Ion channel gene expression predicts survival in glioma patients

Ion channels are important regulators in cell proliferation, migration, and apoptosis. The malfunction and/or aberrant expression of ion channels may disrupt these important biological processes and influence cancer progression. In this study, we investigate the expression pattern of ion channel genes in glioma. We designate 18 ion channel genes that are differentially expressed in high-grade glioma as a prognostic molecular signature. This ion channel gene expression based signature predicts glioma outcome in three independent validation cohorts. Interestingly, 16 of these 18 genes were down-regulated in high-grade glioma. This signature is independent of traditional clinical, molecular, and histological factors. Resampling tests indicate that the prognostic power of the signature outperforms random gene sets selected from human genome in all the validation cohorts. More importantly, this signature performs better than the random gene signatures selected from glioma-associated genes in two out of three validation datasets. This study implicates ion channels in brain cancer, thus expanding on knowledge of their roles in other cancers. Individualized profiling of ion channel gene expression serves as a superior and independent prognostic tool for glioma patients.

[1]  Antonio Felipe,et al.  Potassium channels: new targets in cancer therapy. , 2006, Cancer detection and prevention.

[2]  Michel Eichelbaum,et al.  Pharmacogenomics and individualized drug therapy. , 2006, Annual review of medicine.

[3]  H. Sontheimer,et al.  Role for calcium‐activated potassium channels (BK) in growth control of human malignant glioma cells , 2004, Journal of neuroscience research.

[4]  Wei Zhang,et al.  Tumor Endothelial Inflammation Predicts Clinical Outcome in Diverse Human Cancers , 2012, PloS one.

[5]  T. Golub,et al.  Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. , 2003, Cancer research.

[6]  V. Shoshan-Barmatz,et al.  VDAC1: from structure to cancer therapy , 2012, Front. Oncol..

[7]  Jiaoti Huang,et al.  Cav1.3 channel α1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers. , 2014, Urologic oncology.

[8]  S. Wölfl,et al.  Molecular characterization of voltage-gated sodium channels in human gliomas , 2002, Neuroreport.

[9]  S. Wölfl,et al.  Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas , 2003, Neuroscience Letters.

[10]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[11]  Jianmin Cui,et al.  BK channel activation: structural and functional insights , 2010, Trends in Neurosciences.

[12]  R. Stupp,et al.  High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[13]  M. Duroux,et al.  MicroRNA Expression Signatures and Their Correlation with Clinicopathological Features in Glioblastoma Multiforme , 2014, NeuroMolecular Medicine.

[14]  C. Steinhäuser,et al.  Ion channels in glial cells , 2000, Brain Research Reviews.

[15]  M. J. van den Bent,et al.  MGMT-STP27 Methylation Status as Predictive Marker for Response to PCV in Anaplastic Oligodendrogliomas and Oligoastrocytomas. A Report from EORTC Study 26951 , 2013, Clinical Cancer Research.

[16]  D. Massi,et al.  Transient receptor potential vanilloid 4 (TRPV4) is downregulated in keratinocytes in human non-melanoma skin cancer. , 2014, The Journal of investigative dermatology.

[17]  T. Zhou,et al.  Expression of Nicotinamide Phosphoribosyltransferase-Influenced Genes Predicts Recurrence-Free Survival in Lung and Breast Cancers , 2014, Scientific Reports.

[18]  Jayant P. Menon,et al.  Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. , 2006, Cancer cell.

[19]  Ping Li,et al.  A radiosensitivity gene signature in predicting glioma prognostic via EMT pathway , 2014, Oncotarget.

[20]  T. Jentsch,et al.  Ion channel diseases. , 2002, Human molecular genetics.

[21]  Ahmed Essaghir,et al.  Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas , 2009, Modern Pathology.

[22]  Harald Sontheimer,et al.  Cloning and Characterization of Glioma BK, a Novel BK Channel Isoform Highly Expressed in Human Glioma Cells , 2002, The Journal of Neuroscience.

[23]  Winand N M Dinjens,et al.  Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  Gabriele Schackert,et al.  Long-term survival with glioblastoma multiforme. , 2007, Brain : a journal of neurology.

[25]  Vishal N. Patel,et al.  Network Signatures of Survival in Glioblastoma Multiforme , 2013, PLoS Comput. Biol..

[26]  T. Zhou,et al.  Genes Influenced by the Non-Muscle Isoform of Myosin Light Chain Kinase Impact Human Cancer Prognosis , 2014, PloS one.

[27]  L. Chin,et al.  Malignant astrocytic glioma: genetics, biology, and paths to treatment. , 2007, Genes & development.

[28]  C. B. Ransom,et al.  BK channels in human glioma cells. , 2001, Journal of neurophysiology.

[29]  S. Yuspa,et al.  Intracellular chloride channels: critical mediators of cell viability and potential targets for cancer therapy. , 2005, Current pharmaceutical design.

[30]  So Yeong Lee,et al.  Anti-proliferative effect of Kv1.3 blockers in A549 human lung adenocarcinoma in vitro and in vivo. , 2011, European journal of pharmacology.

[31]  Lincoln D. Stein,et al.  Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes , 2012, Nature.

[32]  Tong Zhou,et al.  Expression profiling of ion channel genes predicts clinical outcome in breast cancer , 2013, Molecular Cancer.

[33]  C. B. Ransom,et al.  BK channels in human glioma cells have enhanced calcium sensitivity , 2002, Glia.

[34]  Diana Conte Camerino,et al.  Ion channel pharmacology , 2007, Neurotherapeutics.

[35]  R Horn,et al.  Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Alberto Orfao,et al.  Gene expression profiles of human glioblastomas are associated with both tumor cytogenetics and histopathology. , 2010, Neuro-oncology.

[37]  Tong Zhou,et al.  Expression Profiling of Mitochondrial Voltage-Dependent Anion Channel-1 Associated Genes Predicts Recurrence-Free Survival in Human Carcinomas , 2014, PloS one.

[38]  M. Welsh.  Abnormal regulation of ion channels in cystic fibrosis epithelia , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  M. J. van den Bent,et al.  Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  Xin-Yun Huang,et al.  Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. , 2009, Cancer cell.

[41]  R. Molenaar,et al.  Ion Channels in Glioblastoma , 2011, ISRN neurology.

[42]  J. Adelman,et al.  Episodic Ataxia Mutations in Kv1.1 Alter Potassium Channel Function by Dominant Negative Effects or Haploinsufficiency , 1998, The Journal of Neuroscience.

[43]  Duo Zheng,et al.  Transient receptor potential type vanilloid 1 suppresses skin carcinogenesis. , 2009, Cancer research.

[44]  Tong Zhou,et al.  Ion Channel Gene Expression in Lung Adenocarcinoma: Potential Role in Prognosis and Diagnosis , 2014, PloS one.

[45]  N. Dang,et al.  α5 Nicotinic acetylcholine receptor mediates nicotine-induced HIF-1α and VEGF expression in non-small cell lung cancer. , 2014, Toxicology and applied pharmacology.

[46]  David Venet,et al.  Most Random Gene Expression Signatures Are Significantly Associated with Breast Cancer Outcome , 2011, PLoS Comput. Biol..

[47]  L. Messerini,et al.  herg1 Gene and HERG1 Protein Are Overexpressed in Colorectal Cancers and Regulate Cell Invasion of Tumor Cells , 2004, Cancer Research.

[48]  T. Crook,et al.  Methylation of the calcium channel regulatory subunit α2δ-3 (CACNA2D3) predicts site-specific relapse in oestrogen receptor-positive primary breast carcinomas , 2012, British Journal of Cancer.

[49]  H. Sontheimer,et al.  A role for ion channels in glioma cell invasion. , 2005, Neuron glia biology.

[50]  M. Ferrari,et al.  Familial hemiplegic migraine: a ion channel disorder , 2001, Brain Research Bulletin.

[51]  H. Sontheimer.  An Unexpected Role for Ion Channels in Brain Tumor Metastasis , 2008, Experimental biology and medicine.

[52]  Margaret Wrensch,et al.  Epidemiology and molecular pathology of glioma , 2006, Nature Clinical Practice Neurology.

[53]  Joshua M. Stuart,et al.  Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion. , 2010, Cancer research.

[54]  Wei-Min Liu,et al.  Analysis of high density expression microarrays with signed-rank call algorithms , 2002, Bioinform..

[55]  R. Coombes.  New targets for cancer therapy. , 1993, Molecular aspects of medicine.

[56]  Prakash Kulkarni,et al.  Competing views on cancer , 2014, Journal of Biosciences.

[57]  H. H. Andersen,et al.  MicroRNA Expression Signatures Determine Prognosis and Survival in Glioblastoma Multiforme—a Systematic Overview , 2014, Molecular Neurobiology.

[58]  Thomas D. Wu,et al.  Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. , 2006, Cancer cell.

[59]  J. Simard,et al.  4‐aminopyridine causes apoptosis and blocks an outward rectifier K+ channel in malignant astrocytoma cell lines , 1997, Journal of neuroscience research.

[60]  A. Arcangeli,et al.  Ion channel expression as promising cancer biomarker. , 2015, Biochimica et biophysica acta.

[61]  Laurence Zitvogel,et al.  Immunogenic cell death in cancer therapy. , 2013, Annual review of immunology.