Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Human tumour viruses and the deregulation of cell polarity in cancer

Nature Reviews Cancer volume 12, pages 877–886 (2012)Cite this article

Subjects

Abstract

The role of cell polarity regulators in the development of cancer has long been an enigma. Despite displaying characteristics of tumour suppressors, the core regulators of polarity are rarely mutated in tumours and there are few data from animal models to suggest that they directly contribute to cancer susceptibility, thus questioning their relevance to human carcinogenesis. However, a body of data from human tumour viruses is now providing compelling evidence of a central role for the perturbation of cell polarity in the development of cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cell polarity control pathways and their perturbation by human cancer-causing viruses.
Figure 2: Progression from HPV infection to HPV-induced malignancy.
Figure 3: Sequence alignments of proteins from human tumour viruses that have PBMs.

Similar content being viewed by others

References

  1. McCaffrey, L. M. & Macara, I. G. Epithelial organization, cell polarity and tumorigenesis. Trends Cell Biol. 21, 727–735 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Martin-Belmonte, F. & Perez-Moreno, M. Epithelial cell polarity, stem cells and cancer. Nature Rev. Cancer 12, 23–38 (2010).

    Article  CAS  Google Scholar 

  3. Qin, Y., Capaldo, C., Gumbiner, B. M. & Macara, I. G. The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J. Cell Biol. 171, 1061–1071 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Georgiou, M., Marinari, E., Burden, J. & Baum, B. Cdc42, Par6, and aPKC regulate Arp2/3-mediated endocytosis to control local adherens junction stability. Curr. Biol. 18, 1631–1638 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Tsukita, S., Yamazaki, Y., Katsuno, T., Tamura, A. & Tsukita, S. Tight junction-based epithelial microenvironment and cell proliferation. Oncogene 27, 6930–6938 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Dow, L. E. et al. Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene 27, 5988–6001 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Nagasaka, K. et al. The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction. Oncogene 29, 5311–5321 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Cordenonsi, M. et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147, 759–772 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Varelas, X. et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev. Cell 19, 831–844 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Osmani, N., Vitale, N., Borg, J.-P. & Etienne-Manneville, S. Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration. Curr. Biol. 16, 2395–2405 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Dow, L. E. et al. The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge. Oncogene 26, 2272–2282 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Zhan, L. et al. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for polarity in carcinoma. Cell 135, 865–878 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nagai-Tamai, Y., Mizuno, K., Hirose, T., Suzuki, A. & Ohno, S. Regulated protein-protein interaction between aPKC and PAR-3 plays an essential role in the polarization of epithelial cells. Genes Cells 7, 1161–1171 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Betschinger, J., Mechtler, K. & Knoblich, J. A. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 422, 326–330 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Bilder, D. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 18, 1909–1925 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Gardiol, D., Zacchi, A., Petrera, F., Stanta, G. & Banks, L. Human discs large and scribble are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression. Int. J. Cancer 119, 1285–1290 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Pearson, H. B. et al. SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. J. Clin. Invest. 121, 4257–4267 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Caruana, G. & Bernstein, A. Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene. Mol. Cell. Biol. 21, 1475–1483 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Klezovitch, O., Fernandez, T. E., Tapscott, S. J. & Vasioukhin, V. Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice. Genes Dev. 18, 559–571 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bouvard, V. et al. A review of human carcinogens-Part B: biological agents. Lancet Oncol. 10, 321–322 (2009).

    Article  PubMed  Google Scholar 

  21. Bouvard, V. et al. Carcinogenicity of malaria and of some polyomaviruses. Lancet Oncol. 13, 339–340 (2012).

    Article  PubMed  Google Scholar 

  22. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Biological Agents Vol. 100B (WHO, 2012).

  23. Moore, P. S. & Chang, Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nature Rev. Cancer 10, 878–889 (2010).

    Article  CAS  Google Scholar 

  24. Rozenblatt-Rosen, O., et al. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 487, 491–495 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mesri, E. A., Cesarman, E. & Boshoff, C. Kaposi's sarcoma and its associated herpesvirus. Nature Rev. Cancer 10, 707–719 (2010).

    Article  CAS  Google Scholar 

  26. Wu, M., Pastor-Pareja, J. C. & Xu, T. Interaction between RasV12 and scribbled clones induces tumour growth and invasion. Nature 463, 545–549 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Magaldi, T. G. et al. Primary human cervical carcinoma cells require human papillomavirus E6 and E7 expression for ongoing proliferation. Virology 422, 114–124 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Butz, K. et al. siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells. Oncogene 22, 5938–5945 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Thomas, M. et al. Human papillomaviruses, cervical cancer and cell polarity. Oncogene 27, 7018–7030 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Barbosa, M. & Schlegel, R. The E6 and E7 genes of HPV-18 are sufficient for inducing two-stage in vitro transformation of human keratinocytes. Oncogene 4, 1529–1532 (1989).

    CAS  PubMed  Google Scholar 

  31. Riley, R. R. et al. Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res. 63, 4862–4871 (2003).

    CAS  PubMed  Google Scholar 

  32. Doorbar, J. Molecular biology of human papillomavirus infection and cervical cancer. Clin. Sci. 110, 525–541 (2006).

    Article  CAS  Google Scholar 

  33. Moody, C. A. & Laimins, L. A. Human papillomavirus oncoproteins: pathways to transformation. Nature Rev. Cancer 10, 550–560 (2010).

    Article  CAS  Google Scholar 

  34. Gardiol, D. et al. Oncogenic human papillomavirus E6 proteins target the discs large tumour suppressor for proteasome-mediated degradation. Oncogene 18, 5487–5496 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Nakagawa, S. & Huibregtse, J. Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6-AP ubiquitin-protein ligase. Mol. Cell. Biol. 20, 8244–8253 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Glaunsinger, B., Lee, S. S., Thomas, M., Banks, L. & Javier, R. Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins. Oncogene 19, 1093–1098 (2000).

    Article  CAS  Google Scholar 

  37. Storrs, C. & Silverstein, S. PATJ, a tight junction-associated PDZ protein, is a novel degradation target of high-risk human papillomavirus E6 and the alternatively spliced isoform 18 E6*. J. Virol. 8, 4080–4090 (2007).

    Article  CAS  Google Scholar 

  38. Thomas, M., Massimi, P., Navarro, C., Borg, J.-P. & Banks, L. The hScrib/Dlg apico-basal control complex is differentially targeted by HPV-16 and HPV-18 E6 proteins. Oncogene 24, 6222–6230 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Tomaić, V. et al. Human and primate tumour viruses use PDZ binding as an evolutionarily conserved mechanism of targeting cell polarity regulators. Oncogene 28, 1–8 (2009).

    Article  PubMed  CAS  Google Scholar 

  40. Zhang, Y. et al. Structures of a human papillomavirus (HPV) E6 polypeptide bound to MAGUK proteins: mechanisms of targeting tumor suppressors by a high-risk HPV oncoprotein. J. Virol. 81, 3618–3626 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lee, C. & Laimins, L. A. Role of the PDZ domain-binding motif of the oncoprotein E6 in the pathogenesis of human papillomavirus type 31. J. Virol. 78, 12366–12377 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nicolaides, L. et al. Stabilization of HPV16 E6 protein by PDZ proteins, and potential implications for genome maintenance. Virology 414, 137–145 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Poulson, N. D. & Lechler, T. Robust control of mitotic spindle orientation in the developing epidermis. J. Cell Biol. 191, 915–922 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hao, Y. Par3 controls epithelial spindle orientation by aPKC-mediated phosphorylation of apical Pins. Curr. Biol. 20, 1809–1818 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Johnson, C. A., Hirono, K., Pehoda, K. E. & Do, C. Q. Identification of an Aurora-A/Pinslinker/Dlg spindle orientation pathway using induced cell polarity in S2 cells. Cell 138, 1150–1163 (2009).

    Article  CAS  Google Scholar 

  47. Knoblich, J. A. Mechanisms of asymmetric stem cell division. Cell 132, 583–597 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Reuter, J. D., Gomez, D., Brandsma, J. L., Rose, J. K. & Roberts, A. Optimization of cottontail rabbit papilloma virus challenge technique. J. Virol. Methods 98, 127–134 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. O'Neill, A. K. et al. Protein kinase Cα promotes cell migration through a PDZ-dependent interaction with its novel substrate discs large homolog 1 (DLG1). J. Biol. Chem. 286, 43559–43568 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Matthews, K. et al. Depletion of Langerhans cells in human papillomavirus type 16-infected skin is associated with E6-mediated downregulation of E-cadherin. J. Virol. 77, 8378–8385 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Laurson, J., Khan, S., Chung, R., Cross, K. & Raj, K. Epigenetic repression of E-cadherin by human papillomavirus 16 E7 protein. DrosophilaCarcinogenesis 31, 918–926 (2010).

    CAS  Google Scholar 

  53. Kranjec, C. & Banks, L. A systematic analysis of human papillomavirus (HPV) E6 PDZ substrates identifies MAGI-1 as a major target of HPV type 16 (HPV-16) and HPV-18 whose loss accompanies disruption of tight junctions. J. Virol. 85, 1757–1764 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Herfs, M. et al. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc. Natl Acad. Sci. USA 109, 10516–10521 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shai, A., Brake, T., Somoza, C. & Lambert, P. F. The human papillomavirus E6 oncogene dysregulates the cell cycle and contributes to cervical carcinogenesis through two independent activities. Cancer Res. 67, 1626–1635 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nguyen, M. L., Nguyen, M. M., Lee, D., Griep, A. E. & Lambert, P. F. The PDZ ligand domain of the human papillomavirus type 16 E6 protein is required for E6's induction of epithelial hyperplasia in vivo. J. Virol. 77, 6957–6964 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Watson, R. A., Thomas, M., Banks, L. & Roberts, S. Activity of the human papillomavirus E6 PDZ-binding motif correlates with an enhanced morphological transformation of immortalized human keratinocytes. J. Cell Sci. 116, 4925–4934 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Watson, R. A. et al. Changes in expression of the human homologue of the Drosophila discs large tumour suppressor in high-grade premalignant cervical neoplasias. Carcinogenesis 23, 1791–1796 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Jeanes, A., Gottardi, C. J. & Yap, A. S. Cadherins and cancer: how does cadherin dysfunction promote tumour progression. Oncogene 27, 6920–6929 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Massimi, P., Narayan, N., Cuenda, A. & Banks, L. Phosphorylation of the discs large tumour suppressor protein controls its membrane localisation and enhances its susceptibility to HPV E6− induced degradation. Oncogene 25, 4276–4285 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Krishna Subbaiah, V. et al. The invasive capacity of HPV transformed cells requires the hDlg-dependent enhancement of SGEF/RhoG activity. PLoS Pathog. 8, e1002543 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Frese, K. K. et al. Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor. EMBO J. 25, 1406–1417 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bonilla-Delgado, J. et al. The E6 oncoprotein from HPV16 enhances the canonical Wnt/β-catenin pathway in skin epidermis in vivo. Mol. Cancer Res. 10, 250–258 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Shannon-Lowe, C. & Rowe, M. Epstein-Barr virus infection of polarised epithelial cells via the basolateral surface by memory B cell-mediated transfer infection. PLoS Pathog. 7, e1001338 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tsai, C. N., Tsai, C. L., Tse, K. P., Chang, H. Y. & Chang, Y. S. The Epstein-Barr virus oncogene product, latent membrane protein 1, induces the downregulation of E-cadherin gene expression via activation of DNA methyltransferases. Proc. Natl Acad. Sci. USA 99, 10084–10089 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Scholle, F., Bendt, K. M. & Raab-Traub, N. Epstein-Barr virus LMP2A transforms epithelial cells, inhibits cell differentiation, and activates Akt. J. Virol. 74, 10681–10689 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Horikawa, T. et al. Twist and epithelial-mesenchymal transition are induced by the EBV oncoprotein latent membrane protein 1 and are associated with metastatic nasopharyngeal carcinoma. Cancer Res. 67, 1970–1978 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Horikawa, T. et al. Epstein-Barr Virus latent membrane protein 1 induces Snail and epithelial-mesenchymal transition in metastatic nasopharyngeal carcinoma. Br. J. Cancer 104, 1160–1167 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cano, A. et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biol. 2, 76–83 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Cavatorta, A. L., Giri, A. A., Banks, L. & Gardiol, D. Cloning and functional analysis of the promoter region of the human Disc large gene. Gene 424, 87–95 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Liu, H. P. et al. Epstein-Barr virus-encoded LMP1 interacts with FGD4 to activate CDC42 and thereby promote migration of nasopharyngeal carcinoma cells. PLoS Pathog. 8, e1002690 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Shackelford, J., Maier, C. & Pagano, J. S. Epstein-Barr virus activates β-catenin in type III latently infected B lymphocyte lines: association with deubiquitinating enzymes. Proc. Natl Acad. Sci. USA 100, 15572–15576 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Morrison, J. A. & Raab-Traub, N. Roles of the ITAM & PY motifs of Epstein-Barr virus latent membrane protein 2A in the inhibition of epithelial cell differentiation and activation of β-catenin signaling. J. Virol. 79, 2375–2382 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Subbaiah, V. K., Narayan, N., Massimi, P. & Banks, L. Regulation of the DLG tumor suppressor by β-catenin. Int. J. Cancer 131, 2223–2233 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fujimuro, M. et al. A novel viral mechanism for dysregulation of β-catenin in Kaposi's sarcoma-associated herpesvirus latency. Nature Med. 9, 300–306 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Wu, Y. H. et al. The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial motility. Blood 111, 2896–2905 (2011).

    Article  CAS  Google Scholar 

  78. Saburi, S. et al. Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nature Genet. 40, 1010–1015 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Ishiuchi, T., Misaki, K., Yonemura, S., Takeichi, M. & Tanoue, T. Mammalian Fat and Dachsous cadherins regulate apical membrane organization in the embryonic cerebral cortex. J. Cell Biol. 185, 959–967 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Matakatsu, H. & Blair, S. S. Separating planar cell polarity and Hippo pathway activities of the protocadherins Fat and Dachsous. Development 139, 1498–1508 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mansouri, M., Rose, P. P., Moses, A. V. & Früh, K. Remodeling of endothelial adherens junctions by Kaposi's sarcoma-associated herpesvirus. J. Virol. 82, 9615–9628 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Qian, L. W., Greene, W., Ye, F. & Gao, S. J. Kaposi's sarcoma-associated herpesvirus disrupts adherens junctions and increases endothelial permeability by inducing degradation of VE-cadherin. J. Virol. 82, 11902–11912 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Dwyer, J. et al. Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor. Oncogene 30, 190–200 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Guilluy, C. et al. Latent KSHV infection increases the vascular permeability of human endothelial cells. Blood 118, 5344–5354 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Satou, Y. et al. HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLoS Pathog. 7, e1001274 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lee, S. S., Weiss, R. S. & Javier, R. T. Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein. Proc. Natl Acad. Sci. USA 94, 6670–6675 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Arpin-André, C. & Mesnard, J. M. The PDZ domain-binding motif of the human T cell leukemia virus type 1 tax protein induces mislocalization of the tumor suppressor hScrib in T cells. J. Biol. Chem. 282, 33132–33141 (2007).

    Article  PubMed  CAS  Google Scholar 

  88. Ohashi, M. et al. Human T-cell leukemia virus type 1 Tax oncoprotein induces and interacts with a multi-PDZ domain protein, MAGI-3. Virology 320, 52–62 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Rousset, R., Fabre, S., Desbois, C., Bantignies, F. & Jalinot, P. The C-terminus of the HTLV-1 Tax oncoprotein mediates interaction with the PDZ domain of cellular proteins. Oncogene 16, 643–654 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Ma, G., Yasunaga, J., Fan, J., Yanagawa, S. & Matsuoka, M. HTLV-1 bZIP factor dysregulates the Wnt pathways to support proliferation and migration of adult T-cell leukemia cells. Oncogene 8 Oct 2012 (doi:10.1038/onc.2012.450).

  91. Higuchi, M. et al. Cooperation of NF-κB2/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line. J. Virol. 81, 11900–11907 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. James, M. A., Lee, J. H. & Klingelhutz, A. J. Human papillomavirus type 16 E6 activates NF-κB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner. J. Virol. 80, 5301–5307 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Blot, V. et al. Human Dlg protein binds to the envelope glycoproteins of human T-cell leukemia virus type 1 and regulates envelope mediated cell-cell fusion in T lymphocytes. J. Cell Sci. 117, 3983–3993 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Tanaka, Y., Fukudome, K., Hayashi, M., Takagi, S. & Yoshie, O. Induction of ICAM-1 and LFA-3 by Tax1 of human T-cell leukemia virus type 1 and mechanism of down-regulation of ICAM-1 or LFA-1 in adult-T-cell-leukemia cell lines. Int. J. Cancer 60, 554–561 (1995).

    Article  CAS  PubMed  Google Scholar 

  95. Nejmeddine, M. et al. HTLV-1-Tax and ICAM-1 act on T-cell signal pathways to polarize the microtubule-organizing center at the virological synapse. Blood 114, 1016–1025 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Hawkins, E. D. & Russell, S. M. Upsides and downsides to polarity and asymmetric cell division in leukemia. Oncogene 27, 7003–7017 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Renkema, G. H., Manninen, A. & Saksela, K. Human immunodeficiency virus type 1 Nef selectively associates with a catalytically active subpopulation of p21-activated kinase (PAK2) independently of PAK2 binding to Nck or β-PIX. J. Virol. 75, 2154–2160 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Stevenson, M. HIV-1 pathogenesis. Nature Med. 9, 853–860 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Margottin, F. et al. A novel human WD protein, h-β-Trcp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol. Cell 1, 565–574 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Besnard-Guerin, C. et al. HIV-1 Vpu sequesters β-transducin repeat-containing protein (b-Trcp) in the cytoplasm and provokes the accumulation of β-catenin and other SCFb-Trcp substrates. J. Biol. Chem. 279, 788–795 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Salim, A. & Ratner, L. Modulation of β-catenin and E-cadherin interaction by Vpu increases human immunodeficiency virus type 1 particle release. J. Virol. 82, 3932–3938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Pu, H. et al. HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK 1/2 activation. J. Cereb. Blood Flow Metab. 25, 1325–1335 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Nazli, A. et al. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathog. 6, e1000852 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Perrault, M. & Pécheur, E. I. The hepatitis C virus and its hepatic environment: a toxic but finely tuned partnership. Biochem. J. 423, 303–314 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Lara-Pezzi, E., Roche, S., Andrisani, O. M., Sánchez-Madrid, F. & López-Cabrera, M. The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner. Oncogene 20, 3323–3331 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Lee, J. O. et al. Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene 24, 6617–6625 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Arzumanyan, A. et al. Epigenetic repression of E-cadherin expression by hepatitis B virus x antigen in liver cancer. Oncogene 31, 563–572 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Hsieh, A., Kim, H. S., Lim, S. O., Yu, D. Y. & Jung, G. Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/β-catenin signaling. Cancer Lett. 300, 162–172 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Zhang, T. et al. Hepatitis B virus X protein (HBx) modulates oncogene YAP via CREB to promote growth of hepatoma cells. Hepatology 18 Jun 2012 (doi:10.1002/hep.25899).

  110. Tsai, W. L. & Chung, R. T. Viral hepatocarcinogenesis. Oncogene 29, 2309–2324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Arora, P., Kim, E. O., Jung, J. K. & Jang, K. L. Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. Cancer Lett. 261, 244–252 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Street, A., Macdonald, A., McCormick, C. & Harris, M. Hepatitis C virus NS5A-mediated activation of phosphoinositide 3-kinase results in stabilization of cellular β-catenin and stimulation of β-catenin-responsive transcription. J. Virol. 79, 5006–5016 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Akkari, L. et al. Hepatitis C viral protein NS5A induces EMT and participates in oncogenic transformation of primary hepatocyte precursors. J. Hepatol. 57, 1021–1028 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Battaglia, S. et al. Liver cancer-derived hepatitis C virus core proteins shift TGF-β responses from tumor suppression to epithelial-mesenchymal transition. PLoS ONE 4, e4355 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Mee, C. J. et al. Effect of cell polarization on hepatitis C virus entry. J. Virol. 82, 461–470 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Benedicto, I. et al. The tight junction-associated protein occludin is required for a postbinding step in hepatitis C virus entry and infection. J. Virol. 83, 8012–8020 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Liu, S. et al. Tight junction proteins claudin-1 and occludin control hepatitis C virus entry and are downregulated during infection to prevent. superinfection. J. Virol. 83, 2011–2014 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Feng, H., Shuda, M., Chang, Y. & Moore, P. S. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319, 1096–1100 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shuda, M. et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc. Natl Acad. Sci. USA 105, 16272–16277 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kirschner, N. et al. CD44 regulates tight-junction assembly and barrier function. J. Invest. Dermatol. 131, 932–943 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Meinke, P., Nguyen, T. D. & Wehnert, M. S. The LINC complex and human disease. Biochem. Soc. Trans. 39, 1693–1697 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Markiewicz, E. et al. The inner nuclear membrane protein emerin regulates β-catenin activity by restricting its accumulation in the nucleus. EMBO J. 25, 3275–3285 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Cheng, J., DeCaprio, J. A., Fluck, M. M. & Schaffhausen, B. S. Cellular transformation by Simian Virus 40 and Murine Polyoma Virus T antigens. Semin. Cancer Biol. 19, 218–228 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tian, Y., Li, D., Dahl, J., You, J. & Benjamin, T. Identification of TAZ as a binding partner of the polyomavirus T antigens. J. Virol. 78, 12657–12664 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

L.B. gratefully acknowledges research support provided by the Associazione Italiana per la Ricerca sul Cancro, Telethon Grant GGP10006 and the Wellcome Trust. This article is dedicated to the memory of Joan Banks and John Pim.

Author information

Authors and Affiliations

  1. Lawrence Banks, David Pim and Miranda Thomas are at The International Centre for Genetic Engineering and Biotechnology, Padriciano 99, I-34149 Trieste, Italy.,

    Lawrence Banks, David Pim & Miranda Thomas

Authors
  1. Lawrence Banks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Pim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miranda Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lawrence Banks.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

FURTHER INFORMATION

Lawrence Banks's homepage

Glossary

Apico-basal polarity

(ABP). The vertical orientation of a cell, defined and maintained by functional differences and molecular gradients between the apical and basal parts of the cell; vital in epithelia.

Cadherins

Transmembrane proteins involved in cell–cell adhesion, often disrupted or altered during tumorigenesis.

E-cadherin

The prototype cadherin in epithelial cells, part of the adherens junction, thus contributing to ABP; thought to sequester β-catenin, thus inhibiting its activation of the canonical WNT signalling pathway.

FAT4 cadherin

A massive cadherin-related protein, homologue of Drosophila melanogaster Fat tumour suppressor, which functions upstream of the Hippo pathway in regulating PCP and organ size.

Immune synapse

Interface between a naive cytotoxic T-lymphocyte (CTL) and an antigen-presenting cell, activating a pathway that results in changes in actin polymerization and cell morphology necessary for CTL maturation.

Keratinocytes

The major cells (∼95%) of the epidermis, which differentiate upwards from the basement membrane, gradually losing nuclei and expressing massive amounts of keratins to form the impermeable skin layer, which is shed by desquamation.

Merkel cell

A cell in the epithelium that is essential for the fine resolution of sensory stimuli; malignantly transformed in Merkel cell carcinoma.

Organotypic raft cultures

A tissue culture method of growing keratinocytes at the liquid–air interface to recapitulate epithelial differentiation in vitro.

Planar cell polarity

(PCP). The horizontal organization of a cell, such that specialized structures (for example, adherens junctions) are orientated in the same plane of the epithelium; also, the polarization of cells within the plane of a tissue.

VE-cadherin

An endothelial cell-specific cadherin that regulates vascular morphology and stability and is instrumental in regulating PCP.

Virological synapse

A virus-induced interface between infected and uninfected cells, allowing efficient cell-to-cell spread of virus.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Banks, L., Pim, D. & Thomas, M. Human tumour viruses and the deregulation of cell polarity in cancer. Nat Rev Cancer 12, 877–886 (2012). https://doi.org/10.1038/nrc3400

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3400

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer