1887

Abstract

Equine sarcoids represent the most common skin tumours in equids worldwide, characterized by localized invasion, rare regression and high recurrence following surgical intervention. Bovine papillomavirus type 1 (BPV-1) and less commonly BPV-2 are now widely recognized as the causative agents of the disease. Fibroblasts isolated from sarcoids are highly invasive. Invasion is associated with a high level of viral gene expression and matrix metalloproteinase upregulation. However, it remains unclear to what extent BPV-1 proteins are involved in the transformation of equine cells. To address this question, the individual viral genes E5, E6 and E7 were overexpressed in normal equine fibroblasts (EqPalF cells) and in the immortal but not fully transformed sarcoid-derived EqS02a cell line. The proliferation and invasiveness of these cell lines were assessed. E5 and E6 were found to be responsible for the enhanced cell proliferation and induction of increased invasion in EqS02a cells, whilst E7 appeared to enhance cell anchorage independence. Knockdown of BPV-1 oncogene expression by small interfering RNA reversed the transformed phenotype of sarcoid fibroblasts. Together, these observations strongly suggest that BPV-1 proteins play indispensable roles in the transformation of equine fibroblasts. These data also suggest that BPV-1 proteins are potential drug targets for equine sarcoid therapy.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.028191-0
2011-04-01
2019-11-22
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/4/773.html?itemId=/content/journal/jgv/10.1099/vir.0.028191-0&mimeType=html&fmt=ahah

References

  1. Akgül, B., García-Escudero, R., Ghali, L., Pfister, H. J., Fuchs, P. G., Navsaria, H. & Storey, A. ( 2005; ). The E7 protein of cutaneous human papillomavirus type 8 causes invasion of human keratinocytes into the dermis in organotypic cultures of skin. Cancer Res 65, 2216–2223. [CrossRef]
    [Google Scholar]
  2. Argyle, D., Ellsmore, V., Gault, E. A., Munro, A. F. & Nasir, L. ( 2003; ). Equine telomeres and telomerase in cellular immortalisation and ageing. Mech Ageing Dev 124, 759–764. [CrossRef]
    [Google Scholar]
  3. Birkedal-Hansen, H. ( 1995; ). Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol 7, 728–735. [CrossRef]
    [Google Scholar]
  4. Bohl, J., Hull, B. & Vande Pol, S. B. ( 2001; ). Cooperative transformation and coexpression of bovine papillomavirus type 1 E5 and E7 proteins. J Virol 75, 513–521. [CrossRef]
    [Google Scholar]
  5. Borzacchiello, G., Iovane, G., Marcante, M. L., Poggiali, F., Roperto, F., Roperto, S. & Venuti, A. ( 2003; ). Presence of bovine papillomavirus type 2 DNA and expression of the viral oncoprotein E5 in naturally occurring urinary bladder tumours in cows. J Gen Virol 84, 2921–2926. [CrossRef]
    [Google Scholar]
  6. Borzacchiello, G., Russo, V., Gentile, F., Roperto, F., Venuti, A., Nitsch, L., Campo, M. S. & Roperto, S. ( 2006; ). Bovine papillomavirus E5 oncoprotein binds to the activated form of the platelet-derived growth factor β receptor in naturally occurring bovine urinary bladder tumours. Oncogene 25, 1251–1260. [CrossRef]
    [Google Scholar]
  7. Borzacchiello, G., Russo, V., Della Salda, L., Roperto, S. & Roperto, F. ( 2008; ). Expression of platelet-derived growth factor-β receptor and bovine papillomavirus E5 and E7 oncoproteins in equine sarcoid. J Comp Pathol 139, 231–237. .[CrossRef]
    [Google Scholar]
  8. Borzacchiello, G., Mogavero, S., De Vita, G., Roperto, S., Della Salda, L. & Roperto, F. ( 2009; ). Activated platelet-derived growth factor β receptor expression, PI3K-AKT pathway molecular analysis, and transforming signals in equine sarcoids. Vet Pathol 46, 589–597. [CrossRef]
    [Google Scholar]
  9. Broccoli, D., Young, J. W. & de Lange, T. ( 1995; ). Telomerase activity in normal and malignant hematopoietic cells. Proc Natl Acad Sci U S A 92, 9082–9086. [CrossRef]
    [Google Scholar]
  10. Campo, M. S. ( 2006; ). Bovine papillomavirus: old system, new lessons? In Papillomvirus Research: From Natural History to Vaccines and Beyond, pp. 373–387. Edited by Campo, M. S.. Norfolk, UK. : Caister Academic Press.
    [Google Scholar]
  11. Carr, E. A., Théon, A. P., Madewell, B. R., Griffey, S. M. & Hitchcock, M. E. ( 2001; ). Bovine papillomavirus DNA in neoplastic and nonneoplastic tissues obtained from horses with and without sarcoids in the western United States. Am J Vet Res 62, 741–744. [CrossRef]
    [Google Scholar]
  12. Chambers, G., Ellsmore, V. A., O'Brien, P. M., Reid, S. W., Love, S., Campo, M. S. & Nasir, L. ( 2003a; ). Association of bovine papillomavirus with the equine sarcoid. J Gen Virol 84, 1055–1062. [CrossRef]
    [Google Scholar]
  13. Chambers, G., Ellsmore, V. A., O'Brien, P. M., Reid, S. W., Love, S., Campo, M. S. & Nasir, L. ( 2003b; ). Sequence variants of bovine papillomavirus E5 detected in equine sarcoids. Virus Res 96, 141–145. [CrossRef]
    [Google Scholar]
  14. Choudhury, G. G., Karamitsos, C., Hernandez, J., Gentilini, A., Bardgette, J. & Abboud, H. E. ( 1997; ). PI-3-kinase and MAPK regulate mesangial cell proliferation and migration in response to PDGF. Am J Physiol 273, F931–F938.
    [Google Scholar]
  15. DeMali, K. A., Whiteford, C. C., Ulug, E. T. & Kazlauskas, A. ( 1997; ). Platelet-derived growth factor-dependent cellular transformation requires either phospholipase Cγ or phosphatidylinositol 3 kinase. J Biol Chem 272, 9011–9018. .[CrossRef]
    [Google Scholar]
  16. DeMasi, J., Huh, K. W., Nakatani, Y., Münger, K. & Howley, P. M. ( 2005; ). Bovine papillomavirus E7 transformation function correlates with cellular p600 protein binding. Proc Natl Acad Sci U S A 102, 11486–11491. [CrossRef]
    [Google Scholar]
  17. Friedl, P. & Wolf, K. ( 2003; ). Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3, 362–374. [CrossRef]
    [Google Scholar]
  18. Fujii, T., Saito, M., Iwasaki, E., Ochiya, T., Takei, Y., Hayashi, S., Ono, A., Hirao, N., Nakamura, M. & other authors ( 2006; ). Intratumor injection of small interfering RNA-targeting human papillomavirus 18 E6 and E7 successfully inhibits the growth of cervical cancer. Int J Oncol 29, 541–548.
    [Google Scholar]
  19. Gobeil, P. A., Yuan, Z., Gault, E. A., Morgan, I. M., Campo, M. S. & Nasir, L. ( 2009; ). Small interfering RNA targeting bovine papillomavirus type 1 E2 induces apoptosis in equine sarcoid transformed fibroblasts. Virus Res 145, 162–165. [CrossRef]
    [Google Scholar]
  20. Gu, W., Putral, L. & McMillan, N. ( 2008; ). siRNA and shRNA as anticancer agents in a cervical cancer model. Methods Mol Biol 442, 159–172.
    [Google Scholar]
  21. Harley, C. B., Kim, N. W., Prowse, K. R., Weinrich, S. L., Hirsch, K. S., West, M. D., Bacchetti, S., Hirte, H. W., Counter, C. M. & other authors ( 1994; ). Telomerase, cell immortality, and cancer. Cold Spring Harb Symp Quant Biol 59, 307–315.[CrossRef]
    [Google Scholar]
  22. Hennigan, R. F., Hawker, K. L. & Ozanne, B. W. ( 1994; ). Fos-transformation activates genes associated with invasion. Oncogene 9, 3591–3600.
    [Google Scholar]
  23. Jackson, C. ( 1936; ). The incidence and pathology of tumours of domestic animals in South Africa. Ondesterpoort J Vet Sci Anim Ind 6, 378–385.
    [Google Scholar]
  24. Jia, R. & Zheng, Z. M. ( 2009; ). Regulation of bovine papillomavirus type 1 gene expression by RNA processing. Front Biosci 14, 1270–1282.
    [Google Scholar]
  25. Jonson, A. L., Rogers, L. M., Ramakrishnan, S. & Downs, L. S., Jr ( 2008; ). Gene silencing with siRNA targeting E6/E7 as a therapeutic intervention in a mouse model of cervical cancer. Gynecol Oncol 111, 356–364. [CrossRef]
    [Google Scholar]
  26. Kim, N. W., Piatyszek, M. A., Prowse, K. R., Harley, C. B., West, M. D., Ho, P. L., Coviello, G. M., Wright, W. E., Weinrich, S. L. & Shay, J. W. ( 1994; ). Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015. [CrossRef]
    [Google Scholar]
  27. Kim, S. J., Kim, S. Y., Kwon, C. H. & Kim, Y. K. ( 2007; ). Differential effect of FGF and PDGF on cell proliferation and migration in osteoblastic cells. Growth Factors 25, 77–86. [CrossRef]
    [Google Scholar]
  28. Kleiner, D. E. & Stetler-Stevenson, W. G. ( 1994; ). Quantitative zymography: detection of picogram quantities of gelatinases. Anal Biochem 218, 325–329. .[CrossRef]
    [Google Scholar]
  29. Klingelhutz, A. J., Foster, S. A. & McDougall, J. K. ( 1996; ). Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 380, 79–82. .[CrossRef]
    [Google Scholar]
  30. Knottenbelt, D. C. ( 2005; ). A suggested clinical classification of the equine sarcoid. Clin Tech Equine Pract 4, 278–295. [CrossRef]
    [Google Scholar]
  31. Lambert, P. F., Baker, C. C. & Howley, P. M. ( 1988; ). The genetics of bovine papillomavirus type 1. Annu Rev Genet 22, 235–258. [CrossRef]
    [Google Scholar]
  32. Lavach, J. D., Sullins, K. E., Roberts, S. M., Severin, G. A., Wheeler, C. & Lueker, D. C. ( 1985; ). BCG treatment of periocular sarcoid. Equine Vet J 17, 445–448. .[CrossRef]
    [Google Scholar]
  33. Marchetti, B., Gault, E. A., Cortese, M. S., Yuan, Z., Ellis, S. A., Nasir, L. & Campo, M. S. ( 2009; ). Bovine papillomavirus type 1 oncoprotein E5 inhibits equine MHC class I and interacts with equine MHC I heavy chain. J Gen Virol 90, 2865–2870. [CrossRef]
    [Google Scholar]
  34. Martens, A., De Moor, A., Demeulemeester, J. & Ducatelle, R. ( 2000; ). Histopathological characteristics of five clinical types of equine sarcoid. Res Vet Sci 69, 295–300. [CrossRef]
    [Google Scholar]
  35. Martens, A., De Moor, A., Demeulemeester, J. & Peelman, L. ( 2001a; ). Polymerase chain reaction analysis of the surgical margins of equine sarcoids for bovine papilloma virus DNA. Vet Surg 30, 460–467. [CrossRef]
    [Google Scholar]
  36. Martens, A., De Moor, A. & Ducatelle, R. ( 2001b; ). PCR detection of bovine papilloma virus DNA in superficial swabs and scrapings from equine sarcoids. Vet J 161, 280–286. [CrossRef]
    [Google Scholar]
  37. Morin, G. B. ( 1989; ). The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59, 521–529. [CrossRef]
    [Google Scholar]
  38. Nasir, L. & Reid, S. W. ( 1999; ). Bovine papillomaviral gene expression in equine sarcoid tumours. Virus Res 61, 171–175. [CrossRef]
    [Google Scholar]
  39. Neary, K. & DiMaio, D. ( 1989; ). Open reading frames E6 and E7 of bovine papillomavirus type 1 are both required for full transformation of mouse C127 cells. J Virol 63, 259–266.
    [Google Scholar]
  40. Otten, N., von Tscharner, C., Lazary, S., Antczak, D. F. & Gerber, H. ( 1993; ). DNA of bovine papillomavirus type 1 and 2 in equine sarcoids: PCR detection and direct sequencing. Arch Virol 132, 121–131. [CrossRef]
    [Google Scholar]
  41. Park, J. S., Boyer, S., Mitchell, K., Gilfor, D., Birrer, M., Darlington, G., El Deiry, W., Firestone, G. L., Munger, K. & other authors ( 2000; ). Expression of human papilloma virus E7 protein causes apoptosis and inhibits DNA synthesis in primary hepatocytes via increased expression of p21Cip-1/WAF1/MDA6. J Biol Chem 275, 18–28. [CrossRef]
    [Google Scholar]
  42. Pascoe, R. R. & Summers, P. M. ( 1981; ). Clinical survey of tumours and tumour-like lesions in horses in south east Queensland. Equine Vet J 13, 235–239. [CrossRef]
    [Google Scholar]
  43. Pennie, W. D., Grindlay, G. J., Cairney, M. & Campo, M. S. ( 1993; ). Analysis of the transforming functions of bovine papillomavirus type 4. Virology 193, 614–620. [CrossRef]
    [Google Scholar]
  44. Petti, L. & DiMaio, D. ( 1994; ). Specific interaction between the bovine papillomavirus E5 transforming protein and the β receptor for platelet-derived growth factor in stably transformed and acutely transfected cells. J Virol 68, 3582–3592.
    [Google Scholar]
  45. Ragland, W. L. & Spencer, G. R. ( 1969; ). Attempts to relate bovine papilloma virus to the cause of equine sarcoid: Equidae inoculated intradermally with bovine papilloma virus. Am J Vet Res 30, 743–752.
    [Google Scholar]
  46. Ragland, K. W. L., III, Keown, G. F. H. & Spencer, G. R. ( 1970; ). Equine sarcoid. Equine Vet J 2, 2–11. [CrossRef]
    [Google Scholar]
  47. Reid, S. W., Smith, K. T. & Jarrett, W. F. ( 1994; ). Detection, cloning and characterisation of papillomaviral DNA present in sarcoid tumours of Equus asinus. Vet Rec 135, 430–432. [CrossRef]
    [Google Scholar]
  48. Sahai, E. & Marshall, C. J. ( 2003; ). Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol 5, 711–719. [CrossRef]
    [Google Scholar]
  49. Schiller, J. T., Vass, W. C. & Lowy, D. R. ( 1984; ). Identification of a second transforming region in bovine papillomavirus DNA. Proc Natl Acad Sci U S A 81, 7880–7884. [CrossRef]
    [Google Scholar]
  50. Shay, J. W. & Bacchetti, S. ( 1997; ). A survey of telomerase activity in human cancer. Eur J Cancer 33, 787–791. [CrossRef]
    [Google Scholar]
  51. Singh, P. K., Wen, Y., Swanson, B. J., Shanmugam, K., Kazlauskas, A., Cerny, R. L., Gendler, S. J. & Hollingsworth, M. A. ( 2007; ). Platelet-derived growth factor receptor β-mediated phosphorylation of MUC1 enhances invasiveness in pancreatic adenocarcinoma cells. Cancer Res 67, 5201–5210. [CrossRef]
    [Google Scholar]
  52. Suprynowicz, F. A., Disbrow, G. L., Simic, V. & Schlegel, R. ( 2005; ). Are transforming properties of the bovine papillomavirus E5 protein shared by E5 from high-risk human papillomavirus type 16? Virology 332, 102–113. [CrossRef]
    [Google Scholar]
  53. Tanaga, K., Bujo, H., Zhu, Y., Kanaki, T., Hirayama, S., Takahashi, K., Inoue, M., Mikami, K., Schneider, W. J. & Saito, Y. ( 2004; ). LRP1B attenuates the migration of smooth muscle cells by reducing membrane localization of urokinase and PDGF receptors. Arterioscler Thromb Vasc Biol 24, 1422–1428. [CrossRef]
    [Google Scholar]
  54. Tarwid, J. N., Fretz, P. B. & Clark, E. G. ( 1985; ). Equine sarcoids: a study with emphasis on pathologic diagnosis. Compend Contin Educ 7, S293–S301.
    [Google Scholar]
  55. Tong, X., Salgia, R., Li, J. L., Griffin, J. D. & Howley, P. M. ( 1997; ). The bovine papillomavirus E6 protein binds to the LD motif repeats of paxillin and blocks its interaction with vinculin and the focal adhesion kinase. J Biol Chem 272, 33373–33376. [CrossRef]
    [Google Scholar]
  56. Westermarck, J. & Kähäri, V. M. ( 1999; ). Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13, 781–792.
    [Google Scholar]
  57. Yasmeen, A., Bismar, T. A., Kandouz, M., Foulkes, W. D., Desprez, P.-Y. & Al Moustafa, A.-E. ( 2007; ). E6/E7 of HPV type 16 promotes cell invasion and metastasis of human breast cancer cells. Cell Cycle 6, 2038–2042. [CrossRef]
    [Google Scholar]
  58. Yuan, Z., Gallagher, A., Gault, E. A., Campo, M. S. & Nasir, L. ( 2007; ). Bovine papillomavirus infection in equine sarcoids and in bovine bladder cancers. Vet J 174, 599–604. .[CrossRef]
    [Google Scholar]
  59. Yuan, Z. Q., Gault, E. A., Gobeil, P., Nixon, C., Campo, M. S. & Nasir, L. ( 2008a; ). Establishment and characterization of equine fibroblast cell lines transformed in vivo and in vitro by BPV-1: model systems for equine sarcoids. Virology 373, 352–361. [CrossRef]
    [Google Scholar]
  60. Yuan, Z. Q., Nicolson, L., Marchetti, B., Gault, E. A., Campo, M. S. & Nasir, L. ( 2008b; ). Transcriptional changes induced by bovine papillomavirus type 1 in equine fibroblasts. J Virol 82, 6481–6491. [CrossRef]
    [Google Scholar]
  61. Yuan, Z., Gobeil, P. A., Campo, M. S. & Nasir, L. ( 2010a; ). Equine sarcoid fibroblasts over-express matrix metalloproteinases and are invasive. Virology 396, 143–151. [CrossRef]
    [Google Scholar]
  62. Yuan, Z. Q., Bennett, L., Campo, M. S. & Nasir, L. ( 2010b; ). Bovine papillomavirus type 1 E2 and E7 proteins down-regulate Toll Like Receptor 4 (TLR4) expression in equine fibroblasts. Virus Res 149, 124–127. [CrossRef]
    [Google Scholar]
  63. Zimmermann, H., Koh, C. H., Degenkolbe, R., O'Connor, M. J., Müller, A., Steger, G., Chen, J. J., Lui, Y., Androphy, E. & Bernard, H. U. ( 2000; ). Interaction with CBP/p300 enables the bovine papillomavirus type 1 E6 oncoprotein to downregulate CBP/p300-mediated transactivation by p53. J Gen Virol 81, 2617–2623.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.028191-0
Loading
/content/journal/jgv/10.1099/vir.0.028191-0
Loading

Data & Media loading...

Supplements

vol. , part 4, pp. 773 - 783

siE7 treatment knocks down BPV-1 gene expression and partly reverses the transformed phenotype of sarcoid fibroblasts [PDF](47 KB)



PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error