Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy

• Published in: PloS one 2017-03, Vol.12 (3), p.e0172884-e0172884
• Main Authors: Pollak, Julia, Rai, Karan G, Funk, Cory C, Arora, Sonali, Lee, Eunjee, Zhu, Jun, Price, Nathan D, Paddison, Patrick J, Ramirez, Jan-Marino, Rostomily, Robert C
• Format: Article
• Language: English
• Subjects: Analysis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Bioinformatics; Biology; Biology and Life Sciences; Brain; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Brain research; Cancer; Care and treatment; Cell cycle; Cell death; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Survival - drug effects; Cell Survival - genetics; Children & youth; Cluster Analysis; Development and progression; Enrichment; Gap Junctions - genetics; Gap Junctions - metabolism; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Gene mutation; Gene sequencing; Genetic aspects; Genomes; Genomics; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma - therapy; Glioblastoma multiforme; Glioblastomas; Health aspects; Humans; Ion channels; Ion Channels - genetics; Ion Channels - metabolism; Malignancy; Medical prognosis; Medical research; Medicine; Medicine and Health Sciences; Mutation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neural stem cells; Neurosurgery; Pharmacology; Physical Sciences; Point mutation; Prognosis; Research and analysis methods; Ribonucleic acid; RNA; RNA sequencing; Signal Transduction; Stem cells; Survival; Survival Analysis; Transcriptome; Treatment Outcome; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0172884

Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.