期刊
ONCOTARGET
卷 7, 期 29, 页码 45730-45744出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10160
关键词
miR-21; in situ; STAT5; IL-2; cutaneous T-cell lymphoma (CTCL)
资金
- Danish Cancer Society
- Fight Cancer Program (Knaek Cancer Programmet)
- Danish Research Council (Forskningsradet for Sundhed og Sygdom)
- Novo Nordic Foundation Tandem Program
- Lundbeck Foundation
- LINAK A/S Nordborg
- Cutaneous Lymphoma Foundation
- Hirschl Charitable Trustl
- Feinberg Lymphoma Foundation
- Novo Nordisk Fonden [NNF15OC0018774] Funding Source: researchfish
- The Danish Cancer Society [R72-A4571, R132-A8475] Funding Source: researchfish
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.
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