STAT5 induces miR-21 expression in cutaneous T cell lymphoma

被引：42

作者：

Lindahl, Lise M. ^{[1
]}

Fredholm, Simon ^{[2
]}

Joseph, Claudine ^{[2
]}

Nielsen, Boye Schnack ^{[3
]}

Jonson, Lars ^{[4
]}

Willerslev-Olsen, Andreas ^{[2
]}

Gluud, Maria ^{[2
]}

Bluemel, Edda ^{[2
]}

Petersen, David L. ^{[2
]}

Sibbesen, Nina ^{[2
]}

Hu, Tengpeng ^{[2
]}

Nastasi, Claudia ^{[2
]}

Krejsgaard, Thorbjorn ^{[2
]}

Jaehger, Ditte ^{[2
]}

Persson, Jenny L. ^{[5
]}

Mongan, Nigel ^{[6
]}

Wasik, Mariusz A. ^{[7
]}

Litvinov, Ivan V. ^{[8
]}

Sasseville, Denis ^{[9
]}

Koralov, Sergei B. ^{[10
]}

Bonefeld, Charlotte M. ^{[2
]}

Geisler, Carsten ^{[2
]}

Woetmann, Anders ^{[2
]}

Ralfkiaer, Elisabeth ^{[11
]}

Iversen, Lars ^{[1
]}

Odum, Niels ^{[2
]}

机构：

[1] Aarhus Univ Hosp, Dept Dermatol, Aarhus, Denmark

[2] Univ Copenhagen, Dept Immunol & Microbiol, Copenhagen, Denmark

[3] Bioneer AS, Horsholm, Denmark

[4] Copenhagen Univ Hosp, Dept Mol Med, Copenhagen, Denmark

[5] Lund Univ, Clin Res Ctr, Malmo, Sweden

[6] Univ Nottingham, Sch Vet Med & Sci, Loughborough, Leics, England

[7] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA

[8] Univ Ottawa, Ottawa Hosp Res Inst, Div Dermatol, Ottawa, ON, Canada

[9] McGill Univ, Ctr Hlth, Div Dermatol, Montreal, PQ, Canada

[10] NYU, Dept Pathol, Sch Med, 550 1St Ave, New York, NY 10016 USA

[11] Copenhagen Univ Hosp, Dept Pathol, Copenhagen, Denmark

来源：

ONCOTARGET | 2016年 / 7卷 / 29期

关键词：

miR-21; in situ; STAT5; IL-2; cutaneous T-cell lymphoma (CTCL); MYCOSIS-FUNGOIDES; TUMOR-SUPPRESSOR; MICRORNA EXPRESSION; INTERNATIONAL-SOCIETY; SEZARY-SYNDROME; ACTIVATION; SURVIVAL; MIR-155; INTERLEUKIN-15; PATHOGENESIS;

D O I：

10.18632/oncotarget.10160

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

In cutaneous T cell lymphomas (CTCL), miR-21 is aberrantly expressed in skin and peripheral blood and displays anti-apoptotic properties in malignant T cells. It is, however, unclear exactly which cells express miR-21 and what mechanisms regulate miR-21. Here, we demonstrate miR-21 expression in situ in both malignant and reactive lymphocytes as well as stromal cells. qRT-PCR analysis of 47 patients with mycosis fungoides (MF) and Sezary Syndrome (SS) confirmed an increased miR-21 expression that correlated with progressive disease. In cultured malignant T cells miR-21 expression was inhibited by Tofacitinib (CP-690550), a clinical-grade JAK3 inhibitor. Chromatin immunoprecipitation (ChIP) analysis showed direct binding of STAT5 to the miR-21 promoter. Cytokine starvation ex vivo triggered a decrease in miR-21 expression, whereas IL-2 induced an increased miR-21 expression in primary SS T cells and cultured cytokine-dependent SS cells (SeAx). siRNA-mediated depletion of STAT5 inhibited constitutive-and IL-2-induced miR-21 expression in cytokine-independent and dependent T cell lines, respectively. IL-15 and IL-2 were more potent than IL-21 in inducing miR-21 expression in the cytokine-dependent T cells. In conclusion, we provide first evidence that miR-21 is expressed in situ in CTCL skin lesions, induced by IL-2 and IL-15 cytokines, and is regulated by STAT5 in malignant T cells. Thus, our data provide novel evidence for a pathological role of IL-2Rg cytokines in promoting expression of the oncogenic miR-21 in CTCL.

引用

页码：45730 / 45744

页数：15

共 75 条

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