title: Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma.
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.
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nina A
authors.initials: NA
authors.lastname: Sibbesen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Kopp
authors.affiliation: Division of Dermatology, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Litvinov
authors.affiliation: Departmen of Molecular Medicine, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Jønson
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Willerslev-Olsen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Fredholm
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: David L
authors.initials: DL
authors.lastname: Petersen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claudia
authors.initials: C
authors.lastname: Nastasi
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thorbjørn
authors.initials: T
authors.lastname: Krejsgaard
authors.affiliation: Department of Dermatology, Aarhus University Hospital, Skejby, Aarhus, Denmark.
authors.forename: Lise M
authors.initials: LM
authors.lastname: Lindahl
authors.affiliation: Departmen of Dermatology, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark.
authors.forename: Robert
authors.initials: R
authors.lastname: Gniadecki
authors.affiliation: Faculty of Medicine and Health Science, School of Veterinary Medicine and Science, University of Nottingham, Loughborough, United Kingdom.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.affiliation: Division of Dermatology, McGill University Health Centre, Montréal, Quebec, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Sasseville
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
authors.affiliation: Department of Dermatology, Aarhus University Hospital, Skejby, Aarhus, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Iversen
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Bonefeld
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carsten
authors.initials: C
authors.lastname: Geisler
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
authors.affiliation: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Odum
mesh_terms: D045744:Cell Line, Tumor; D016147:Genes, Tumor Suppressor; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C479163:tofacitinib; C507933:JAK3 protein, human; D053616:Janus Kinase 3
keywords: JAK3; STAT3; STAT5; cutaneous T-cell lymphoma (CTCL); miR-22; mycosis fungoides (MF)