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Implications and challenges of connexin connections to cancer

Nature Reviews Cancer volume 10, pages 435–441 (2010)Cite this article

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Abstract

The idea that the gap junction family of proteins, connexins, are tumour suppressors has been widely supported through numerous cancer models. However, the paradigm that connexins and enhanced gap junctional intercellular communication is of universal benefit by restricting tumour growth has been challenged by more recent evidence that suggests a role for connexins in facilitating tumour progression and metastasis. Therefore, connexins might be better classified as conditional tumour suppressors that modulate cell proliferation, as well as adhesion and migration.

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Figure 1: Overview of the life of Cx43.
Figure 2: Proposed connexin involvement in stages of breast cancer.
Figure 3: Proposed connexin involvement in glioma growth and migration.
Figure 4: Proposed role of connexins in the bystander effect.

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References

  1. Loewenstein, W. R. & Kanno, Y. Intercellular communication and the control of tissue growth: lack of communication between cancer cells. Nature 209, 1248–1249 (1966).

    Article  CAS  PubMed  Google Scholar 

  2. Goodenough, D. A. & Paul, D. L. Gap junctions. Cold Spring Harbor Perspect. Biol. 1, a002576 (2009).

    Article  Google Scholar 

  3. Herve, J. C. Gap junction channels: from protein genes to diseases. Prog. Biophys. Mol. Biol. 94, 1–4 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Laird, D. W. Life cycle of connexins in health and disease. Biochem. J. 394, 527–543 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mesnil, M., Crespin, S., Avanzo, J. L. & Zaidan-Dagli, M. L. Defective gap junctional intercellular communication in the carcinogenic process. Biochim. Biophys. Acta 1719, 125–145 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Cronier, L., Crespin, S., Strale, P. O., Defamie, N. & Mesnil, M. Gap junctions and cancer: new functions for an old story. Antioxid. Redox Signal. 11, 323–338 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Laird, D. W. et al. Deficiency of connexin 43 gap junctions is an independent marker for breast tumors. Cancer Res. 59, 4104–4110 (1999).

    CAS  PubMed  Google Scholar 

  8. Naus, C. C., Goldberg, G. S., Sin, W. C. & Winterhager, E. in Gap Junctions in Development and Disease 253–273 (Springer-Verlag Heidelberg, 2005).

    Book  Google Scholar 

  9. Azarnia, R. & Loewenstein, W. R. Intercellular communication and the control of growth: XII. Alteration of junctional permeability by simian virus 40. Roles of the large and small T antigens. J. Membr. Biol. 82, 213–220 (1984).

    Article  CAS  PubMed  Google Scholar 

  10. Azarnia, R. & Loewenstein, W. R. Intercellular communication and the control of growth: XI. Alteration of junctional permeability by the src gene in a revertant cell with normal cytoskeleton. J. Membr. Biol. 82, 207–212 (1984).

    Article  CAS  PubMed  Google Scholar 

  11. Azarnia, R. & Loewenstein, W. R. Intercellular communication and the control of growth: X. Alteration of junctional permeability by the src gene. A study with temperature-sensitive mutant Rous sarcoma virus. J. Membr. Biol. 82, 191–205 (1984).

    Article  CAS  PubMed  Google Scholar 

  12. Lampe, P. D. Analyzing phorbol ester effects on gap junctional communication: a dramatic inhibition of assembly. J. Cell Biol. 127, 1895–1905 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Trosko, J. E., Chang, C. C., Madhukar, B. V. & Klaunig, J. E. Chemical, oncogene and growth factor inhibition gap junctional intercellular communication: an integrative hypothesis of carcinogenesis. Pathobiology 58, 265–278 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Atkinson, M. M., Menko, A. S., Johnson, R. G., Sheppard, J. R. & Sheridan, J. D. Rapid and reversible reduction of junctional permeability in cells infected with a temperature-sensitive mutant of avian sarcoma virus. J. Cell Biol. 91, 573–578 (1981).

    Article  CAS  PubMed  Google Scholar 

  15. Lee, S. W., Tomasetto, C. & Sager, R. Positive selection of candidate tumor-suppressor genes by subtractive hybridization. Proc. Natl Acad. Sci. USA 88, 2825–2829 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shao, Q., Wang, H., McLachlan, E., Veitch, G. I. & Laird, D. W. Down-regulation of Cx43 by retroviral delivery of small interfering RNA promotes an aggressive breast cancer cell phenotype. Cancer Res. 65, 2705–2711 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Eghbali, B., Kessler, J. A., Reid, L. M., Roy, C. & Spray, D. C. Involvement of gap junctions in tumorigenesis: transfection of tumor cells with connexin 32 cDNA retards growth in vivo. Proc. Natl Acad. Sci. USA 88, 10701–10705 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Loewenstein, W. R. & Rose, B. The cell-cell channel in the control of growth. Semin. Cell Biol. 3, 59–79 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Zhu, D., Caveney, S., Kidder, G. M. & Naus, C. C. Transfection of C6 glioma cells with connexin 43 cDNA: analysis of expression, intercellular coupling, and cell proliferation. Proc. Natl Acad. Sci. USA 88, 1883–1887 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McLachlan, E., Shao, Q., Wang, H. L., Langlois, S. & Laird, D. W. Connexins act as tumor suppressors in three-dimensional mammary cell organoids by regulating differentiation and angiogenesis. Cancer Res. 66, 9886–9894 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Hellmann, P. et al. Transfection with different connexin genes alters growth and differentiation of human choriocarcinoma cells. Exp. Cell Res. 246, 480–490 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Hirschi, K. K., Xu, C. E., Tsukamoto, T. & Sager, R. Gap junction genes Cx26 and Cx43 individually suppress the cancer phenotype of human mammary carcinoma cells and restore differentiation potential. Cell Growth Differ. 7, 861–870 (1996).

    CAS  PubMed  Google Scholar 

  23. Temme, A. et al. High incidence of spontaneous and chemically induced liver tumors in mice deficient for connexin32. Curr. Biol. 7, 713–716 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. King, T. J. & Lampe, P. D. The gap junction protein connexin32 is a mouse lung tumor suppressor. Cancer Res. 64, 7191–7196 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. King, T. J. & Lampe, P. D. Mice deficient for the gap junction protein connexin 32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/Erk1, p42/Erk2) activation. Carcinogenesis 25, 669–680 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Avanzo, J. L. et al. Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of connexin43. Carcinogenesis 25, 1973–1982 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Dagli, M. L., Yamasaki, H., Krutovskikh, V. & Omori, Y. Delayed liver regeneration and increased susceptibility to chemical hepatocarcinogenesis in transgenic mice expressing a dominant-negative mutant of connexin 32 only in the liver. Carcinogenesis 25, 483–492 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Bertram, J. S. & Vine, A. L. Cancer prevention by retinoids and carotenoids: independent action on a common target. Biochim. Biophys. Acta 1740, 170–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Bertram, J. S. Inhibition of chemically induced neoplastic transformation by carotenoids. Mechanistic studies. Ann. N. Y. Acad. Sci. 686, 161–176 (1993).

    Article  CAS  PubMed  Google Scholar 

  30. Rogers, M. et al. Retinoid-enhanced gap junctional communication is achieved by increased levels of connexin 43 mRNA and protein. Mol. Carcinog. 3, 335–343 (1990).

    Article  CAS  PubMed  Google Scholar 

  31. Mesnil, M. Connexins and cancer. Biol. Cell. 94, 493–500 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Janssen-Timmen, U., Traub, O., Dermietzel, R., Rabes, H. M. & Willecke, K. Reduced number of gap junctions in rat hepatocarcinomas detected by monoclonal antibody. Carcinogenesis 7, 1475–1482 (1986).

    Article  CAS  PubMed  Google Scholar 

  33. Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dobrowolski, R. et al. The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans. Hum. Mol. Genet. 17, 539–554 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Li, Q. et al. Cytoplasmic accumulation of connexin 32 protein enhances motility and metastatic ability of human hepatoma cells in vitro and in vivo. Int. J. Cancer 121, 536–546 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. el-Sabban, M. E. & Pauli, B. U. Cytoplasmic dye transfer between metastatic tumor cells and vascular endothelium. J. Cell Biol. 115, 1375–1382 (1991).

    Article  CAS  PubMed  Google Scholar 

  37. Ezumi, K. et al. Aberrant expression of connexin 26 is associated with lung metastasis of colorectal cancer. Clin. Cancer Res. 14, 677–684 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Ito, A. et al. A role for heterologous gap junctions between melanoma and endothelial cells in metastasis. J. Clin. Invest. 105, 1189–1197 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Elzarrad, M. K. et al. Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium. BMC Med. 6, 20 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Lin, J. H. et al. Connexin 43 enhances the adhesivity and mediates the invasion of malignant glioma cells. J. Neurosci. 22, 4302–4311 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shah, S. P. et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461, 809–813 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Goldberg, G. S., Lampe, P. D. & Nicholson, B. J. Selective transfer of endogenous metabolites through gap junctions composed of different connexins. Nature Cell Biol. 1, 457–459 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Harris, A. L. Connexin channel permeability to cytoplasmic molecules. Prog. Biophys. Mol. Biol. 94, 120–143 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rouach, N., Koulakoff, A., Abudara, V., Willecke, K. & Giaume, C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551–1555 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Glick, A. B. & Yuspa, S. H. Tissue homeostasis and the control of the neoplastic phenotype in epithelial cancers. Semin. Cancer Biol. 15, 75–83 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Balendiran, G. K., Dabur, R. & Fraser, D. The role of glutathione in cancer. Cell Biochem. Funct. 22, 343–352 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Prise, K. M. & O'Sullivan, J. M. Radiation-induced bystander signalling in cancer therapy. Nature Rev. Cancer 9, 351–360 (2009).

    Article  CAS  Google Scholar 

  48. Andrade-Rozental, A. F. et al. Gap junctions: the “kiss of death” and the “kiss of life”. Brain Res. Brain Res. Rev. 32, 308–315 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Mesnil, M. & Yamasaki, H. Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. Cancer Res. 60, 3989–3999 (2000).

    CAS  PubMed  Google Scholar 

  50. Goodenough, D. A. & Paul, D. L. Beyond the gap: functions of unpaired connexon channels. Nature Rev. Mol. Cell Biol. 4, 285–294 (2003).

    Article  CAS  Google Scholar 

  51. Spray, D. C., Ye, Z. C. & Ransom, B. R. Functional connexin “hemichannels”: a critical appraisal. Glia 54, 758–773 (2006).

    Article  PubMed  Google Scholar 

  52. Jiang, J. X. & Gu, S. Gap junction- and hemichannel-independent actions of connexins. Biochim. Biophys. Acta 1711, 208–214 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Zhang, Y. W., Kaneda, M. & Morita, I. The gap junction-independent tumor-suppressing effect of connexin 43. J. Biol. Chem. 278, 44852–44856 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Duflot-Dancer, A., Mesnil, M. & Yamasaki, H. Dominant-negative abrogation of connexin-mediated cell growth control by mutant connexin genes. Oncogene 15, 2151–2158 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Huang, R. P. et al. Reversion of the neoplastic phenotype of human glioblastoma cells by connexin 43 (cx43). Cancer Res. 58, 5089–5096 (1998).

    CAS  PubMed  Google Scholar 

  56. Krutovskikh, V. A. et al. Differential effect of subcellular localization of communication impairing gap junction protein connexin 43 on tumor cell growth in vivo. Oncogene 19, 505–513 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Lee, H. J., Lee, I. K., Seul, K. H. & Rhee, S. K. Growth inhibition by connexin 26 expression in cultured rodent tumor cells. Mol. Cells 14, 136–142 (2002).

    CAS  PubMed  Google Scholar 

  58. Omori, Y. & Yamasaki, H. Mutated connexin43 proteins inhibit rat glioma cell growth suppression mediated by wild-type connexin 43 in a dominant-negative manner. Int. J. Cancer 78, 446–453 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Laird, D. W. The gap junction proteome and its relationship to disease. Trends Cell Biol. 20, 92–101 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Langlois, S., Cowan, K. N., Shao, Q., Cowan, B. J. & Laird, D. W. Caveolin-1 and -2 interact with connexin 43 and regulate gap junctional intercellular communication in keratinocytes. Mol. Biol. Cell 19, 912–928 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Langlois, S., Cowan, K. N., Shao, Q., Cowan, B. J. & Laird, D. W. The tumor suppressive function of connexin 43 in keratinocytes is mediated in part via interaction with caveolin-1. Cancer Res. 20 April 2010 [epub ahead of print].

  62. Capozza, F. et al. Absence of caveolin-1 sensitizes mouse skin to carcinogen-induced epidermal hyperplasia and tumor formation. Am. J. Pathol. 162, 2029–2039 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Goetz, J. G., Lajoie, P., Wiseman, S. M. & Nabi, I. R. Caveolin-1 in tumor progression: the good, the bad and the ugly. Cancer Metastasis Rev. 27, 715–735 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Fu, C. T., Bechberger, J. F., Ozog, M. A., Perbal, B. & Naus, C. C. CCN3 (NOV) interacts with connexin 43 in C6 glioma cells: possible mechanism of connexin-mediated growth suppression. J. Biol. Chem. 279, 36943–36950 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Gellhaus, A. et al. Connexin43 interacts with NOV: a possible mechanism for negative regulation of cell growth in choriocarcinoma cells. J. Biol. Chem. 279, 36931–36942 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Leithe, E. et al. Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101. J. Cell Sci. 122, 3883–3893 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Kieken, F. et al. Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. Circ. Res. 104, 1103–1112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gupta, N. et al. Inhibition of glioma cell growth and tumorigenic potential by CCN3 (NOV). Mol. Pathol. 54, 293–299 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Perbal, B. The CCN3 protein and cancer. Adv. Exp. Med. Biol. 587, 23–40 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Oh, H. et al. Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1). Proc. Natl Acad. Sci. USA 99, 5430–5435 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fujimoto, E. et al. Inhibition of Src activity enhances the tumor-suppressive effect of the connexin 32 gene in Caki-1 renal cancer cells. Oncol. Rep. 15, 1359–1365 (2006).

    CAS  PubMed  Google Scholar 

  72. Fujimoto, E. et al. Connexin32 as a tumor suppressor gene in a metastatic renal cell carcinoma cell line. Oncogene 24, 3684–3690 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Elias, L. A., Wang, D. D. & Kriegstein, A. R. Gap junction adhesion is necessary for radial migration in the neocortex. Nature 448, 901–907 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Cina, C. et al. Involvement of the cytoplasmic C-terminal domain of connexin 43 in neuronal migration. J. Neurosci. 29, 2009–2021 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cotrina, M. L., Lin, J. H. & Nedergaard, M. Adhesive properties of connexin hemichannels. Glia 56, 1791–1798 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Meyer, R. A., Laird, D. W., Revel, J. P. & Johnson, R. G. Inhibition of gap junction and adherens junction assembly by connexin and A-CAM antibodies. J. Cell Biol. 119, 179–189 (1992).

    Article  CAS  PubMed  Google Scholar 

  77. Musil, L. S., Cunningham, B. A., Edelman, G. M. & Goodenough, D. A. Differential phosphorylation of the gap junction protein connexin 43 in junctional communication-competent and -deficient cell lines. J. Cell Biol. 111, 2077–2088 (1990).

    Article  CAS  PubMed  Google Scholar 

  78. Wei, C. J., Francis, R., Xu, X. & Lo, C. W. Connexin 43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells. J. Biol. Chem. 280, 19925–19936 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Reaume, A. G. et al. Cardiac malformation in neonatal mice lacking connexin43. Science 267, 1831–1834 (1995).

    Article  CAS  PubMed  Google Scholar 

  80. Xu, X., Francis, R., Wei, C. J., Linask, K. L. & Lo, C. W. Connexin 43-mediated modulation of polarized cell movement and the directional migration of cardiac neural crest cells. Development 133, 3629–3639 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Simpson, K. J. et al. Identification of genes that regulate epithelial cell migration using an siRNA screening approach. Nature Cell Biol. 10, 1027–1038 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Olk, S. et al. Proteomic analysis of astroglial connexin 43 silencing uncovers a cytoskeletal platform involved in process formation and migration. Glia 58, 494–505.

  83. Lampe, P. D. et al. Cellular interaction of integrin a3b1 with laminin 5 promotes gap junctional communication. J. Cell Biol. 143, 1735–1747 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Burt, J. M., Nelson, T. K., Simon, A. M. & Fang, J. S. Connexin 37 profoundly slows cell cycle progression in rat insulinoma cells. Am. J. Physiol. Cell Physiol. 295, C1103–C1112 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Solan, J. L., Fry, M. D., TenBroek, E. M. & Lampe, P. D. Connexin 43 phosphorylation at S368 is acute during S and G2/M and in response to protein kinase C activation. J. Cell Sci. 116, 2203–2211 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Chen, S. C., Pelletier, D. B., Ao, P. & Boynton, A. L. Connexin 43 reverses the phenotype of transformed cells and alters their expression of cyclin/cyclin-dependent kinases. Cell Growth Differ. 6, 681–690 (1995).

    CAS  PubMed  Google Scholar 

  87. Zhang, Y. W., Morita, I., Ikeda, M., Ma, K. W. & Murota, S. Connexin 43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27. Oncogene 20, 4138–4149 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Sanchez-Alvarez, R., Paino, T., Herrero-Gonzalez, S., Medina, J. M. & Tabernero, A. Tolbutamide reduces glioma cell proliferation by increasing connexin43, which promotes the up-regulation of p21 and p27 and subsequent changes in retinoblastoma phosphorylation. Glia 54, 125–134 (2006).

    Article  PubMed  Google Scholar 

  89. Tanaka, M. & Grossman, H. B. Connexin 26 induces growth suppression, apoptosis and increased efficacy of doxorubicin in prostate cancer cells. Oncol. Rep. 11, 537–541 (2004).

    CAS  PubMed  Google Scholar 

  90. Mesnil, M. et al. Negative growth control of HeLa cells by connexin genes: connexin species specificity. Cancer Res. 55, 629–639 (1995).

    CAS  PubMed  Google Scholar 

  91. Iacobas, D. A., Scemes, E. & Spray, D. C. Gene expression alterations in connexin null mice extend beyond the gap junction. Neurochem. Int. 45, 243–250 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Saito-Katsuragi, M. et al. Role for connexin 26 in metastasis of human malignant melanoma: communication between melanoma and endothelial cells via connexin 26. Cancer 110, 1162–1172 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Pollmann, M. A., Shao, Q., Laird, D. W. & Sandig, M. Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture. Breast Cancer Res. 7, R522–R534 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Naoi, Y. et al. Connexin 26 expression is associated with lymphatic vessel invasion and poor prognosis in human breast cancer. Breast Cancer Res. Treat 106, 11–17 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Yano, T. et al. Connexin 32 as an anti-invasive and anti-metastatic gene in renal cell carcinoma. Biol. Pharm. Bull. 29, 1991–1994 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Li, Z., Zhou, Z. & Donahue, H. J. Alterations in Cx43 and OB-cadherin affect breast cancer cell metastatic potential. Clin. Exp. Metastasis 25, 265–272 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Sato, H. et al. The inhibitory effect of connexin 32 gene on metastasis in renal cell carcinoma. Mol. Carcinog. 47, 403–409 (2008).

    Article  PubMed  CAS  Google Scholar 

  98. Cohn, E. S. & Kelley, P. M. Clinical phenotype and mutations in connexin 26 (DFNB1/GJB2), the most common cause of childhood hearing loss. Am. J. Med. Genet. 89, 130–136 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Nyquist, G. G. et al. Malignant proliferating pilar tumors arising in KID syndrome: a report of two patients. Am. J. Med. Genet. A 143, 734–741 (2007).

    Article  Google Scholar 

  100. Collignon, F. et al. Altered expression of connexin subtypes in mesial temporal lobe epilepsy in humans. J. Neurosurg. 105, 77–87 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Proulx, E. et al. Functional contribution of specific brain areas to absence seizures: role of thalamic gap-junctional coupling. Eur. J. Neurosci. 23, 489–496 (2006).

    Article  PubMed  Google Scholar 

  102. Nemani, V. M. & Binder, D. K. Emerging role of gap junctions in epilepsy. Histol. Histopathol. 20, 253–259 (2005).

    CAS  PubMed  Google Scholar 

  103. Gabriel, H. D. et al. Transplacental uptake of glucose is decreased in embryonic lethal connexin 26-deficient mice. J. Cell Biol. 140, 1453–1461 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kruger, O. et al. Defective vascular development in connexin 45-deficient mice. Development 127, 4179–4193 (2000).

    CAS  PubMed  Google Scholar 

  105. Yamakage, K., Omori, Y., Zaidan-Dagli, M. L., Cros, M. P. & Yamasaki, H. Induction of skin papillomas, carcinomas, and sarcomas in mice in which the connexin 43 gene is heterologously deleted. J. Invest. Dermatol. 114, 289–294 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Evert, M., Ott, T., Temme, A., Willecke, K. & Dombrowski, F. Morphology and morphometric investigation of hepatocellular preneoplastic lesions and neoplasms in connexin 32-deficient mice. Carcinogenesis 23, 697–703 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Moennikes, O., Buchmann, A., Ott, T., Willecke, K. & Schwarz, M. The effect of connexin 32 null mutation on hepatocarcinogenesis in different mouse strains. Carcinogenesis 20, 1379–1382 (1999).

    Article  CAS  PubMed  Google Scholar 

  108. Moennikes, O., Buchmann, A., Willecke, K., Traub, O. & Schwarz, M. Hepatocarcinogenesis in female mice with mosaic expression of connexin 32. Hepatology 32, 501–506 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. King, T. J. et al. Deficiency in the gap junction protein connexin 32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner. Oncogene 24, 1718–1726 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Bakirtzis, G. et al. Targeted epidermal expression of mutant connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders. Hum. Mol. Genet. 12, 1737–1744 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Flenniken, A. M. et al. A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia. Development 132, 4375–4386 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Kalcheva, N. et al. Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia. Proc. Natl Acad. Sci. USA 104, 20512–20516 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. VanSlyke, J. K. & Musil, L. S. Dislocation and degradation from the ER are regulated by cytosolic stress. J. Cell Biol. 157, 381–394 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Musil, L. S. & Goodenough, D. A. Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin 43, occurs after exit from the ER. Cell 74, 1065–1077 (1993).

    Article  CAS  PubMed  Google Scholar 

  115. Giepmans, B. N. et al. Gap junction protein connexin-43 interacts directly with microtubules. Curr. Biol. 11, 1364–1368 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Shaw, R. M. et al. Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions. Cell 128, 547–560 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Preus, D., Johnson, R., Sheridan, J. & Meyer, R. Analysis of gap junctions and formation plaques between reaggregating Novikoff hepatoma cells. J. Ultrastruct. Res. 77, 263–276 (1981).

    Article  CAS  PubMed  Google Scholar 

  118. Evans, W. H., De Vuyst, E. & Leybaert, L. The gap junction cellular internet: connexin hemichannels enter the signalling limelight. Biochem. J. 397, 1–14 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. McLachlan, E., Shao, Q. & Laird, D. W. Connexins and gap junctions in mammary gland development and breast cancer progression. J. Membr. Biol. 218, 107–121 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank E. Jewlel for compiling some literature on this topic and P. Lampe, M. Mesnil, I. Plante, M. Sandig and L. Matsuuchi for their critical reading of the manuscript. The authors also apologize to the numerous authors who have contributed to this exciting field but whose work was not cited in this short article. C.C.N. and D.W.L. are supported by grants from Canadian Institutes of Health Research, Canada Breast Cancer Research Alliance, and the Canada Research Chairs Program.

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  1. Dale W. Laird is at the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A-5C1, Canada.,

    Dale W. Laird

  2. Department of Cellular and Physiological Sciences, Christian C. Naus is at the Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T-1Z3, Canada.,

    Christian C. Naus

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  1. Christian C. Naus
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  2. Dale W. Laird
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Correspondence to Christian C. Naus.

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Naus, C., Laird, D. Implications and challenges of connexin connections to cancer. Nat Rev Cancer 10, 435–441 (2010). https://doi.org/10.1038/nrc2841

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