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
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
Institute for Systems Biology, Seattle, Washington, United States of America.
PLoS One. 2017 Mar 6;12(3):e0172884. doi: 10.1371/journal.pone.0172884. eCollection 2017.
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.
离子通道和转运体通过调节细胞增殖、迁移和死亡，在癌症进展中的作用日益受到认可。胶质母细胞瘤干细胞（GSCs）是多形性胶质母细胞瘤（一种高度侵袭性的脑癌）肿瘤形成和复发的来源，这表明该细胞群体中的离子通道表达可能受到干扰。然而，对于可能导致GSC恶性肿瘤的离子通道的表达及其功能相关性知之甚少。我们使用RNA测序评估了GSC分离株和非肿瘤神经细胞类型中离子通道的富集情况。我们通过差异表达分析确定了一组独特的GSC富集离子通道，这些通道也与不同的基因突变特征相关。为支持其潜在的临床相关性，在癌症基因组图谱和常春藤胶质母细胞瘤图谱项目的人类胶质母细胞瘤数据库中评估的选定GSC富集离子通道的表达与患者生存时间相关。最后，与正常神经干细胞相比，对GSC富集离子通道的单个或类别进行基因敲低以及药物抑制，可抑制GSCs的生长。这项首次进行的全面研究对GSCs中富集的离子通道进行了表征，并探讨了它们与胶质母细胞瘤分子亚型、基因突变、生存结果、肿瘤区域表达以及功能丧失实验反应的潜在临床相关性。总之，这些数据支持离子通道对GSC恶性肿瘤的潜在生物学和治疗影响，并为进一步研究其机制和治疗重要性提供了有力依据。
