KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma

Molecular Cancer

Research

Casey M. Wright¹  Yuen Yee Cheng¹  Kadir H. Sarun¹  Michaela B. Kirschner²  Ruby C. Y. Lin³  Nico van Zandwijk⁴  Glen Reid⁴  Marissa Williams⁴  Michael P. Vallely⁵  J. James Edelman⁵  Sonja Klebe⁶  Iryna Leshchynska⁷  Vladimir Sytnyk⁷  Brian C. McCaughan⁸ 

[1] Asbestos Diseases Research Institute, Gate 3, Hospital Road, Concord, 2139, Sydney, NSW, Australia;Asbestos Diseases Research Institute, Gate 3, Hospital Road, Concord, 2139, Sydney, NSW, Australia;Division of Thoracic Surgery, University Hospital Zurich, 8091, Zurich, Switzerland;Asbestos Diseases Research Institute, Gate 3, Hospital Road, Concord, 2139, Sydney, NSW, Australia;School of Medical Sciences, University of New South Wales, 2052, Sydney, NSW, Australia;Asbestos Diseases Research Institute, Gate 3, Hospital Road, Concord, 2139, Sydney, NSW, Australia;School of Medicine, University of Sydney, 2006, Sydney, NSW, Australia;Cardiothoracic Surgical Unit, Royal Prince Alfred Hospital; The Baird Institute and Faculty of Medicine, The University of Sydney, 2006, Sydney, NSW, Australia;Department of Anatomical Pathology, Flinders Medical Centre, 5042, Adelaide, SA, Australia;School of Biotechnology and Biomolecular Sciences, University of New South Wales, 2052, Sydney, NSW, Australia;Sydney Cardiothoracic Surgeons, RPA Medical Centre, 2050, Sydney, NSW, Australia;

关键词: KCNMA1;    miR-17-5p;    Mesothelioma;    Therapeutic targets;    KCa1.1;    microRNA;    Integrative analysis;   

DOI  :  10.1186/s12943-016-0529-z

 received in 2015-10-01, accepted in 2016-05-20,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets.MethodsUtilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy.ResultsWe identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. Interestingly, lower expression of miR-17-5p (P = 0.022) and miR-20a-5p (P = 0.026) was clearly associated with epithelioid histology. We interrogated the predicted targets of these differentially expressed microRNA families in MPM cell lines, and identified KCa1.1, a calcium-activated potassium channel subunit alpha 1 encoded by the KCNMA1 gene, as a target of miR-17-5p. KCa1.1 was overexpressed in MPM cells compared to the (normal) mesothelial line MeT-5A, and was also upregulated in patient tumor samples compared to normal mesothelium. Transfection of MPM cells with a miR-17-5p mimic or KCNMA1-specific siRNAs reduced mRNA expression of KCa1.1 and inhibited MPM cell migration. Similarly, treatment with paxilline, a small molecule inhibitor of KCa1.1, resulted in suppression of MPM cell migration.ConclusionThese functional data implicating KCa1.1 in MPM cell migration support our integrative approach using MPM gene expression datasets to identify novel and potentially druggable targets.

【 授权许可】

CC BY   
© Lin et al. 2016