Oncotarget

Research Papers:

Transcriptional suppression of the miR-15/16 family by c-Myc in malignant pleural mesothelioma

Marissa Williams, Yuen Yee Cheng, Michaela B. Kirschner, Kadir H. Sarun, Karin Schelch, Patrick Winata, Brian McCaughan, Steven Kao, Nico Van Zandwijk and Glen Reid

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Oncotarget. 2019; 10:4125-4138. https://doi.org/10.18632/oncotarget.27010

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Abstract

Marissa Williams1,2, Yuen Yee Cheng1,2, Michaela B. Kirschner1,§, Kadir H. Sarun1, Karin Schelch1,#, Patrick Winata1,2, Brian McCaughan3, Steven Kao1,2,4, Nico Van Zandwijk1,2, and Glen Reid1,2,*,*

1 Asbestos Diseases Research Institute, Sydney, Australia

2 Sydney Medical School, The University of Sydney, Sydney, Australia

3 PAH Medical Centre, Sydney, Australia

4 Chris O'Brien Lifehouse, Sydney, Australia

§ Current address: Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland

Current address: Sydney Local Health District, Concord, Australia

# Current address: Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria

* Current address: Department of Pathology, University of Otago, Dunedin, New Zealand

* These authors contributed equally to this work

Correspondence to:

Marissa Williams,email: marissawilliams@live.com.au
Yuen Yee Cheng,email: yycheng@adri.org.au

Keywords: mesothelioma; microRNA; c-MYC; transcriptional repression; tumor suppressor

Received: February 12, 2019     Accepted: May 04, 2019     Published: June 25, 2019

ABSTRACT

MicroRNA downregulation is frequent in malignant pleural mesothelioma (MPM), but the mechanisms responsible for loss of miR-15/16 and miR-193a are yet to be elucidated and were investigated in this study. Copy Number Variation (CNV) of microRNA-coding genes was analyzed in MPM cells by digital droplet PCR (ddPCR) and revealed heterozygous loss of miR-193a and miR-15a/16-1, but no change in miR-15b/16-2. Epigenetic control of microRNA expression was inferred following decitabine and Trichostatin A (TSA) treatment which did not substantially affect microRNA expression. Knockdown of c-Myc expression led to upregulation of SMC4, miR-15b and 16, and to a lesser extent DLEU2 and miR-15a, whereas c-Myc overexpression repressed microRNA expression. Chromatin immunoprecipitation (ChIP) assays confirmed the interaction of c-Myc with the DLEU2 and SMC4 promoters. Tumor microRNA expression was determined in samples from MPM patients, with samples of pleura from cardiac surgery patients used as controls. In tumor samples, a strong correlation was observed between the expression of miR-15b and 16 (R2=0.793), but not miR-15a and 16. Our data suggest that in MPM, the downregulation of miR-15/16 is due to transcriptional repression by c-Myc, primarily via control of the miR-15b/16-2 locus, while miR-193a-3p loss is due to genomic deletion.


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