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Gap junctions and cancer: communicating for 50 years

Nature Reviews Cancer volume 16, pages 775–788 (2016)Cite this article

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A Corrigendum to this article was published on 02 December 2016

This article has been updated

Abstract

Fifty years ago, tumour cells were found to lack electrical coupling, leading to the hypothesis that loss of direct intercellular communication is commonly associated with cancer onset and progression. Subsequent studies linked this phenomenon to gap junctions composed of connexin proteins. Although many studies support the notion that connexins are tumour suppressors, recent evidence suggests that, in some tumour types, they may facilitate specific stages of tumour progression through both junctional and non-junctional signalling pathways. This Timeline article highlights the milestones connecting gap junctions to cancer, and underscores important unanswered questions, controversies and therapeutic opportunities in the field.

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Figure 1: The Timeline shows key discoveries related to gap junctions and cancer.
Figure 2: Assembly of connexins into gap junctions.
Figure 3: Connexin involvement during cancer progression.
Figure 4: The Cx43 interactome.

Change history

  • 02 December 2016

    On page 779 of the above article there were errors in line 7 of Table 1. The carcinogen used in the mouse model was DEN and the outcome was increased liver tumours in males only. This has now been corrected in the online version.

  • 26 October 2016

    In the original version of this article published online the DOI number was incorrect. This error has been corrected in the HTML and PDF versions of the article.

References

  1. Loewenstein, W. R., Socolar, S. J., Higashino, S., Kanno, Y. & Davidson, N. Intercellular communication: renal, urinary bladder, sensory, and salivary gland cells. Science 149, 295–298 (1965).

    Article  CAS  PubMed  Google Scholar 

  2. Kanno, Y. & Loewenstein, W. R. Cell-to-cell passage of large molecules. Nature 212, 629–630 (1966).

    Article  CAS  PubMed  Google Scholar 

  3. Loewenstein, W. R. & Kanno, Y. Studies on an epithelial (gland) cell junction. I. Modifications of surface membrane permeability. J. Cell Biol. 22, 565–586 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. Loewenstein, W. R. & Kanno, Y. Intercellular communication and tissue growth. I. Cancerous growth. J. Cell Biol. 33, 225–234 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jamakosmanovic´, A. & Loewenstein, W. R. Intercellular communication and tissue growth. III. Thyroid cancer. J. Cell Biol. 38, 556–561 (1968).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Borek, C., Higashino, S. & Loewenstein, W. R. Intercellular communication and tissue growth: IV. Conductance of membrane junctions of normal and cancerous cells in culture. J. Membr. Biol. 1, 274–293 (1969).

    Article  CAS  PubMed  Google Scholar 

  8. Johnson, R. G. & Sheridan, J. D. Junctions between cancer cells in culture: ultrastructure and permeability. Science 174, 717–719 (1971).

    Article  CAS  PubMed  Google Scholar 

  9. McNutt, N. S. & Weinstein, R. S. Carcinoma of the cervix: deficiency of nexus intercellular junctions. Science 165, 597–599 (1969).

    Article  CAS  PubMed  Google Scholar 

  10. Revel, J. P. & Karnovsky, M. J. Hexagonal array of subunits in intercellular junctions of the mouse heart and liver. J. Cell Biol. 33, C7–C12 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Payton, B. W., Bennett, M. V. & Pappas, G. D. Permeability and structure of junctional membranes at an electrotonic synapse. Science 166, 1641–1643 (1969).

    Article  CAS  PubMed  Google Scholar 

  12. Goodenough, D. A. & Stoeckenius, W. The isolation of mouse hepatocyte gap junctions. Preliminary chemical characterization and X-ray diffraction. J. Cell Biol. 54, 646–656 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Goodenough, D. A. Bulk isolation of mouse hepatocyte gap junctions. Characterization of the principal protein, connexin. J. Cell Biol. 61, 557–563 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Beyer, E. C., Paul, D. L. & Goodenough, D. A. Connexin family of gap junction proteins. J. Membr. Biol. 116, 187–194 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. Subak-Sharpe, H., Bürk, R. R. & Pitts, J. D. Metabolic co-operation between biochemically marked mammalian cells in tissue culture. J. Cell Sci. 4, 353–367 (1969).

    Article  CAS  PubMed  Google Scholar 

  16. Gilula, N. B., Reeves, O. R. & Steinbach, A. Metabolic coupling, ionic coupling and cell contacts. Nature 235, 262–265 (1972).

    Article  CAS  PubMed  Google Scholar 

  17. Fentiman, I. S. & Taylor-Papadimitriou, J. Cultured human breast cancer cells lose selectivity in direct intercellular communication. Nature 269, 156–158 (1977).

    Article  CAS  PubMed  Google Scholar 

  18. Nicolas, J. F., Jakob, H. & Jacob, F. Metabolic cooperation between mouse embryonal carcinoma cells and their differentiated derivatives. Proc. Natl Acad. Sci. USA 75, 3292–3296 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yotti, L. P., Chang, C. C. & Trosko, J. E. Elimination of metabolic cooperation in Chinese hamster cells by a tumor promoter. Science 206, 1089–1091 (1979).

    Article  CAS  PubMed  Google Scholar 

  20. Murray, A. W. & Fitzgerald, D. J. Tumor promoters inhibit metabolic cooperation in cocultures of epidermal and 3T3 cells. Biochem. Biophys. Res. Commun. 91, 395–401 (1979).

    Article  CAS  PubMed  Google Scholar 

  21. Kalimi, G. H. & Sirsat, S. M. Phorbol ester tumor promoter affects the mouse epidermal gap junctions. Cancer Lett. 22, 343–350 (1984).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Trosko, J. E., Jone, C. & Chang, C. C. Oncogenes, inhibited intercellular communication and tumor promotion. Princess Takamatsu Symp. 14, 101–113 (1983).

    CAS  PubMed  Google Scholar 

  24. Dahl, G., Azarnia, R. & Werner, R. Induction of cell–cell channel formation by mRNA. Nature 289, 683–685 (1981).

    Article  CAS  PubMed  Google Scholar 

  25. Heynkes, R., Kozjek, G., Traub, O. & Willecke, K. Identification of a rat liver cDNA and mRNA coding for the 28 kDa gap junction protein. FEBS Lett. 205, 56–60 (1986).

    Article  CAS  PubMed  Google Scholar 

  26. Paul, D. L. Molecular cloning of cDNA for rat liver gap junction protein. J. Cell Biol. 103, 123–134 (1986).

    Article  CAS  PubMed  Google Scholar 

  27. Kumar, N. M. & Gilula, N. B. Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein. J. Cell Biol. 103, 767–776 (1986).

    Article  CAS  PubMed  Google Scholar 

  28. Beyer, E. C., Paul, D. L. & Goodenough, D. A. Connexin43: a protein from rat heart homologous to a gap junction protein from liver. J. Cell Biol. 105, 2621–2629 (1987).

    Article  CAS  PubMed  Google Scholar 

  29. Dahl, G., Miller, T., Paul, D., Voellmy, R. & Werner, R. Expression of functional cell–cell channels from cloned rat liver gap junction complementary DNA. Science 236, 1290–1293 (1987).

    Article  CAS  PubMed  Google Scholar 

  30. Bai, D. Structural analysis of key gap junction domains — lessons from genome data and disease-linked mutants. Semin. Cell Dev. Biol. 50, 74–82 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  32. Evans, W. H. Cell communication across gap junctions: a historical perspective and current developments. Biochem. Soc. Trans. 43, 450–459 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Stauffer, K. A. The gap junction proteins β1-connexin (connexin-32) and β2-connexin (connexin-26) can form heteromeric hemichannels. J. Biol. Chem. 270, 6768–6772 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Kanaporis, G. et al. Gap junction channels exhibit connexin-specific permeability to cyclic nucleotides. J. Gen. Physiol. 131, 293–305 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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 

  36. Kyo, N. et al. Overexpression of connexin 26 in carcinoma of the pancreas. Oncol. Rep. 19, 627–631 (2008).

    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. Mehta, P. P. et al. Suppression of human prostate cancer cell growth by forced expression of connexin genes. Dev. Genet. 24, 91–110 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Benko, G. et al. Prognostic value of connexin43 expression in patients with clinically localized prostate cancer. Prostate Cancer Prostatic Dis. 14, 90–95 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Liang, Q. L., Wang, B. R., Chen, G. Q., Li, G. H. & Xu, Y. Y. Clinical significance of vascular endothelial growth factor and connexin43 for predicting pancreatic cancer clinicopathologic parameters. Med. Oncol. 27, 1164–1170 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Teleki, I. et al. Correlations of differentially expressed gap junction connexins Cx26, Cx30, Cx32, Cx43 and Cx46 with breast cancer progression and prognosis. PLoS ONE 9, e112541 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Dános, K. et al. The potential prognostic value of connexin 43 expression in head and neck squamous cell carcinomas. Appl. Immunohistochem. Mol. Morphol. 24, 476–481 (2016).

    Article  PubMed  CAS  Google Scholar 

  43. Du, G. et al. Thrombocytosis and immunohistochemical expression of connexin 43 at diagnosis predict survival in advanced non-small-cell lung cancer treated with cisplatin-based chemotherapy. Cancer Chemother. Pharmacol. 71, 893–904 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Sirnes, S. et al. Connexin43 acts as a colorectal cancer tumor suppressor and predicts disease outcome. Int. J. Cancer 131, 570–581 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Nomura, S. et al. Clinical significance of the expression of connexin26 in colorectal cancer. J. Exp. Clin. Cancer Res. 29, 79 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Liu, X. et al. Connexin 26 expression correlates with less aggressive phenotype of intestinal type-gastric carcinomas. Int. J. Mol. Med. 25, 709–716 (2010).

    CAS  PubMed  Google Scholar 

  47. Brockmeyer, P., Jung, K., Perske, C., Schliephake, H. & Hemmerlein, B. Membrane connexin 43 acts as an independent prognostic marker in oral squamous cell carcinoma. Int. J. Oncol. 45, 273–281 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Tanaka, T., Kimura, M., Ishiguro, H., Mizoguchi, K. & Takeyama, H. Connexin 43 expression is associated with poor survival in patients with esophageal squamous cell carcinoma. Mol. Clin. Oncol. 4, 989–993 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Poyet, C. et al. Connexin 43 expression predicts poor progression-free survival in patients with non-muscle invasive urothelial bladder cancer. J. Clin. Pathol. 68, 819–824 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Teleki, I. et al. The potential prognostic value of connexin 26 and 46 expression in neoadjuvant-treated breast cancer. BMC Cancer 13, 50 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Naoi, Y. et al. Connexin26 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 

  52. Ito, A. et al. Increased expression of connexin 26 in the invasive component of lung squamous cell carcinoma: significant correlation with poor prognosis. Cancer Lett. 234, 239–248 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Inose, T. et al. Correlation between connexin 26 expression and poor prognosis of esophageal squamous cell carcinoma. Ann. Surg. Oncol. 16, 1704–1710 (2009).

    Article  PubMed  Google Scholar 

  54. Naoi, Y. et al. Connexin26 expression is associated with aggressive phenotype in human papillary and follicular thyroid cancers. Cancer Lett. 262, 248–256 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Mehta, P. P., Hotz-Wagenblatt, A., Rose, B., Shalloway, D. & Loewenstein, W. R. Incorporation of the gene for a cell–cell channel protein into transformed cells leads to normalization of growth. J. Membr. Biol. 124, 207–225 (1991).

    Article  CAS  PubMed  Google Scholar 

  56. 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 

  57. Naus, C. C., Elisevich, K., Zhu, D., Belliveau, D. J. & Del Maestro, R. F. In vivo growth of C6 glioma cells transfected with connexin43 cDNA. Cancer Res. 52, 4208–4213 (1992).

    CAS  PubMed  Google Scholar 

  58. 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 

  59. Aasen, T. Connexins: junctional and non-junctional modulators of proliferation. Cell Tissue Res. 360, 685–699 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Carette, D., Gilleron, J., Chevallier, D., Segretain, D. & Pointis, G. Connexin a check-point component of cell apoptosis in normal and physiopathological conditions. Biochimie 101, 1–9 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. King, T. J. & Bertram, J. S. Connexins as targets for cancer chemoprevention and chemotherapy. Biochim. Biophys. Acta 1719, 146–160 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Kotini, M. & Mayor, R. Connexins in migration during development and cancer. Dev. Biol. 401, 143–151 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Defamie, N., Chepied, A. & Mesnil, M. Connexins, gap junctions and tissue invasion. FEBS Lett. 588, 1331–1338 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. 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 

  65. Wang, W. K. et al. Connexin 43 suppresses tumor angiogenesis by down-regulation of vascular endothelial growth factor via hypoxic-induced factor-1α. Int. J. Mol. Sci. 16, 439–451 (2015).

    Article  CAS  Google Scholar 

  66. Naus, C. C. & Laird, D. W. Implications and challenges of connexin connections to cancer. Nat. Rev. Cancer 10, 435–441 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Igarashi, I. et al. Background lesions during a 24-month observation period in connexin 32-deficient mice. J. Vet. Med. Sci. 75, 207–210 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. Evert, M., Ott, T., Temme, A., Willecke, K. & Dombrowski, F. Morphology and morphometric investigation of hepatocellular preneoplastic lesions and neoplasms in connexin32-deficient mice. Carcinogenesis 23, 697–703 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. 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 

  71. Oyamada, M. et al. Aberrant expression of gap junction gene in primary human hepatocellular carcinomas: increased expression of cardiac-type gap junction gene connexin 43. Mol. Carcinog. 3, 273–278 (1990).

    Article  CAS  PubMed  Google Scholar 

  72. Krutovskikh, V. et al. Altered homologous and heterologous gap-junctional intercellular communication in primary human liver tumors associated with aberrant protein localization but not gene mutation of connexin 32. Int. J. Cancer 56, 87–94 (1994).

    Article  CAS  PubMed  Google Scholar 

  73. Rae, R. S., Mehta, P. P., Chang, C. C., Trosko, J. E. & Ruch, R. J. Neoplastic phenotype of gap-junctional intercellular communication-deficient WB rat liver epithelial cells and its reversal by forced expression of connexin 32. Mol. Carcinog. 22, 120–127 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. 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 connexin32 only in the liver. Carcinogenesis 25, 483–492 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. King, T. J. & Lampe, P. D. Mice deficient for the gap junction protein connexin32 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 

  76. King, T. J. et al. Deficiency in the gap junction protein connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner. Oncogene 24, 1718–1726 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Marx-Stoelting, P. et al. Tumor promotion in liver of mice with a conditional Cx26 knockout. Toxicol. Sci. 103, 260–267 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Stewart, M. K., Bechberger, J. F., Welch, I., Naus, C. C. & Laird, D. W. Cx26 knockout predisposes the mammary gland to primary mammary tumors in a DMBA-induced mouse model of breast cancer. Oncotarget 6, 37185–37199 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  79. 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 

  80. de Oliveira, K. D., Tedardi, M. V., Cogliati, B. & Dagli, M. L. Higher incidence of lung adenocarcinomas induced by DMBA in connexin 43 heterozygous knockout mice. Biomed. Res. Int. 2013, 618475 (2013).

    PubMed  Google Scholar 

  81. Fukumasu, H. et al. Higher susceptibility of spontaneous and NNK-induced lung neoplasms in connexin 43 deficient CD1 x AJ F1 mice: paradoxical expression of connexin 43 during lung carcinogenesis. Mol. Carcinog. 52, 497–506 (2012).

    Article  PubMed  CAS  Google Scholar 

  82. Plante, I., Stewart, M. K., Barr, K., Allan, A. L. & Laird, D. W. Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease. Oncogene 30, 1681–1692 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Alonso, F. et al. Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion. Oncotarget 7, 14015–14028 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Sin, W. C. et al. Astrocytes promote glioma invasion via the gap junction protein connexin43. Oncogene 35, 1504–1516 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. Dubina, M. V., Iatckii, N. A., Popov, D. E., Vasil'ev, S. V. & Krutovskikh, V. A. Connexin 43, but not connexin 32, is mutated at advanced stages of human sporadic colon cancer. Oncogene 21, 4992–4996 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Gonzalez-Perez, A. et al. IntOGen-mutations identifies cancer drivers across tumor types. Nat. Methods 10, 1081–1082 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kelly, J. J., Simek, J. & Laird, D. W. Mechanisms linking connexin mutations to human diseases. Cell Tissue Res. 360, 701–721 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Sakabe, J. et al. Connexin 26 (GJB2) mutations in keratitis-ichthyosis-deafness syndrome presenting with squamous cell carcinoma. J. Dermatol. 39, 814–815 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Gasparini, P. et al. High carrier frequency of the 35delG deafness mutation in European populations. Eur. J. Hum. Genet. 8, 19–23 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Bergoffen, J. et al. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 262, 2039–2042 (1993).

    Article  CAS  PubMed  Google Scholar 

  91. Vinken, M. Regulation of connexin signaling by the epigenetic machinery. Biochim. Biophys. Acta 1859, 262–268 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Salat-Canela, C., Munoz, M. J., Sesé, M., Ramón, Y. C. S. & Aasen, T. Post-transcriptional regulation of connexins. Biochem. Soc. Trans. 43, 465–470 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Sirnes, S. et al. DNA methylation analyses of the connexin gene family reveal silencing of GJC1 (connexin45) by promoter hypermethylation in colorectal cancer. Epigenetics 6, 602–609 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Hao, J. et al. miR-221/222 is the regulator of Cx43 expression in human glioblastoma cells. Oncol. Rep. 27, 1504–1510 (2012).

    CAS  PubMed  Google Scholar 

  95. Jin, Z. et al. miR-125b inhibits connexin43 and promotes glioma growth. Cell. Mol. Neurobiol. 33, 1143–1148 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Li, X. et al. Suppression of CX43 expression by miR-20a in the progression of human prostate cancer. Cancer Biol. Ther. 13, 890–898 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Poliseno, L. et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033–1038 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yang, B. et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat. Med. 13, 486–491 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Bier, A. et al. Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target. Mol. Cancer Ther. 8, 786–793 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Kandouz, M., Bier, A., Carystinos, G. D., Alaoui-Jamali, M. A. & Batist, G. Connexin43 pseudogene is expressed in tumor cells and inhibits growth. Oncogene 23, 4763–4770 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Lahlou, H., Fanjul, M., Pradayrol, L., Susini, C. & Pyronnet, S. Restoration of functional gap junctions through internal ribosome entry site-dependent synthesis of endogenous connexins in density-inhibited cancer cells. Mol. Cell. Biol. 25, 4034–4045 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Smyth, J. W. & Shaw, R. M. Autoregulation of connexin43 gap junction formation by internally translated isoforms. Cell Rep. 5, 611–618 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Maqbool, R. et al. The carboxy-terminal domain of connexin 43 (CT-Cx43) modulates the expression of p53 by altering miR-125b expression in low-grade human breast cancers. Cell. Oncol. 38, 443–451 (2015).

    Article  CAS  Google Scholar 

  104. Mennecier, G., Derangeon, M., Coronas, V., Hervé, J. C. & Mesnil, M. Aberrant expression and localization of connexin43 and connexin30 in a rat glioma cell line. Mol. Carcinog. 47, 391–401 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Salat-Canela, C., Sesé, M., Peula, C., Ramón, Y. C. S. & Aasen, T. Internal translation of the connexin 43 transcript. Cell Commun. Signal. 12, 31 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Ul-Hussain, M. et al. Internal ribosomal entry site (IRES) activity generates endogenous carboxyl-terminal domains of Cx43 and is responsive to hypoxic conditions. J. Biol. Chem. 289, 20979–20990 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wincewicz, A. et al. Aberrant distributions and relationships among E-cadherin, β-catenin, and connexin 26 and 43 in endometrioid adenocarcinomas. Int. J. Gynecol. Pathol. 29, 358–365 (2010).

    Article  PubMed  Google Scholar 

  108. Kanczuga-Koda, L. et al. Gradual loss of functional gap junction within progression of colorectal cancer — a shift from membranous CX32 and CX43 expression to cytoplasmic pattern during colorectal carcinogenesis. In Vivo 24, 101–107 (2010).

    CAS  PubMed  Google Scholar 

  109. Kanczuga-Koda, L. et al. Expression of connexin 43 in breast cancer in comparison with mammary dysplasia and the normal mammary gland. Folia Morphol. 62, 439–442 (2003).

    Google Scholar 

  110. Johnstone, S. R., Billaud, M., Lohman, A. W., Taddeo, E. P. & Isakson, B. E. Posttranslational modifications in connexins and pannexins. J. Membr. Biol. 245, 319–332 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wiener, E. C. & Loewenstein, W. R. Correction of cell–cell communication defect by introduction of a protein kinase into mutant cells. Nature 305, 433–435 (1983).

    Article  CAS  PubMed  Google Scholar 

  112. Saez, J. C. et al. cAMP increases junctional conductance and stimulates phosphorylation of the 27-kDa principal gap junction polypeptide. Proc. Natl Acad. Sci. USA 83, 2473–2477 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Azarnia, R., Reddy, S., Kmiecik, T. E., Shalloway, D. & Loewenstein, W. R. The cellular src gene product regulates junctional cell-to-cell communication. Science 239, 398–401 (1988).

    Article  CAS  PubMed  Google Scholar 

  114. Vanhamme, L., Rolin, S. & Szpirer, C. Inhibition of gap-junctional intercellular communication between epithelial cells transformed by the activated H-ras-1 oncogene. Exp. Cell Res. 180, 297–301 (1989).

    Article  CAS  PubMed  Google Scholar 

  115. Crow, D. S., Beyer, E. C., Paul, D. L., Kobe, S. S. & Lau, A. F. Phosphorylation of connexin43 gap junction protein in uninfected and Rous sarcoma virus-transformed mammalian fibroblasts. Mol. Cell. Biol. 10, 1754–1763 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Swenson, K. I., Piwnica-Worms, H., McNamee, H. & Paul, D. L. Tyrosine phosphorylation of the gap junction protein connexin43 is required for the pp60v-src-induced inhibition of communication. Cell Regul. 1, 989–1002 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Laird, D. W., Puranam, K. L. & Revel, J. P. Turnover and phosphorylation dynamics of connexin43 gap junction protein in cultured cardiac myocytes. Biochem. J. 273, 67–72 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Musil, L. S. & Goodenough, D. A. Biochemical analysis of connexin43 intracellular transport, phosphorylation, and assembly into gap junctional plaques. J. Cell Biol. 115, 1357–1374 (1991).

    Article  CAS  PubMed  Google Scholar 

  119. Lau, A. F., Hatch-Pigott, V. & Crow, D. S. Evidence that heart connexin43 is a phosphoprotein. J. Mol. Cell Cardiol. 23, 659–663 (1991).

    Article  CAS  PubMed  Google Scholar 

  120. Brissette, J. L., Kumar, N. M., Gilula, N. B. & Dotto, G. P. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate and the ras oncogene modulate expression and phosphorylation of gap junction proteins. Mol. Cell. Biol. 11, 5364–5371 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Oh, S. Y., Grupen, C. G. & Murray, A. W. Phorbol ester induces phosphorylation and down-regulation of connexin 43 in WB cells. Biochim. Biophys. Acta 1094, 243–245 (1991).

    Article  CAS  PubMed  Google Scholar 

  122. Asamoto, M., Oyamada, M., el Aoumari, A., Gros, D. & Yamasaki, H. Molecular mechanisms of TPA-mediated inhibition of gap-junctional intercellular communication: evidence for action on the assembly or function but not the expression of connexin 43 in rat liver epithelial cells. Mol. Carcinog. 4, 322–327 (1991).

    Article  CAS  PubMed  Google Scholar 

  123. Ruch, R. J., Trosko, J. E. & Madhukar, B. V. Inhibition of connexin43 gap junctional intercellular communication by TPA requires ERK activation. J. Cell Biochem. 83, 163–169 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Sirnes, S., Kjenseth, A., Leithe, E. & Rivedal, E. Interplay between PKC and the MAP kinase pathway in connexin43 phosphorylation and inhibition of gap junction intercellular communication. Biochem. Biophys. Res. Commun. 382, 41–45 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Solan, J. L. & Lampe, P. D. Connexin43 phosphorylation: structural changes and biological effects. Biochem. J. 419, 261–272 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Johnson, K. E. et al. Phosphorylation on Ser-279 and Ser-282 of connexin43 regulates endocytosis and gap junction assembly in pancreatic cancer cells. Mol. Biol. Cell 24, 715–733 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Dunn, C. A. & Lampe, P. D. Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size. J. Cell Sci. 127, 455–464 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lampe, P. D. & Lau, A. F. The effects of connexin phosphorylation on gap junctional communication. Int. J. Biochem. Cell Biol. 36, 1171–1186 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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 

  132. 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 

  133. Hong, X., Sin, W. C., Harris, A. L. & Naus, C. C. Gap junctions modulate glioma invasion by direct transfer of microRNA. Oncotarget 6, 15566–15577 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Zhang, A. et al. Connexin 43 expression is associated with increased malignancy in prostate cancer cell lines and functions to promote migration. Oncotarget 6, 11640–11651 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Ghosh, S., Kumar, A., Tripathi, R. P. & Chandna, S. Connexin-43 regulates p38-mediated cell migration and invasion induced selectively in tumour cells by low doses of γ-radiation in an ERK-1/2-independent manner. Carcinogenesis 35, 383–395 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Ogawa, K. et al. Silencing of connexin 43 suppresses invasion, migration and lung metastasis of rat hepatocellular carcinoma cells. Cancer Sci. 103, 860–867 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Bates, D. C., Sin, W. C., Aftab, Q. & Naus, C. C. Connexin43 enhances glioma invasion by a mechanism involving the carboxy terminus. Glia 55, 1554–1564 (2007).

    Article  PubMed  Google Scholar 

  138. 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 

  139. el-Sabban, M. E. & Pauli, B. U. Adhesion-mediated gap junctional communication between lung-metastatatic cancer cells and endothelium. Invasion Metastasis 14, 164–176 (1994).

    CAS  PubMed  Google Scholar 

  140. Tang, B. et al. Aberrant expression of Cx43 is associated with the peritoneal metastasis of gastric cancer and Cx43-mediated gap junction enhances gastric cancer cell diapedesis from peritoneal mesothelium. PLoS ONE 8, e74527 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 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 

  142. Stoletov, K. et al. Role of connexins in metastatic breast cancer and melanoma brain colonization. J. Cell Sci. 126, 904–913 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Zibara, K. et al. Anti-angiogenesis therapy and gap junction inhibition reduce MDA-MB-231 breast cancer cell invasion and metastasis in vitro and in vivo. Sci. Rep. 5, 12598 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lamiche, C. et al. The gap junction protein Cx43 is involved in the bone-targeted metastatic behaviour of human prostate cancer cells. Clin. Exp. Metastasis 29, 111–122 (2012).

    Article  CAS  PubMed  Google Scholar 

  145. Chen, Q. et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533, 493–498 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Yu, M. et al. Cx43 reverses the resistance of A549 lung adenocarcinoma cells to cisplatin by inhibiting EMT. Oncol. Rep. 31, 2751–2758 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Yang, J. et al. Reciprocal positive regulation between Cx26 and PI3K/Akt pathway confers acquired gefitinib resistance in NSCLC cells via GJIC-independent induction of EMT. Cell Death Dis. 6, e1829 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Dertinger, H. & Hulser, D. Increased radioresistance of cells in cultured multicell spheroids. I. Dependence on cellular interaction. Radiat. Environ. Biophys. 19, 101–107 (1981).

    Article  CAS  PubMed  Google Scholar 

  149. Artesi, M. et al. Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy. Neuro Oncol. 17, 392–406 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. 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 

  151. Chandrasekhar, A. et al. Intercellular redistribution of cAMP underlies selective suppression of cancer cell growth by connexin26. PLoS ONE 8, e82335 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. 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 

  153. Bruzzone, S., Guida, L., Zocchi, E., Franco, L. & De Flora, A. Connexin 43 hemi channels mediate Ca2+-regulated transmembrane NAD+ fluxes in intact cells. FASEB J. 15, 10–12 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Song, D. et al. Connexin 43 hemichannel regulates H9c2 cell proliferation by modulating intracellular ATP and [Ca2+]. Acta Biochim. Biophys. Sin. (Shanghai) 42, 472–482 (2010).

    Article  CAS  Google Scholar 

  155. Pearson, R. A., Dale, N., Llaudet, E. & Mobbs, P. ATP released via gap junction hemichannels from the pigment epithelium regulates neural retinal progenitor proliferation. Neuron 46, 731–744 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Franco, L. et al. Paracrine roles of NAD+ and cyclic ADP-ribose in increasing intracellular calcium and enhancing cell proliferation of 3T3 fibroblasts. J. Biol. Chem. 276, 21642–21648 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. Essenfelder, G. M. et al. Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity. Hum. Mol. Genet. 13, 1703–1714 (2004).

    Article  CAS  PubMed  Google Scholar 

  158. Zhang, J. et al. Connexin hemichannel induced vascular leak suggests a new paradigm for cancer therapy. FEBS Lett. 588, 1365–1371 (2014).

    Article  CAS  PubMed  Google Scholar 

  159. Zhou, J. Z. et al. Osteocytic connexin hemichannels suppress breast cancer growth and bone metastasis. Oncogene http://dx.doi.org/10.1038/onc.2016.101 (2016).

  160. Schalper, K. A., Carvajal-Hausdorf, D. & Oyarzo, M. P. Possible role of hemichannels in cancer. Front. Physiol. 5, 237 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Moorby, C. & Patel, M. Dual functions for connexins: Cx43 regulates growth independently of gap junction formation. Exp. Cell Res. 271, 238–248 (2001).

    Article  CAS  PubMed  Google Scholar 

  162. 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 

  163. Dang, X., Doble, B. W. & Kardami, E. The carboxy-tail of connexin-43 localizes to the nucleus and inhibits cell growth. Mol. Cell Biochem. 242, 35–38 (2003).

    Article  CAS  PubMed  Google Scholar 

  164. Langlois, S., Cowan, K. N., Shao, Q., Cowan, B. J. & Laird, D. W. The tumor-suppressive function of connexin43 in keratinocytes is mediated in part via interaction with caveolin-1. Cancer Res. 70, 4222–4232 (2010).

    Article  CAS  PubMed  Google Scholar 

  165. Fu, C. T., Bechberger, J. F., Ozog, M. A., Perbal, B. & Naus, C. C. CCN3 (NOV) interacts with connexin43 in C6 glioma cells: possible mechanism of connexin-mediated growth suppression. J. Biol. Chem. 279, 36943–36950 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Gellhaus, A., Wotzlaw, C., Otto, T., Fandrey, J. & Winterhager, E. More insights into the CCN3/connexin43 interaction complex and its role for signaling. J. Cell Biochem. 110, 129–140 (2010).

    CAS  PubMed  Google Scholar 

  167. Macdonald, A. I. et al. A functional interaction between the MAGUK protein hDlg and the gap junction protein connexin 43 in cervical tumour cells. Biochem. J. 446, 9–21 (2012).

    Article  CAS  PubMed  Google Scholar 

  168. Giepmans, B. N., Hengeveld, T., Postma, F. R. & Moolenaar, W. H. Interaction of c-Src with gap junction protein connexin-43. Role in the regulation of cell–cell communication. J. Biol. Chem. 276, 8544–8549 (2001).

    Article  CAS  PubMed  Google Scholar 

  169. Sun, Y. et al. Connexin 43 interacts with Bax to regulate apoptosis of pancreatic cancer through a gap junction-independent pathway. Int. J. Oncol. 41, 941–948 (2012).

    Article  CAS  PubMed  Google Scholar 

  170. Marquez-Rosado, L., Singh, D., Rincon-Arano, H., Solan, J. L. & Lampe, P. D. CASK (LIN2) interacts with Cx43 in wounded skin and their coexpression affects cell migration. J. Cell Sci. 125, 695–702 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  172. Chakraborty, S. et al. E-Cadherin differentially regulates the assembly of connexin43 and connexin32 into gap junctions in human squamous carcinoma cells. J. Biol. Chem. 285, 10761–10776 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Zhang, Y. W., Nakayama, K., Nakayama, K. & Morita, I. A novel route for connexin 43 to inhibit cell proliferation: negative regulation of S-phase kinase-associated protein (Skp 2). Cancer Res. 63, 1623–1630 (2003).

    CAS  PubMed  Google Scholar 

  174. Boengler, K. et al. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc. Res. 67, 234–244 (2005).

    Article  CAS  PubMed  Google Scholar 

  175. Goubaeva, F. et al. Cardiac mitochondrial connexin 43 regulates apoptosis. Biochem. Biophys. Res. Commun. 352, 97–103 (2007).

    Article  CAS  PubMed  Google Scholar 

  176. Huang, R. P. et al. Connexin 43 (cx43) enhances chemotherapy-induced apoptosis in human glioblastoma cells. Int. J. Cancer 92, 130–138 (2001).

    Article  CAS  PubMed  Google Scholar 

  177. Gielen, P. R. et al. Connexin43 confers temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. Neuropharmacology 75, 539–548 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. Ghosh, S., Kumar, A. & Chandna, S. Connexin-43 downregulation in G2/M phase enriched tumour cells causes extensive low-dose hyper-radiosensitivity (HRS) associated with mitochondrial apoptotic events. Cancer Lett. 363, 46–59 (2015).

    Article  CAS  PubMed  Google Scholar 

  179. Trosko, J. E., Chang, C. C., Upham, B. L. & Tai, M. H. Ignored hallmarks of carcinogenesis: stem cells and cell–cell communication. Ann. N.Y. Acad. Sci. 1028, 192–201 (2004).

    Article  CAS  PubMed  Google Scholar 

  180. Yu, S. C. et al. Connexin 43 reverses malignant phenotypes of glioma stem cells by modulating E-cadherin. Stem Cells 30, 108–120 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. Kawasaki, Y. et al. Cytoplasmic accumulation of connexin32 expands cancer stem cell population in human HuH7 hepatoma cells by enhancing its self-renewal. Int. J. Cancer 128, 51–62 (2010).

    Article  CAS  Google Scholar 

  182. Hitomi, M. et al. Differential connexin function enhances self-renewal in glioblastoma. Cell Rep. 11, 1031–1042 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Hidalgo, M. et al. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 4, 998–1013 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Giuliano, M. et al. Circulating and disseminated tumor cells from breast cancer patient-derived xenograft-bearing mice as a novel model to study metastasis. Breast Cancer Res. 17, 3 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Lim, P. K. et al. Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Res. 71, 1550–1560 (2011).

    Article  CAS  PubMed  Google Scholar 

  186. Katakowski, M., Buller, B., Wang, X., Rogers, T. & Chopp, M. Functional microRNA is transferred between glioma cells. Cancer Res. 70, 8259–8263 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Suzhi, Z. et al. Gap junctions enhance the antiproliferative effect of microRNA-124-3p in glioblastoma cells. J. Cell. Physiol. 230, 2476–2488 (2015).

    Article  CAS  PubMed  Google Scholar 

  188. Menachem, A. et al. Intercellular transfer of small RNAs from astrocytes to lung tumor cells induces resistance to chemotherapy. Oncotarget 7, 12489–12504 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Zong, L., Zhu, Y., Liang, R. & Zhao, H. B. Gap junction mediated miRNA intercellular transfer and gene regulation: a novel mechanism for intercellular genetic communication. Sci. Rep. 6, 19884 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Soares, A. R. et al. Gap junctional protein Cx43 is involved in the communication between extracellular vesicles and mammalian cells. Sci. Rep. 5, 13243 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Neijssen, J., Pang, B. & Neefjes, J. Gap junction-mediated intercellular communication in the immune system. Prog. Biophys. Mol. Biol. 94, 207–218 (2007).

    Article  CAS  PubMed  Google Scholar 

  192. Neijssen, J. et al. Cross-presentation by intercellular peptide transfer through gap junctions. Nature 434, 83–88 (2005).

    Article  CAS  PubMed  Google Scholar 

  193. Mendoza-Naranjo, A. et al. Functional gap junctions facilitate melanoma antigen transfer and cross-presentation between human dendritic cells. J. Immunol. 178, 6949–6957 (2007).

    Article  CAS  PubMed  Google Scholar 

  194. Tittarelli, A., Janji, B., Van Moer, K., Noman, M. Z. & Chouaib, S. The selective degradation of synaptic connexin 43 protein by hypoxia-induced autophagy impairs natural killer cell-mediated tumor cell killing. J. Biol. Chem. 290, 23670–23679 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Aucher, A., Rudnicka, D. & Davis, D. M. MicroRNAs transfer from human macrophages to hepato-carcinoma cells and inhibit proliferation. J. Immunol. 191, 6250–6260 (2013).

    Article  CAS  PubMed  Google Scholar 

  196. Saccheri, F. et al. Bacteria-induced gap junctions in tumors favor antigen cross-presentation and antitumor immunity. Sci. Transl Med. 2, 44ra57 (2010).

    Article  PubMed  Google Scholar 

  197. Osswald, M. et al. Brain tumour cells interconnect to a functional and resistant network. Nature 528, 93–98 (2015).

    Article  CAS  PubMed  Google Scholar 

  198. Mehta, P. P., Bertram, J. S. & Loewenstein, W. R. Growth inhibition of transformed cells correlates with their junctional communication with normal cells. Cell 44, 187–196 (1986).

    Article  CAS  PubMed  Google Scholar 

  199. Yamasaki, H. & Katoh, F. Further evidence for the involvement of gap-junctional intercellular communication in induction and maintenance of transformed foci in BALB/c 3T3 cells. Cancer Res. 48, 3490–3495 (1988).

    CAS  PubMed  Google Scholar 

  200. Yamasaki, H. & Katoh, F. Novel method for selective killing of transformed rodent cells through intercellular communication, with possible therapeutic applications. Cancer Res. 48, 3203–3207 (1988).

    CAS  PubMed  Google Scholar 

  201. Bi, W. L., Parysek, L. M., Warnick, R. & Stambrook, P. J. In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy. Hum. Gene Ther. 4, 725–731 (1993).

    Article  CAS  PubMed  Google Scholar 

  202. Pitts, J. D. Cancer gene therapy: a bystander effect using the gap junctional pathway. Mol. Carcinog. 11, 127–130 (1994).

    Article  CAS  PubMed  Google Scholar 

  203. Fick, J. et al. The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro. Proc. Natl Acad. Sci. USA 92, 11071–11075 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Elshami, A. A. et al. Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro. Gene Ther. 3, 85–92 (1996).

    CAS  PubMed  Google Scholar 

  205. Mesnil, M., Piccoli, C., Tiraby, G., Willecke, K. & Yamasaki, H. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc. Natl Acad. Sci. USA 93, 1831–1835 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Dilber, M. S. et al. Gap junctions promote the bystander effect of herpes simplex virus thymidine kinase in vivo. Cancer Res. 57, 1523–1528 (1997).

    CAS  PubMed  Google Scholar 

  207. Vrionis, F. D. et al. The bystander effect exerted by tumor cells expressing the herpes simplex virus thymidine kinase (HSVtk) gene is dependent on connexin expression and cell communication via gap junctions. Gene Ther. 4, 577–585 (1997).

    Article  CAS  PubMed  Google Scholar 

  208. Touraine, R. L., Ishii-Morita, H., Ramsey, W. J. & Blaese, R. M. The bystander effect in the HSVtk/ganciclovir system and its relationship to gap junctional communication. Gene Ther. 5, 1705–1711 (1998).

    Article  CAS  PubMed  Google Scholar 

  209. Duflot-Dancer, A., Piccoli, C., Rolland, A., Yamasaki, H. & Mesnil, M. Long-term connexin-mediated bystander effect in highly tumorigenic human cells in vivo in herpes simplex virus thymidine kinase/ganciclovir gene therapy. Gene Ther. 5, 1372–1378 (1998).

    Article  CAS  PubMed  Google Scholar 

  210. Yang, L. et al. Intercellular communication mediates the bystander effect during herpes simplex thymidine kinase/ganciclovir-based gene therapy of human gastrointestinal tumor cells. Hum. Gene Ther. 9, 719–728 (1998).

    Article  CAS  PubMed  Google Scholar 

  211. 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 

  212. Kong, H. et al. All-trans retinoic acid enhances bystander effect of suicide gene therapy in the treatment of breast cancer. Oncol. Rep. 35, 1868–1874 (2016).

    Article  CAS  PubMed  Google Scholar 

  213. Dahle, J., Mikalsen, S. O., Rivedal, E. & Steen, H. B. Gap junctional intercellular communication is not a major mediator in the bystander effect in photodynamic treatment of MDCK II cells. Radiat. Res. 154, 331–341 (2000).

    Article  CAS  PubMed  Google Scholar 

  214. Wygoda, M. R. et al. Protection of herpes simplex virus thymidine kinase-transduced cells from ganciclovir-mediated cytotoxicity by bystander cells: the Good Samaritan effect. Cancer Res. 57, 1699–1703 (1997).

    CAS  PubMed  Google Scholar 

  215. 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 

  216. Drake, R. R. et al. Connexin-independent ganciclovir-mediated killing conferred on bystander effect-resistant cell lines by a herpes simplex virus-thymidine kinase-expressing colon cell line. Mol. Ther. 2, 515–523 (2000).

    Article  CAS  PubMed  Google Scholar 

  217. Bertram, J. S. Dietary carotenoids, connexins and cancer: what is the connection? Biochem. Soc. Trans. 32, 985–989 (2004).

    Article  CAS  PubMed  Google Scholar 

  218. Kelsey, L., Katoch, P., Johnson, K. E., Batra, S. K. & Mehta, P. P. Retinoids regulate the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells. PLoS ONE 7, e32846 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Mehta, P. P., Bertram, J. S. & Loewenstein, W. R. The actions of retinoids on cellular growth correlate with their actions on gap junctional communication. J. Cell Biol. 108, 1053–1065 (1989).

    Article  CAS  PubMed  Google Scholar 

  220. 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 

  221. Takahashi, H. et al. The preventive effect of green tea on the gap junction intercellular communication in renal epithelial cells treated with a renal carcinogen. Anticancer Res. 24, 3757–3762 (2004).

    CAS  PubMed  Google Scholar 

  222. Yu, B. B. et al. Total flavonoids of litsea coreana enhance the cytotoxicity of oxaliplatin by increasing gap junction intercellular communication. Biol. Pharm. Bull. 37, 1315–1322 (2014).

    Article  CAS  PubMed  Google Scholar 

  223. Conklin, C. M. et al. Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells. Carcinogenesis 28, 93–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  224. Ding, Y. & Nguyen, T. A. Gap junction enhancer potentiates cytotoxicity of cisplatin in breast cancer cells. J. Cancer Sci. Ther. 4, 371–378 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Bernzweig, J. et al. Anti-breast cancer agents, quinolines, targeting gap junction. Med. Chem. 7, 448–453 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Na, H. K. et al. Restoration of gap junctional intercellular communication by caffeic acid phenethyl ester (CAPE) in a ras-transformed rat liver epithelial cell line. Cancer Lett. 157, 31–38 (2000).

    Article  CAS  PubMed  Google Scholar 

  227. Sigler, K. & Ruch, R. J. Enhancement of gap junctional intercellular communication in tumor promoter-treated cells by components of green tea. Cancer Lett. 69, 15–19 (1993).

    Article  CAS  PubMed  Google Scholar 

  228. Nielsen, M., Ruch, R. J. & Vang, O. Resveratrol reverses tumor-promoter-induced inhibition of gap-junctional intercellular communication. Biochem. Biophys. Res. Commun. 275, 804–809 (2000).

    Article  CAS  PubMed  Google Scholar 

  229. Forster, T. et al. Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication. Oncotarget 5, 1621–1634 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Grek, C. L. et al. Topical administration of a connexin43-based peptide augments healing of chronic neuropathic diabetic foot ulcers: a multicenter, randomized trial. Wound Repair Regen. 23, 203–212 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  231. Davidson, J. S., Baumgarten, I. M. & Harley, E. H. Reversible inhibition of intercellular junctional communication by glycyrrhetinic acid. Biochem. Biophys. Res. Commun. 134, 29–36 (1986).

    Article  CAS  PubMed  Google Scholar 

  232. Yusubalieva, G. M. et al. Antitumor effects of monoclonal antibodies to connexin 43 extracellular fragment in induced low-differentiated glioma. Bull. Exp. Biol. Med. 153, 163–169 (2012).

    Article  CAS  PubMed  Google Scholar 

  233. Yusubalieva, G. M. et al. Treatment of poorly differentiated glioma using a combination of monoclonal antibodies to extracellular connexin-43 fragment, temozolomide, and radiotherapy. Bull. Exp. Biol. Med. 157, 510–515 (2014).

    Article  CAS  PubMed  Google Scholar 

  234. Chekhonin, V. P. et al. Targeted delivery of liposomal nanocontainers to the peritumoral zone of glioma by means of monoclonal antibodies against GFAP and the extracellular loop of Cx43. Nanomedicine 8, 63–70 (2012).

    Article  CAS  PubMed  Google Scholar 

  235. Nukolova, N. V. et al. Targeted delivery of cisplatin by connexin 43 vector nanogels to the focus of experimental glioma C6. Bull. Exp. Biol. Med. 157, 524–529 (2014).

    Article  CAS  PubMed  Google Scholar 

  236. O'Carroll, S. J. et al. The use of connexin-based therapeutic approaches to target inflammatory diseases. Methods Mol. Biol. 1037, 519–546 (2013).

    Article  CAS  PubMed  Google Scholar 

  237. Murphy, S. F. et al. Connexin 43 inhibition sensitizes chemoresistant glioblastoma cells to temozolomide. Cancer Res. 76, 139–149 (2016).

    Article  CAS  PubMed  Google Scholar 

  238. Grek, C. L. et al. Targeting connexin 43 with α-connexin carboxyl-terminal (ACT1) peptide enhances the activity of the targeted inhibitors, tamoxifen and lapatinib, in breast cancer: clinical implication for ACT1. BMC Cancer 15, 296 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  239. Gangoso, E., Thirant, C., Chneiweiss, H., Medina, J. M. & Tabernero, A. A cell-penetrating peptide based on the interaction between c-Src and connexin43 reverses glioma stem cell phenotype. Cell Death Dis. 5, e1023 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Panchin, Y. et al. A ubiquitous family of putative gap junction molecules. Curr. Biol. 10, R473–R474 (2000).

    Article  CAS  PubMed  Google Scholar 

  241. Bruzzone, R., Hormuzdi, S. G., Barbe, M. T., Herb, A. & Monyer, H. Pannexins, a family of gap junction proteins expressed in brain. Proc. Natl Acad. Sci. USA 100, 13644–13649 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Penuela, S., Gehi, R. & Laird, D. W. The biochemistry and function of pannexin channels. Biochim. Biophys. Acta (2012).

  243. Lai, C. P. et al. Tumor-suppressive effects of pannexin 1 in C6 glioma cells. Cancer Res. 67, 1545–1554 (2007).

    Article  CAS  PubMed  Google Scholar 

  244. Lai, C. P., Bechberger, J. F. & Naus, C. C. Pannexin2 as a novel growth regulator in C6 glioma cells. Oncogene 28, 4402–4408 (2009).

    Article  CAS  PubMed  Google Scholar 

  245. Celetti, S. J. et al. Implications of pannexin 1 and pannexin 3 for keratinocyte differentiation. J. Cell Sci. 123, 1363–1372 (2010).

    Article  CAS  PubMed  Google Scholar 

  246. Iwamoto, T. et al. Pannexin 3 regulates intracellular ATP/cAMP levels and promotes chondrocyte differentiation. J. Biol. Chem. 285, 18948–18958 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Ishikawa, M., Iwamoto, T., Fukumoto, S. & Yamada, Y. Pannexin 3 inhibits proliferation of osteoprogenitor cells by regulating Wnt and p21 signaling. J. Biol. Chem. 289, 2839–2851 (2014).

    Article  CAS  PubMed  Google Scholar 

  248. Wicki-Stordeur, L. E., Dzugalo, A. D., Swansburg, R. M., Suits, J. M. & Swayne, L. A. Pannexin 1 regulates postnatal neural stem and progenitor cell proliferation. Neural Dev. 7, 11 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Penuela, S. et al. Loss of pannexin 1 attenuates melanoma progression by reversion to a melanocytic phenotype. J. Biol. Chem. 287, 29184–29193 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Furlow, P. W. et al. Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival. Nat. Cell Biol. 17, 943–952 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Chekeni, F. B. et al. Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis. Nature 467, 863–867 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. 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 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Given that there are more than 1,500 papers dealing with connexins and cancer, the authors apologize to authors whose work was not cited in this review. Work in the authors' laboratories is supported by; Instituto de Salud Carlos III grant PI13/00763 and CP10/00624, co-financed by the European Regional Development Fund (ERDF) to T.A., Ligue contre le cancer (Comités de Charente, de Charente-maritime, des Deux-Sèvres, du Morbihan et de la Vienne) to M.M., US National Institutes of Health grant GM55632 to P.D.L., Canadian Institutes of Health Research, Canadian Cancer Society and Canada Research Chairs Program to C.C.N. and Canadian Institutes of Health Research (130530; 123228), Canadian Cancer Society (701459) and Canada Research Chair Program to D.W.L.

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Authors and Affiliations

  1. Translational Molecular Pathology, Vall d'Hebron Institute of Research, Barcelona, 08035, Spain

    Trond Aasen

  2. STIM Laboratory ERL 7368 CNRS – Faculté des Sciences Fondamentales et Appliquées, Université de Poitiers, Poitiers, 86073, France

    Marc Mesnil

  3. the Department of Cellular and Physiological Sciences, The Life Sciences Institute, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

    Christian C. Naus

  4. Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Paul D. Lampe

  5. Department of Anatomy and Cell Biology, The University of Western Ontario, London, N6A 5C1, Ontario, Canada

    Dale W. Laird

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  1. Trond Aasen
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Correspondence to Trond Aasen or Dale W. Laird.

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Supplementary information

Supplementary information S1 (figure)

The extended Cx43 interactome. (PDF 1948 kb)

Supplementary information S2 (table)

The extended Cx43 interactome retrieved and constructed using the STRING database version 10.0 (http://string-db.org), using a high confidence score prediction setting (>0.7) as viewed in Supplementary Information S1. In bold are hits from the highest prediction setting of (>0.9) as viewed in Figure 4. (PDF 513 kb)

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Aasen, T., Mesnil, M., Naus, C. et al. Gap junctions and cancer: communicating for 50 years. Nat Rev Cancer 16, 775–788 (2016). https://doi.org/10.1038/nrc.2016.105

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