title: Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy.
abstract: BACKGROUND
  Glioblastomas remain ominous tumors that almost invariably escape treatment. Connexins are a family of transmembrane, gap junction-forming proteins, some members of which were reported to act as tumor suppressors and to modulate cellular metabolism in response to cytotoxic stress.
  
  
  METHODS
  We analyzed the copy number and expression of the connexin (Cx)30 gene gap junction beta-6 (GJB6), as well as of its protein immunoreactivity in several public and proprietary repositories of glioblastomas, and their influence on patient survival. We evaluated the effect of the expression of this gap junction protein on the growth, DNA repair and energy metabolism, and treatment resistance of these tumors.
  
  
  RESULTS
  The GJB6 gene was deleted in 25.8% of 751 analyzed tumors and mutated in 15.8% of 158 tumors. Cx30 immunoreactivity was absent in 28.9% of 145 tumors. Restoration of Cx30 expression in human glioblastoma cells reduced their growth in vitro and as xenografts in the striatum of immunodeficient mice. Cx30 immunoreactivity was, however, found to adversely affect survival in 2 independent retrospective cohorts of glioblastoma patients. Cx30 was found in clonogenic assays to protect glioblastoma cells against radiation-induced mortality and to decrease radiation-induced DNA damage. This radioprotection correlated with a heat shock protein 90-dependent mitochondrial translocation of Cx30 following radiation and an improved ATP production following this genotoxic stress.
  
  
  CONCLUSIONS
  These results underline the complex relationship between potential tumor suppressors and treatment resistance in glioblastomas and single out GJB6/Cx30 as a potential biomarker and target for therapeutic intervention in these tumors.
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Maria
authors.initials: M
authors.lastname: Artesi
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Jerome
authors.initials: J
authors.lastname: Kroonen
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Markus
authors.initials: M
authors.lastname: Bredel
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen-Khac
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Manuel
authors.initials: M
authors.lastname: Deprez
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Schoysman
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Christophe
authors.initials: C
authors.lastname: Poulet
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Denise
authors.initials: D
authors.lastname: Scholtens
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Tatjana
authors.initials: T
authors.lastname: Seute
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Bernard
authors.initials: B
authors.lastname: Rogister
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.affiliation: Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
authors.forename: Pierre A
authors.initials: PA
authors.lastname: Robe
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D000075302:Connexin 30; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D064593:Heterografts / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D000075302:Connexin 30; D017630:Connexins; C491020:GJB6 protein, human; D018841:HSP90 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D000077022:Survivin
keywords: connexin 30; glioblastoma; mitochondria; proliferation; radiation resistance