Academic Journal
KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma
| العنوان: | KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma |
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| المؤلفون: | Cheng, YY, Wright, CM, Kirschner, MB, Williams, M, Sarun, KH, Sytnyk, V, Leshchynska, I, Edelman, JJ, Vallely, MP, McCaughan, BC, Klebe, S, van Zandwijk, N, Lin, RCY, Reid, G |
| المصدر: | urn:ISSN:1476-4598 ; Molecular Cancer, 15, 1, 44 |
| بيانات النشر: | Springer Nature |
| سنة النشر: | 2016 |
| المجموعة: | UNSW Sydney (The University of New South Wales): UNSWorks |
| مصطلحات موضوعية: | Lung, Cancer, Orphan Drug, Rare Diseases, Prevention, Lung Cancer, Biotechnology, Genetics, 2.1 Biological and endogenous factors, 2 Aetiology, 3' Untranslated Regions, Binding Sites, Cell Line, Tumor, Cell Movement, Databases, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Lung Neoplasms, Mesothelioma, Malignant, MicroRNAs, Oligonucleotide Array Sequence Analysis, Pleural Neoplasms, Integrative analysis, KCNMA1 |
| الوصف: | Background: Malignant 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. Methods: Utilizing 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. Results: We 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. Conclusion: These 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| Relation: | http://hdl.handle.net/1959.4/unsworks_49821; https://unsworks.unsw.edu.au/bitstreams/60d6864d-40aa-4473-9cea-d00df20f691c/download; https://doi.org/10.1186/s12943-016-0529-z |
| DOI: | 10.1186/s12943-016-0529-z |
| الاتاحة: | http://hdl.handle.net/1959.4/unsworks_49821 https://unsworks.unsw.edu.au/bitstreams/60d6864d-40aa-4473-9cea-d00df20f691c/download https://doi.org/10.1186/s12943-016-0529-z |
| Rights: | open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ ; free_to_read |
| رقم الانضمام: | edsbas.52285FA |
| قاعدة البيانات: | BASE |
| DOI: | 10.1186/s12943-016-0529-z |
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