Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2016

Open Access 01-12-2016 | Research

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

Authors: Yuen Yee Cheng, Casey M. Wright, Michaela B. Kirschner, Marissa Williams, Kadir H. Sarun, Vladimir Sytnyk, Iryna Leshchynska, J. James Edelman, Michael P. Vallely, Brian C. McCaughan, Sonja Klebe, Nico van Zandwijk, Ruby C. Y. Lin, Glen Reid

Published in: Molecular Cancer | Issue 1/2016

Login to get access

Abstract

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.
Appendix
Available only for authorised users
Literature
1.
Kao SC, Reid G, Lee K, Vardy J, Clarke S, van Zandwijk N. Malignant mesothelioma. Intern Med J. 2010;40:742–50.CrossRefPubMed
2.
Tsao AS, Wistuba I, Roth JA, Kindler HL. Malignant pleural mesothelioma. J Clin Oncol. 2009;27:2081–90.CrossRefPubMed
3.
Scherpereel A, Astoul P, Baas P, Berghmans T, Clayson H, de Vuyst P, Dienemann H, Galateau-Salle F, Hennequin C, Hillerdal G, et al. Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma. Eur Respir J. 2010;35:479–95.CrossRefPubMed
4.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.CrossRefPubMedPubMedCentral
5.
Crispi S, Calogero RA, Santini M, Mellone P, Vincenzi B, Citro G, Vicidomini G, Fasano S, Meccariello R, Cobellis G, et al. Global gene expression profiling of human pleural mesotheliomas: identification of matrix metalloproteinase 14 (MMP-14) as potential tumour target. PLoS One. 2009;4:e7016.CrossRefPubMedPubMedCentral
6.
Ishiguro F, Murakami H, Mizuno T, Fujii M, Kondo Y, Usami N, Yokoi K, Osada H, Sekido Y. Activated leukocyte cell-adhesion molecule (ALCAM) promotes malignant phenotypes of malignant mesothelioma. J Thorac Oncol. 2012;7:890–9.CrossRefPubMed
7.
Gordon GJ, Rockwell GN, Jensen RV, Rheinwald JG, Glickman JN, Aronson JP, et al. Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling. Am J Pathol. 2005;166:1827–40.
8.
Singhal S, Wiewrodt R, Malden LD, Amin KM, Matzie K, Friedberg J, Kucharczuk JC, Litzky LA, Johnson SW, Kaiser LR, Albelda SM. Gene expression profiling of malignant mesothelioma. Clin Cancer Res. 2003;9:3080–97.PubMed
9.
Suraokar MB, Nunez MI, Diao L, Chow CW, Kim D, Behrens C, Lin H, Lee S, Raso G, Moran C, et al. Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications. Ann Oncol. 2014;25:1184–92.CrossRefPubMedPubMedCentral
10.
Reid G. MicroRNAs in mesothelioma: from tumour suppressors and biomarkers to therapeutic targets. J Thorac Dis. 2015;7:1031–40.PubMedPubMedCentral
11.
Kao SC, Fulham M, Wong K, Cooper W, Brahmbhatt H, MacDiarmid J, Pattison S, Sagong JO, Huynh Y, Leslie F, et al. A significant metabolic and radiological response after a novel targeted MicroRNA-based treatment approach in malignant pleural mesothelioma. Am J Respir Crit Care Med. 2015;191:1467–9.CrossRefPubMed
12.
13.
14.
15.
Lin SC, Wang CC, Wu MH, Yang SH, Li YH, Tsai SJ. Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells. J Clin Endocrinol Metab. 2012;97:E1515–23.CrossRefPubMed
16.
Hossain A, Kuo MT, Saunders GF. Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA. Mol Cell Biol. 2006;26:8191–201.CrossRefPubMedPubMedCentral
17.
Kirschner MB, Cheng YY, Armstrong NJ, Lin RC, Kao SC, Linton A, Klebe S, McCaughan BC, van Zandwijk N, Reid G. MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma. Mol Oncol. 2015;9:715–26.CrossRefPubMed
18.
Reid G, Pel ME, Kirschner MB, Cheng YY, Mugridge N, Weiss J, Williams M, Wright C, Edelman JJ, Vallely MP, et al. Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma. Ann Oncol. 2013;24:3128–35.CrossRefPubMed
19.
Wright CM, Kirschner MB, Cheng YY, O'Byrne KJ, Gray SG, Schelch K, Hoda MA, Klebe S, McCaughan B, van Zandwijk N, Reid G. Long non coding RNAs (lncRNAs) are dysregulated in Malignant Pleural Mesothelioma (MPM). PLoS One. 2013;8:e70940.CrossRefPubMedPubMedCentral
20.
Williams M, Kirschner MB, Cheng YY, Hanh J, Weiss J, Mugridge N, Wright CM, Linton A, Kao SC, Edelman JJ, et al. miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma. Oncotarget. 2015;6(27):23480–95.CrossRefPubMedPubMedCentral
21.
Mogilyansky E, Rigoutsos I. The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ. 2013;20:1603–14.CrossRefPubMedPubMedCentral
22.
Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, et al. microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci U S A. 2006;103:9136–41.CrossRefPubMedPubMedCentral
23.
24.
Baraniskin A, Birkenkamp-Demtroder K, Maghnouj A, Zollner H, Munding J, Klein-Scory S, Reinacher-Schick A, Schwarte-Waldhoff I, Schmiegel W, Hahn SA. MiR-30a-5p suppresses tumor growth in colon carcinoma by targeting DTL. Carcinogenesis. 2012;33:732–9.CrossRefPubMed
25.
Li X, Zhang Y, Zhang Y, Ding J, Wu K, Fan D. Survival prediction of gastric cancer by a seven-microRNA signature. Gut. 2010;59:579–85.CrossRefPubMed
26.
Kumarswamy R, Mudduluru G, Ceppi P, Muppala S, Kozlowski M, Niklinski J, et al. MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer. Int J Cancer. 2012;130:2044–53.
27.
Visone R, Pallante P, Vecchione A, Cirombella R, Ferracin M, Ferraro A, Volinia S, Coluzzi S, Leone V, Borbone E, et al. Specific microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene. 2007;26:7590–5.CrossRefPubMed
28.
Cheng CW, Wang HW, Chang CW, Chu HW, Chen CY, Yu JC, Chao JI, Liu HF, Ding SL, Shen CY. MicroRNA-30a inhibits cell migration and invasion by downregulating vimentin expression and is a potential prognostic marker in breast cancer. Breast Cancer Res Treat. 2012;134:1081–93.CrossRefPubMed
29.
Wang W, Lin H, Zhou L, Zhu Q, Gao S, Xie H, Liu Z, Xu Z, Wei J, Huang X, Zheng S. MicroRNA-30a-3p inhibits tumor proliferation, invasiveness and metastasis and is downregulated in hepatocellular carcinoma. Eur J Surg Oncol. 2014;40:1586–94.CrossRefPubMed
30.
Zhou S, Liu L, Li H, Eilers G, Kuang Y, Shi S, et al. Multipoint targeting of the PI3K/mTOR pathway in mesothelioma. Br J Cancer. 2014;110:2479–88.
31.
Kawaguchi K, Murakami H, Taniguchi T, Fujii M, Kawata S, Fukui T, Kondo Y, Osada H, Usami N, Yokoi K, et al. Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells. Carcinogenesis. 2009;30:1097–105.CrossRefPubMed
32.
Shapiro IM, Kolev VN, Vidal CM, Kadariya Y, Ring JE, Wright Q, Weaver DT, Menges C, Padval M, McClatchey AI, et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med. 2014;6:237ra268.
33.
Carbone M, Yang H. Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma. Clin Cancer Res. 2012;18:598–604.CrossRefPubMedPubMedCentral
34.
Stevenson JP, Kindler HL, Papasavvas E, Sun J, Jacobs-Small M, Hull J, Schwed D, Ranganathan A, Newick K, Heitjan DF, et al. Immunological effects of the TGFbeta-blocking antibody GC1008 in malignant pleural mesothelioma patients. Oncoimmunology. 2013;2:e26218.CrossRefPubMedPubMedCentral
35.
36.
Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103:2257–61.CrossRefPubMedPubMedCentral
37.
Bloch M, Ousingsawat J, Simon R, Schraml P, Gasser TC, Mihatsch MJ, Kunzelmann K, Bubendorf L. KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer. Oncogene. 2007;26:2525–34.CrossRefPubMed
38.
Oeggerli M, Tian Y, Ruiz C, Wijker B, Sauter G, Obermann E, Guth U, Zlobec I, Sausbier M, Kunzelmann K, Bubendorf L. Role of KCNMA1 in breast cancer. PLoS One. 2012;7:e41664.CrossRefPubMedPubMedCentral
39.
Mazar J, DeYoung K, Khaitan D, Meister E, Almodovar A, Goydos J, Ray A, Perera RJ. The regulation of miRNA-211 expression and its role in melanoma cell invasiveness. PLoS One. 2010;5:e13779.CrossRefPubMedPubMedCentral
40.
Rabjerg M, Olivan-Viguera A, Hansen LK, Jensen L, Sevelsted-Moller L, Walter S, Jensen BL, Marcussen N, Kohler R. High expression of KCa3.1 in patients with clear cell renal carcinoma predicts high metastatic risk and poor survival. PLoS One. 2015;10:e0122992.CrossRefPubMedPubMedCentral
41.
42.
43.
Bai Y, Liao H, Liu T, Zeng X, Xiao F, Luo L, Guo H, Guo L. MiR-296-3p regulates cell growth and multi-drug resistance of human glioblastoma by targeting ether-a-go-go (EAG1). Eur J Cancer. 2013;49:710–24.CrossRefPubMed
44.
Wu X, Zhong D, Gao Q, Zhai W, Ding Z, Wu J. MicroRNA-34a inhibits human osteosarcoma proliferation by downregulating ether a go-go 1 expression. Int J Med Sci. 2013;10:676–82.CrossRefPubMedPubMedCentral
45.
Feng J, Yu J, Pan X, Li Z, Chen Z, Zhang W, Wang B, Yang L, Xu H, Zhang G, Xu Z. HERG1 functions as an oncogene in pancreatic cancer and is downregulated by miR-96. Oncotarget. 2014;5:5832–44.CrossRefPubMedPubMedCentral
46.
Fan M, Krutilina R, Sun J, Sethuraman A, Yang CH, Wu ZH, Yue J, Pfeffer LM. Comprehensive analysis of microRNA (miRNA) targets in breast cancer cells. J Biol Chem. 2013;288:27480–93.CrossRefPubMedPubMedCentral
47.
Birnie KA, Yip YY, Ng DC, Kirschner MB, Reid G, Prele CM, Musk AW, Lee YC, Thompson PJ, Mutsaers SE, Badrian B. Loss of miR-223 and JNK signaling contribute to elevated Stathmin in malignant pleural mesothelioma. Mol Cancer Res. 2015;13:1106–18.CrossRefPubMed
48.
Khaitan D, Sankpal UT, Weksler B, Meister EA, Romero IA, Couraud PO, Ningaraj NS. Role of KCNMA1 gene in breast cancer invasion and metastasis to brain. BMC Cancer. 2009;9:258.CrossRefPubMedPubMedCentral
49.
50.
Bose T, Cieslar-Pobuda A, Wiechec E. Role of ion channels in regulating Ca2+ homeostasis during the interplay between immune and cancer cells. Cell Death Dis. 2015;6:e1648.CrossRefPubMedPubMedCentral
51.
Deliot N, Constantin B. Plasma membrane calcium channels in cancer: Alterations and consequences for cell proliferation and migration. Biochim Biophys Acta. 1848;2015:2512–22.
52.
53.
54.
55.
Patergnani S, Giorgi C, Maniero S, Missiroli S, Maniscalco P, Bononi I, Martini F, Cavallesco G, Tognon M, Pinton P. The endoplasmic reticulum mitochondrial calcium cross talk is downregulated in malignant pleural mesothelioma cells and plays a critical role in apoptosis inhibition. Oncotarget. 2015;6:23427–44.CrossRefPubMedPubMedCentral
56.
Zhang R, Tian P, Chi Q, Wang J, Wang Y, Sun L, Liu Y, Tian S, Zhang Q. Human ether-a-go-go-related gene expression is essential for cisplatin to induce apoptosis in human gastric cancer. Oncol Rep. 2012;27:433–40.PubMed
57.
Marklund L, Henriksson R, Grankvist K. Cisplatin-induced apoptosis of mesothelioma cells is affected by potassium ion flux modulator amphotericin B and bumetanide. Int J Cancer. 2001;93:577–83.CrossRefPubMed
58.
Chantome A, Potier-Cartereau M, Clarysse L, Fromont G, Marionneau-Lambot S, Gueguinou M, et al. Pivotal role of the lipid Raft SK3-Orai1 complex in human cancer cell migration and bone metastases. Cancer Res. 2013;73:4852–61.
59.
Steinle M, Palme D, Misovic M, Rudner J, Dittmann K, Lukowski R, Ruth P, Huber SM. Ionizing radiation induces migration of glioblastoma cells by activating BK K(+) channels. Radiother Oncol. 2011;101:122–6.CrossRefPubMed
60.
Relan V, Morrison L, Parsonson K, Clarke BE, Duhig EE, Windsor MN, Matar KS, Naidoo R, Passmore L, McCaul E, et al. Phenotypes and karyotypes of human malignant mesothelioma cell lines. PLoS One. 2013;8:e58132.CrossRefPubMedPubMedCentral
61.
Smythe WR, Kaiser LR, Hwang HC, Amin KM, Pilewski JM, Eck SJ, Wilson JM, Albelda SM. Successful adenovirus-mediated gene transfer in an in vivo model of human malignant mesothelioma. Ann Thorac Surg. 1994;57:1395–401.CrossRefPubMed
62.
Kao SC, Lee K, Armstrong NJ, Clarke S, Vardy J, van Zandwijk N, Reid G, Burn J, McCaughan BC, Henderson DW, Klebe S. Validation of tissue microarray technology in malignant pleural mesothelioma. Pathology. 2011;43:128–32.CrossRefPubMed
63.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.CrossRefPubMed
64.
Kirschner MB, Cheng YY, Badrian B, Kao SC, Creaney J, Edelman JJ, Armstrong NJ, Vallely MP, Musk AW, Robinson BW, et al. Increased circulating miR-625-3p: a potential biomarker for patients with malignant pleural mesothelioma. J Thorac Oncol. 2012;7:1184–91.CrossRefPubMed
65.
Reid G, Wallant NC, Patel R, Antonic A, Saxon-Aliifaalogo F, Cao H, Webster G, Watson JD. Potent subunit-specific effects on cell growth and drug sensitivity from optimised siRNA-mediated silencing of ribonucleotide reductase. J RNAi Gene Silenc. 2009;5:321–30.
66.
Akerboom J, Chen TW, Wardill TJ, Tian L, Marvin JS, Mutlu S, Calderon NC, Esposti F, Borghuis BG, Sun XR, et al. Optimization of a GCaMP calcium indicator for neural activity imaging. J Neurosci. 2012;32:13819–40.CrossRefPubMedPubMedCentral
67.
Sheng L, Leshchyns'ka I, Sytnyk V. Neural cell adhesion molecule 2 promotes the formation of filopodia and neurite branching by inducing submembrane increases in Ca2+ levels. J Neurosci. 2015;35:1739–52.CrossRefPubMed
68.
Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2008;4:44–57.CrossRef
Metadata
Title
KCa1.1, a calcium-activated potassium channel subunit alpha 1, is targeted by miR-17-5p and modulates cell migration in malignant pleural mesothelioma
Authors
Yuen Yee Cheng
Casey M. Wright
Michaela B. Kirschner
Marissa Williams
Kadir H. Sarun
Vladimir Sytnyk
Iryna Leshchynska
J. James Edelman
Michael P. Vallely
Brian C. McCaughan
Sonja Klebe
Nico van Zandwijk
Ruby C. Y. Lin
Glen Reid
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2016
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-016-0529-z

Other articles of this Issue 1/2016

Molecular Cancer 1/2016 Go to the issue

Review

Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis

Research

MicroRNA-505 functions as a tumor suppressor in endometrial cancer by targeting TGF-α

Research

Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling

Review

Long noncoding RNAs in cancer: mechanisms of action and technological advancements

Research

Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib

Research

Effect of low doses of actinomycin D on neuroblastoma cell lines
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits