Sibbesen, Nina A. and Kopp, Katharina L. and Litvinov, Ivan V. and Jønson, Lars and Willerslev-Olsen, Andreas and Fredholm, Simon and Petersen, David L. and Nastasi, Claudia and Krejsgaard, Thorbjørn and Lindahl, Lise M. and Gniadecki, Robert and Mongan, Nigel P. and Sasseville, Denis and Wasik, Mariusz A. and Iversen, Lars and Bonefeld, Charlotte M. and Geisler, Carsten and Woetmann, Anders and Odum, Niels
Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma.
Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.
||University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
||15 Jan 2016 09:28
||14 Sep 2016 03:51
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