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

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 Andersen; Niels Odum

doi:10.18632/oncotarget.4111

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

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 Andersen, Niels Odum

58 Citations (Scopus)

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.

Original language	English
Journal	OncoTarget
Volume	6
Issue number	24
Pages (from-to)	20555-69
Number of pages	15
ISSN	1949-2553
DOIs	https://doi.org/10.18632/oncotarget.4111
Publication status	Published - 2015

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Sibbesen, N. A., Kopp, K. L., Litvinov, I. V., Jønson, L., Willerslev-Olsen, A., Fredholm, S., Petersen, D. L., Nastasi, C., Krejsgaard, T., Lindahl, L. M., Gniadecki, R., Mongan, N. P., Sasseville, D., Wasik, M. A., Iversen, L., Bonefeld, C. M., Geisler, C., Andersen, A. W., & 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), 20555-69. https://doi.org/10.18632/oncotarget.4111

Sibbesen, NA, Kopp, KL, Litvinov, IV, Jønson, L, Willerslev-Olsen, A, Fredholm, S, Petersen, DL, Nastasi, C, Krejsgaard, T, Lindahl, LM, Gniadecki, R, Mongan, NP, Sasseville, D, Wasik, MA, Iversen, L, Bonefeld, CM, Geisler, C , Andersen, AW & Odum, N 2015, 'Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma', OncoTarget, vol. 6, no. 24, pp. 20555-69. https://doi.org/10.18632/oncotarget.4111

@article{e9b33e4065484f588b3c5aba18c642f1,

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.",

author = "Sibbesen, {Nina A} and Kopp, {Katharina L} and Litvinov, {Ivan V} and Lars J{\o}nson and Andreas Willerslev-Olsen and Simon Fredholm and Petersen, {David L} and Claudia Nastasi and Thorbj{\o}rn Krejsgaard and Lindahl, {Lise M} and Robert Gniadecki and Mongan, {Nigel P} and Denis Sasseville and Wasik, {Mariusz A} and Lars Iversen and Bonefeld, {Charlotte M} and Carsten Geisler and Andersen, {Anders Woetmann} and Niels Odum",

year = "2015",

doi = "10.18632/oncotarget.4111",

language = "English",

volume = "6",

pages = "20555--69",

journal = "OncoTarget",

issn = "1949-2553",

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TY - JOUR

T1 - Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma

AU - Sibbesen, Nina A

AU - Kopp, Katharina L

AU - Litvinov, Ivan V

AU - Jønson, Lars

AU - Willerslev-Olsen, Andreas

AU - Fredholm, Simon

AU - Petersen, David L

AU - Nastasi, Claudia

AU - Krejsgaard, Thorbjørn

AU - Lindahl, Lise M

AU - Gniadecki, Robert

AU - Mongan, Nigel P

AU - Sasseville, Denis

AU - Wasik, Mariusz A

AU - Iversen, Lars

AU - Bonefeld, Charlotte M

AU - Geisler, Carsten

AU - Andersen, Anders Woetmann

AU - Odum, Niels

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.18632/oncotarget.4111

DO - 10.18632/oncotarget.4111

M3 - Journal article

C2 - 26244872

SN - 1949-2553

VL - 6

SP - 20555

EP - 20569

JO - OncoTarget

JF - OncoTarget

IS - 24

ER -

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

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