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

Autor:	Williams M; Asbestos Diseases Research Institute, Sydney, Australia.; Sydney Medical School, The University of Sydney, Sydney, Australia., Cheng YY; Asbestos Diseases Research Institute, Sydney, Australia.; Sydney Medical School, The University of Sydney, Sydney, Australia., Kirschner MB; Asbestos Diseases Research Institute, Sydney, Australia.; Current address: Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland., Sarun KH; Asbestos Diseases Research Institute, Sydney, Australia., Schelch K; Asbestos Diseases Research Institute, Sydney, Australia.; Current address: Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria., Winata P; Asbestos Diseases Research Institute, Sydney, Australia.; Sydney Medical School, The University of Sydney, Sydney, Australia., McCaughan B; PAH Medical Centre, Sydney, Australia., Kao S; Asbestos Diseases Research Institute, Sydney, Australia.; Sydney Medical School, The University of Sydney, Sydney, Australia.; Chris O'Brien Lifehouse, Sydney, Australia., Van Zandwijk N; Asbestos Diseases Research Institute, Sydney, Australia.; Sydney Medical School, The University of Sydney, Sydney, Australia.; Current address: Sydney Local Health District, Concord, Australia., Reid G; Asbestos Diseases Research Institute, Sydney, Australia.; Sydney Medical School, The University of Sydney, Sydney, Australia.; Current address: Department of Pathology, University of Otago, Dunedin, New Zealand.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2019 Jun 25; Vol. 10 (41), pp. 4125-4138. Date of Electronic Publication: 2019 Jun 25 (Print Publication: 2019).
DOI:	10.18632/oncotarget.27010
Abstrakt:	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 (R 2 =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. Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interests.
Databáze:	MEDLINE
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