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STAT5 induces miR-21 expression in cutaneous T cell lymphoma

In English

Författare

  • Lise M. Lindahl
  • Simon Fredholm
  • Claudine Joseph
  • Boye Schnack Nielsen
  • Lars Jønson
  • Andreas Willerslev-Olsen
  • Maria Gluud
  • Edda Blümel
  • David L. Petersen
  • Nina Sibbesen
  • Tengpeng Hu
  • Claudia Nastasi
  • Thorbjørn Krejsgaard
  • Ditte Jæhger
  • Jenny L. Persson
  • Nigel Mongan
  • Mariusz A. Wasik
  • Ivan V. Litvinov
  • Denis Sasseville
  • Sergei B. Koralov
  • Charlotte M. Bonefeld
  • Carsten Geisler
  • Anders Woetmann
  • Elisabeth Ralfkiaer
  • Lars Iversen
  • Niels Odum
Visa allt

Summary, in English

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.

Avdelning/ar

Publiceringsår

2016-06-18

Språk

Engelska

Sidor

45730-45744

Publikation/Tidskrift/Serie

Oncotarget

Volym

7

Issue

29

Dokumenttyp

Artikel i tidskrift

Förlag

Impact Journals

Ämne

  • Microbiology in the medical area
  • Dermatology and Venereal Diseases

Nyckelord

  • Cutaneous T-cell lymphoma (CTCL)
  • IL-2
  • In situ
  • miR-21
  • STAT5

Status

Published

Forskningsgrupp

  • Experimental Cancer Research, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 1949-2553