Dermatology

Skin Cancer – Research Article

MicroRNA-93 Targets p21 and Promotes Proliferation in Mycosis Fungoides T Cells

Gluud M.a · Fredholm S.a · Blümel E.a · Willerslev-Olsen A.a · Buus T.B.a · Nastasi C.a · Krejsgaard T.a · Bonefeld C.M.a · Woetmann A.a · Iversen L.b · Litman T.a · Geisler C.a · Ødum N.a · Lindahl L.M.b

Author affiliations

aLeo Foundation Skin Immunology Research Center, Institute of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
bDepartment of Dermatology, Aarhus University Hospital, Skejby, Aarhus, Denmark

Keywords: Cutaneous T-cell lymphomaMycosis fungoidesmicroRNA-93p21Tumor progressionSAHA/Vorinostat

Related Articles for ""
Dermatology 2021;237:277–282
https://doi.org/10.1159/000505743

Log in to MyKarger to check if you already have access to this content.




Forgot your password
Sign up to MyKarger

Buy

  • FullText & PDF
  • Unlimited re-access via MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more
CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!


If you would like to redeem your KAB credit, please log in.

Save over 20% compared to the individual article price.

Learn more

Rent/Cloud

  • Rent for 48h to view
  • Buy Cloud Access for unlimited viewing via different devices
  • Synchronizing in the ReadCube Cloud
  • Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00

Select

Subscribe

  • Access to all articles of the subscribed year(s) guaranteed for 5 years
  • Unlimited re-access via Subscriber Login or MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

Subcription rates

Select
* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview
Abstract of Skin Cancer – Research Article

Received: September 12, 2019
Accepted: January 04, 2020
Published online: April 24, 2020
Issue release date: March 2021

Number of Print Pages: 6
Number of Figures: 3
Number of Tables: 0

ISSN: 1018-8665 (Print)
eISSN: 1421-9832 (Online)

For additional information: https://www.karger.com/DRM

Abstract

Background: Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is a lymphoproliferative disorder characterized by proliferation of malignant T cells in a chronic inflammatory environment in the skin. The nature of MF is still not fully understood, but aberrant microRNA (miR) expression and function seem to play an important role in the pathogenesis and disease progression and have been proposed as a putative disease marker. Recent studies have reported aberrant expression of miR-93 in situin MF lesions and linked dysregulated miR-93 expression to advanced stages of MF. However, the pathophysiological role of miR-93 in MF is unknown. Objective: Here, we provide the first evidence that miR-93 targets the cell cycle regulator cyclin-dependent kinase inhibitor p21 and promotes growth of malignant T cells in MF. Methods/Results: Thus, inhibition of miR-93 in MF patient-derived malignant T-cell lines increases expression of p21 and inhibition of malignant proliferation. Notably, treatment with the histone deacetylase inhibitor Vorinostat (SAHA) reduces miR-93 expression and enhances p21 expression in the malignant T cells. Importantly, transfection with an miR-93 mimic partly blocks SAHA-induced p21 expression. Conclusions: we provide evidence that enhanced expression of the putative oncogenic miR, miR-93, represses the cell cycle inhibitor p21 and promotes proliferation of malignant T cells. Moreover, we demonstrate that SAHA triggers p21 expression – at least partly – through an inhibition of miR-93.

© 2020 S. Karger AG, Basel



Related Articles:

References

  1. Kim EJ, Hess S, Richardson SK, Newton S, Showe LC, Benoit BM, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest. 2005 Apr;115(4):798–812.
    External Resources
  2. Wilcox RA. Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol. 2017 Oct;92(10):1085–102.
  3. Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood. 2010 Aug;116(5):767–71.
    External Resources
  4. Litvinov IV, Shtreis A, Kobayashi K, Glassman S, Tsang M, Woetmann A, et al. Investigating potential exogenous tumor initiating and promoting factors for Cutaneous T-Cell Lymphomas (CTCL), a rare skin malignancy. OncoImmunology. 2016 Jun;5(7):e1175799.
    External Resources
  5. Buus TB, Willerslev-Olsen A, Fredholm S, Blümel E, Nastasi C, Gluud M, et al. Single-cell heterogeneity in Sézary syndrome. Blood Adv. 2018 Aug;2(16):2115–26.
    External Resources
  6. Bastidas Torres AN, Najidh S, Tensen CP, Vermeer MH. Molecular advances in cutaneous T-cell lymphoma. Semin Cutan Med Surg. 2018 Mar;37(1):81–6.
    External Resources
  7. Odum N, Lindahl LM, Wod M, Krejsgaard T, Skytthe A, Woetmann A, et al. Investigating heredity in cutaneous T-cell lymphoma in a unique cohort of Danish twins. Blood Cancer J. 2017 Jan;7(1):e517.
    External Resources
  8. Willerslev-Olsen A, Krejsgaard T, Lindahl LM, Litvinov IV, Fredholm S, Petersen DL, et al. Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma. Blood. 2016 Jan;127(10):1287–96.
  9. Ghazawi FM, Netchiporouk E, Rahme E, Tsang M, Moreau L, Glassman S, et al. Comprehensive analysis of cutaneous T-cell lymphoma (CTCL) incidence and mortality in Canada reveals changing trends and geographic clustering for this malignancy. Cancer. 2017 Sep;123(18):3550–67.
    External Resources
  10. Lindahl LM, Willerslev-Olsen A, Gjerdrum LM, Nielsen PR, Blümel E, Rittig AH, et al. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma. Blood. 2019 Sep;134(13):1072–83.
    External Resources
  11. Blümel E, Willerslev-Olsen A, Gluud M, Lindahl LM, Fredholm S, Nastasi C, et al. Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+ T cells in cutaneous T-cell lymphoma. Oncoimmunology. 2019 Jul;8(11):e1641387.
    External Resources
  12. Sors A, Jean-Louis F, Pellet C, Laroche L, Dubertret L, Courtois G, et al. Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis. Blood. 2006 Mar;107(6):2354–63.
    External Resources
  13. Nielsen M, Nissen MH, Gerwien J, Zocca MB, Rasmussen HM, Nakajima K, et al. Spontaneous interleukin-5 production in cutaneous T-cell lymphoma lines is mediated by constitutively activated Stat3. Blood. 2002 Feb;99(3):973–7.
    External Resources
  14. Kiel MJ, Sahasrabuddhe AA, Rolland DC, Velusamy T, Chung F, Schaller M, et al. Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome. Nat Commun. 2015 Sep;6(1):8470.
    External Resources
  15. Krejsgaard T, Lindahl LM, Mongan NP, Wasik MA, Litvinov IV, Iversen L, et al. Malignant inflammation in cutaneous T-cell lymphoma-a hostile takeover. Semin Immunopathol. 2017 Apr;39(3):269–82.
    External Resources
  16. Kopp KL, Ralfkiaer U, Gjerdrum LM, Helvad R, Pedersen IH, Litman T, et al. STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. Cell Cycle. 2013 Jun;12(12):1939–47.
    External Resources
  17. van Kester MS, Ballabio E, Benner MF, Chen XH, Saunders NJ, van der Fits L, et al. miRNA expression profiling of mycosis fungoides. Mol Oncol. 2011 Jun;5(3):273–80.
    External Resources
  18. Lindahl LM, Fredholm S, Joseph C, Nielsen BS, Jønson L, Willerslev-Olsen A, et al. STAT5 induces miR-21 expression in cutaneous T cell lymphoma. Oncotarget. 2016 Jul;7(29):45730–44.
    External Resources
  19. Ralfkiaer U, Lindahl LM, Litman T, Gjerdrum LM, Ahler CB, Gniadecki R, et al. MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma. Anticancer Res. 2014 Dec;34(12):7207–17.
    External Resources
  20. Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017 Mar;16(3):203–22.
    External Resources
  21. Lindahl LM, Besenbacher S, Rittig AH, Celis P, Willerslev-Olsen A, Gjerdrum LM, et al. Prognostic miRNA classifier in early-stage mycosis fungoides: development and validation in a Danish nationwide study. Blood. 2018 Feb;131(7):759–70.
    External Resources
  22. Ralfkiaer U, Hagedorn PH, Bangsgaard N, Løvendorf MB, Ahler CB, Svensson L, et al. Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL). Blood. 2011 Nov;118(22):5891–900.
    External Resources
  23. Fredholm S, Willerslev-Olsen A, Met Ö, Kubat L, Gluud M, Mathiasen SL, et al. SATB1 in malignant T cells. J Invest Dermatol. 2018 Aug;138(8):1805–15.
  24. Sibbesen NA, Kopp KL, Litvinov IV, Jønson L, Willerslev-Olsen A, Fredholm S, et al. Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma. Oncotarget. 2015 Aug;6(24):20555–69.
    External Resources
  25. Marosvári D, Téglási V, Csala I, Marschalkó M, Bödör C, Timár B, et al. Altered microRNA expression in folliculotropic and transformed mycosis fungoides. Pathol Oncol Res. 2015 Jul;21(3):821–5.
    External Resources
  26. Ballabio E, Mitchell T, van Kester MS, Taylor S, Dunlop HM, Chi J, et al. MicroRNA expression in Sezary syndrome: identification, function, and diagnostic potential. Blood. 2010 Aug;116(7):1105–13.
    External Resources
  27. Jankowska-Konsur A, Kobierzycki C, Reich A, Grzegrzolka J, Maj J, Dziegiel P. Expression of MCM-3 and MCM-7 in Primary Cutaneous T-cell Lymphomas. Anticancer Res. 2015 Nov;35(11):6017–26.
    External Resources
  28. Gambichler T, Bischoff S, Bechara FG, Altmeyer P, Kreuter A. Expression of proliferation markers and cell cycle regulators in T cell lymphoproliferative skin disorders. J Dermatol Sci. 2008 Feb;49(2):125–32.
    External Resources
  29. Li N, Miao Y, Shan Y, Liu B, Li Y, Zhao L, et al. MiR-106b and miR-93 regulate cell progression by suppression of PTEN via PI3K/Akt pathway in breast cancer. Cell Death Dis. 2017 May;8(5):e2796.
    External Resources
  30. Bagherani N, Smoller BR. An overview of cutaneous T cell lymphomas. F1000Res. 2016 Jul;5:F1000 Faculty Rev-1882.
    External Resources
  31. Woetmann A, Lovato P, Eriksen KW, Krejsgaard T, Labuda T, Zhang Q, et al. Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins. Blood. 2007 Apr;109(8):3325–32.
  32. Fredholm S, Gjerdrum LMR, Willerslev-Olsen A, Petersen DL, Nielsen IØ, Kauczok C-S, et al. STAT3 Activation and infiltration of eosinophil granulocytes in mycosis fungoides. Anticancer Res. 2014 Jan;34(10):5277–86.
  33. Zhang C, Richon V, Ni X, Talpur R, Duvic M. Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. J Invest Dermatol. 2005 Nov;125(5):1045–52.
    External Resources
  34. Lopez AT, Bates S, Geskin L. Current Status of HDAC Inhibitors in Cutaneous T-cell Lymphoma. Am J Clin Dermatol. 2018 Dec;19(6):805–19.
    External Resources
  35. Kitadate A, Ikeda S, Teshima K, Ito M, Toyota I, Hasunuma N, et al. MicroRNA-16 mediates the regulation of a senescence-apoptosis switch in cutaneous T-cell and other non-Hodgkin lymphomas. Oncogene. 2016 Jul;35(28):3692–704.
  36. Gui CY, Ngo L, Xu WS, Richon VM, Marks PA. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA. 2004 Feb;101(5):1241–6.
    External Resources
  37. Querfeld C, Foss FM, Pinter-Brown LC, Porcu P, William BM, Pacheco T, et al. Phase 1 Study of the Safety and Efficacy of MRG-106, a Synthetic Inhibitor of microRNA-155, in CTCL Patients. Blood. 2017 Dec;130 Suppl 1:820.
  38. Al-Yacoub N, Fecker LF, Möbs M, Plötz M, Braun FK, Sterry W, et al. Apoptosis induction by SAHA in cutaneous T-cell lymphoma cells is related to downregulation of c-FLIP and enhanced TRAIL signaling. J Invest Dermatol. 2012 Sep;132(9):2263–74.
    External Resources

Article / Publication Details

First-Page Preview
Abstract of Skin Cancer – Research Article

Received: September 12, 2019
Accepted: January 04, 2020
Published online: April 24, 2020
Issue release date: March 2021

Number of Print Pages: 6
Number of Figures: 3
Number of Tables: 0

ISSN: 1018-8665 (Print)
eISSN: 1421-9832 (Online)

For additional information: https://www.karger.com/DRM

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Article Tools
Article Details

2021, Vol.237, No. 2

March 2021

Free Supplementary Material

Article

Recommend This
TOP