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Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma

Sibbesen, Nina A.; Kopp, Katharina L.; Litvinov, Ivan V.; Jønson, Lars; Willerslev-Olsen, Andreas; Fredholm, Simon; Petersen, David L.; Nastasi, Claudia; Krejsgaard, Thorbjørn; Lindahl, Lise M.; Gniadecki, Robert; Mongan, Nigel P.; Sasseville, Denis; Wasik, Mariusz A.; Iversen, Lars; Bonefeld, Charlotte M.; Geisler, Carsten; Woetmann, Anders; Odum, Niels

Authors

Nina A. Sibbesen

Katharina L. Kopp

Ivan V. Litvinov

Lars Jønson

Andreas Willerslev-Olsen

Simon Fredholm

David L. Petersen

Claudia Nastasi

Thorbjørn Krejsgaard

Lise M. Lindahl

Robert Gniadecki

Nigel P. Mongan

Denis Sasseville

Mariusz A. Wasik

Lars Iversen

Charlotte M. Bonefeld

Carsten Geisler

Anders Woetmann

Niels Odum



Abstract

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.

Journal Article Type Article
Publication Date Aug 21, 2015
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 6
Issue 24
APA6 Citation Sibbesen, N. A., Kopp, K. L., Litvinov, I. V., Jønson, L., Willerslev-Olsen, A., Fredholm, S., …Odum, N. (2015). Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma. Oncotarget, 6(24),
Publisher URL http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=4111&path[]=8998
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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