. Implications of HPV infection in uterine cervical cancer. Cancer Ther. 3 (2005) 419–434.
Saslow, D., Castle, P.E., Cox, J.T., Davey, D.D., Einstein, M.H., Ferris, D.G., Goldie, S.J., Harper, D.M., Kinney, W., Moscicki, A.B., Noller, K.L., Wheeler, C.M., Ades, T., Andrews, K.S., Doroshenk, M.K., Kahn, K.G., Schmidt, C., Shafey, O., Smith, R.A., Partridge, E.E. and Garcia, F. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. C.A. Cancer J. Clin. 57 (2007) 7–28.
Morris, M., Eifel, P.J., Lu, J., Grigsby, P.W., Levenback, C., Stevens, R.E., Rotman, M., Gershenson, D.M. and Mutch, D.G. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N. Engl. J. Med. 340 (1999) 1137–1143.
Rose, P.G., Bundy, B.N., Watkins, E.B., Thigpen, J.T., Deppe, G., Maiman, M.A., Clarke-Pearson, D.L. and Insalaco, S. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N. Engl. J. Med. 340 (1999) 1144–1153.
Thomas, G.M. Improved treatment for cervical cancer—concurrent chemotherapy and radiotherapy. N. Engl. J. Med. 340 (1999) 1198–1200.
Rein, D.T. and Kurbacher, C.M. The role of chemotherapy in invasive cancer of the cervix uteri: current standards and future prospects. Anticancer Drugs 12 (2001) 787–795.
Rein, D.T., Breidenbach, M., Wu, H., Han, T., Haviv, Y.S., Wang, M., Kirby, T.O., Kawakami, Y., Dall, P., Alvarez, R.D. and Curiel, D.T. Gene transfer to cervical cancer with fiber-modified adenoviruses. Int. J. Cancer 111 (2004) 698–704.
Dorer, D.E. and Nettelbeck, D.M. Targeting cancer by transcriptional control in cancer gene therapy and viral oncolysis. Adv. Drug. Deliv. Rev. 61 (2009) 554–571.
Chan, J.K. and Berek, J.S. Impact of the human papilloma vaccine on cervical cancer. J. Clin. Oncol. 25 (2007) 2975–2982.
Doorbar, J. Molecular biology of human papillomavirus infection and cervical cancer. Clin. Sci. (Lond) 110 (2006) 525–541.
Evans, M.F., Adamson, C.S., Schned, L.M., St John, T.L., Leiman, G., Ashikaga, T. and Cooper, K. HPV is detectable in virtually all abnormal cervical cytology samples after reinvestigation of HPV negatives with multiple alternative PCR tests. Diagn. Mol. Pathol. 19 (2010) 144–150.
Butz, K., Denk, C., Ullmann, A., Scheffner, M. and Hoppe-Seyler, F. Induction of apoptosis in human papillomaviruspositive cancer cells by peptide aptamers targeting the viral E6 oncoprotein. Proc. Natl. Acad. Sci. U.S.A. 97 (2000) 6693–6697.
Steger, G., Rehtanz, M. and Schnabel, C. Identification of a promoter in position 56 within the long control region of human papillomavirus type 18. Arch. Virol. 146 (2001) 2069–2084.
Thierry, F., Heard, J.M., Dartmann, K. and Yaniv, M. Characterization of a transcriptional promoter of human papillomavirus 18 and modulation of its expression by simian virus 40 and adenovirus early antigens. J. Virol. 61 (1987) 134–142.
Yee, C., Krishnan-Hewlett, I., Baker, C.C., Schlegel, R. and Howley, P.M. Presence and expression of human papillomavirus sequences in human cervical carcinoma cell lines. Am. J. Pathol. 119 (1985) 361–366.
Romanczuk, H., Villa, L.L., Schlegel, R. and Howley, P.M. The viral transcriptional regulatory region upstream of the E6 and E7 genes is a major determinant of the differential immortalization activities of human papillomavirus types 16 and 18. J. Virol. 65 (1991) 2739–2744.
Bodily, J. and Laimins, L.A. Persistence of human papillomavirus infection: keys to malignant progression. Trends Microbiol. 19 (2011) 33–39.
Hansen, C.N., Nielsen, L. and Norrild, B. Activities of E7 promoters in the human papillomavirus type 16 genome during cell differentiation. Virus Res. 150 (2010) 34–42.
Moody, C.A. and Laimins, L.A. Human papillomavirus oncoproteins: pathways to transformation. Nat. Rev. Cancer 10 (2010) 550–560.
Hsu, K.F., Wu, C.L., Huang, S.C., Hsieh, J.L., Huang, Y.S., Chen, Y.F., Shen, M.R., Chung, W.J., Chou, C.Y. and Shiau, A.L. Conditionally replicating E1B-deleted adenovirus driven by the squamous cell carcinoma antigen 2 promoter for uterine cervical cancer therapy. Cancer Gene Ther. 15 (2008) 526–534.
Sharma, R. and Palefsky, J.M. Addition of a single E2 binding site to the human papillomavirus (HPV) type 16 long control region enhances killing of HPV positive cells via HPV E2 protein-regulated herpes simplex virus type 1 thymidine kinase-mediated suicide gene therapy. Hum. Gene Ther. 21 (2010) 843–854.
von Knebel Doeberitz, M., Rittmuller, C., zur Hausen, H. and Durst, M. Inhibition of tumorigenicity of cervical cancer cells in nude mice by HPV E6–E7 anti-sense RNA. Int. J. Cancer 51 (1992) 831–834.
Cole, S.T. and Danos, O. Nucleotide sequence and comparative analysis of the human papillomavirus type 18 genome. Phylogeny of papillomaviruses and repeated structure of the E6 and E7 gene products. J. Mol. Biol. 193 (1987) 599–608.
Garcia-Carranca, A., Thierry, F. and Yaniv, M. Interplay of viral and cellular proteins along the long control region of human papillomavirus type 18. J. Virol. 62 (1988) 4321–4330.
Gius, D., Grossman, S., Bedell, M.A. and Laimins, L.A. Inducible and constitutive enhancer domains in the noncoding region of human papillomavirus type 18. J. Virol. 62 (1988) 665–672.
Bauknecht, T., Angel, P., Royer, H.D. and zur Hausen, H. Identification of a negative regulatory domain in the human papillomavirus type 18 promoter: interaction with the transcriptional repressor YY1. EMBO J. 11 (1992) 4607–4617.
Hines, C.S., Meghoo, C., Shetty, S., Biburger, M., Brenowitz, M. and Hegde, R.S. DNA structure and flexibility in the sequence-specific binding of papillomavirus E2 proteins. J. Mol. Biol. 276 (1998) 809–818.
Swindle, C.S., Zou, N., Van Tine, B.A., Shaw, G.M., Engler, J.A. and Chow, L.T. Human papillomavirus DNA replication compartments in a transient DNA replication system. J. Virol. 73 (1999) 1001–1009.
Tan, S.H., Gloss, B. and Bernard, H.U. During negative regulation of the human papillomavirus-16 E6 promoter, the viral E2 protein can displace Sp1 from a proximal promoter element. Nucleic Acids Res. 20 (1992) 251–256.
Thierry, F. Transcriptional regulation of the papillomavirus oncogenes by cellular and viral transcription factors in cervical carcinoma. Virology 384 (2009) 375–379.
Sverdrup, F. and Khan, S.A. Two E2 binding sites alone are sufficient to function as the minimal origin of replication of human papillomavirus type 18 DNA. J. Virol. 69 (1995) 1319–1323.
Boner, W. and Morgan, I.M. Novel cellular interacting partners of the human papillomavirus 16 transcription/replication factor E2. Virus Res. 90 (2002) 113–118.
Demeret, C., Yaniv, M. and Thierry, F. The E2 transcriptional repressor can compensate for Sp1 activation of the human papillomavirus type 18 early promoter. J. Virol. 68 (1994) 7075–7082.
McBride, A.A., Romanczuk, H. and Howley, P.M. The papillomavirus E2 regulatory proteins. J. Biol. Chem. 266 (1991) 18411–18414.
McBride, A. and Myers, G. (1997) The E2 proteins. The E2 proteins. Los Alamos National Laboratory Bioscience Division.
McBride, A.A., Androphy, E. and Munger, K. (1998) Regulation of the papillomavirus E6 and E7 oncoprotreins by the viral E1 and E2 proteins, in: Regulation of the papillomavirus E6 and E7 oncoprotreins by the viral E1 and E2 proteins (Myers, G, Ed.) Addison-Wesley: p. 35–52.
Hoppe-Seyler, F. and Butz, K. Activation of human papillomavirus type 18 E6–E7 oncogene expression by transcription factor Sp1. Nucleic Acids Res. 20 (1992) 6701–6706.
Hoppe-Seyler, F., Butz, K. and zur Hausen, H. Repression of the human papillomavirus type 18 enhancer by the cellular transcription factor Oct-1. J. Virol. 65 (1991) 5613–5618.
Bernard, B.A., Bailly, C., Lenoir, M.C., Darmon, M., Thierry, F. and Yaniv, M. The human papillomavirus type 18 (HPV18) E2 gene product is a repressor of the HPV18 regulatory region in human keratinocytes. J. Virol. 63 (1989) 4317–4324.
Finzer, P., Aguilar-Lemarroy, A. and Rosl, F. The role of human papillomavirus oncoproteins E6 and E7 in apoptosis. Cancer Lett. 188 (2002) 15–24.
Shillitoe, E.J. Papillomaviruses as targets for cancer gene therapy. Cancer Gene Ther. 13 (2006) 445–450.
Phelps, W.C. and Howley, P.M. Transcriptional trans-activation by the human papillomavirus type 16 E2 gene product. J. Virol. 61 (1987) 1630–1638.
Dostatni, N., Thierry, F. and Yaniv, M. A dimer of BPV-1 E2 containing a protease resistant core interacts with its DNA target. EMBO J. 7 (1988) 3807–3816.
Dong, G., Broker, T.R. and Chow, L.T. Human papillomavirus type 11 E2 proteins repress the homologous E6 promoter by interfering with the binding of host transcription factors to adjacent elements. J. Virol. 68 (1994) 1115–1127.
Dostatni, N., Lambert, P.F., Sousa, R., Ham, J., Howley, P.M. and Yaniv, M. The functional BPV-1 E2 trans-activating protein can act as a repressor by preventing formation of the initiation complex. Genes Dev. 5 (1991) 1657–1671.
Karstensen, B., Poppelreuther, S., Bonin, M., Walter, M., Iftner, T. and Stubenrauch, F. Gene expression profiles reveal an upregulation of E2F and downregulation of interferon targets by HPV18 but no changes between keratinocytes with integrated or episomal viral genomes. Virology 353 (2006) 200–209.
Valencia-Hernandez, A., Cuevas-Bennett, C. and Garrido, E. Transcriptional regulation of human papillomavirus type 18 P105 promoter by the coactivator CBP. Intervirology 50 (2007) 418–425.
Ottinger, M., Smith, J.A., Schweiger, M.R., Robbins, D., Powell, M.L., You, J. and Howley, P.M. Cell-type specific transcriptional activities among different papillomavirus long control regions and their regulation by E2. Virology 395 (2009) 161–171.
Teissier, S., Pang, C.L. and Thierry, F. The E2F5 repressor is an activator of E6/E7 transcription and of the S-phase entry in HPV18-associated cells. Oncogene 29 (2010) 5061–5070.
Romanczuk, H., Thierry, F. and Howley, P.M. Mutational analysis of cis elements involved in E2 modulation of human papillomavirus type 16 P97 and type 18 P105 promoters. J. Virol. 64 (1990) 2849–2859.
Lace, M.J., Anson, J.R., Klingelhutz, A.J., Harada, H., Taniguchi, T., Bossler, A.D., Haugen, T.H. and Turek, L.P. Interferon-beta treatment increases human papillomavirus early gene transcription and viral plasmid genome replication by activating interferon regulatory factor (IRF)-1. Carcinogenesis 30 (2009) 1336–1344.
Lace, M.J., Anson, J.R., Turek, L.P. and Haugen, T.H. Functional mapping of the human papillomavirus type 16 E1 cistron. J. Virol. 82 (2008) 10724–10734.
Lace, M.J., Isacson, C., Anson, J.R., Lorincz, A.T., Wilczynski, S.P., Haugen, T.H. and Turek, L.P. Upstream regulatory region alterations found in human papillomavirus type 16 (HPV-16) isolates from cervical carcinomas increase transcription, ori function, and HPV immortalization capacity in culture. J. Virol. 83 (2009) 7457–7466.
Lace, M.J., Anson, J.R., Haugen, T.H. and Turek, L.P. Interferon regulatory factor (IRF)-2 activates the HPV-16 E6-E7 promoter in keratinocytes. Virology 399 (2010) 270–279.
Zarovni, N., Vago, R., Solda, T., Monaco, L. and Fabbrini, M.S. Saporin as a novel suicide gene in anticancer gene therapy. Cancer Gene Ther. 14 (2007) 165–173.
Shillitoe, E.J. and Noonan, S. Strength and specificity of different gene promoters in oral cancer cells. Oral Oncol. 36 (2000) 214–220.
Arendt, M.L., Nasir, L. and Morgan, I.M. A novel two-step transcriptional activation system for gene therapy directed toward epithelial cells. Mol. Cancer Ther. 8 (2009) 3244–3254.
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Lung, M.S.Y., Mak, W.M. & Murray, V. The use of a human papillomavirus 18 promoter for tissue-specific expression in cervical carcinoma cells. Cell Mol Biol Lett 16, 477–492 (2011). https://doi.org/10.2478/s11658-011-0018-8
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DOI: https://doi.org/10.2478/s11658-011-0018-8