TY - JOUR

T1 - MicroRNA-93 Targets p21 and Promotes Proliferation in Mycosis Fungoides T Cells

AU - Gluud, Maria

AU - Fredholm, Simon

AU - Blümel, Edda

AU - Willerslev-Olsen, Andreas

AU - Buus, Terkild Brink

AU - Nastasi, Claudia

AU - Krejsgaard, Thorbjørn

AU - Bonefeld, Charlotte Menné

AU - Woetmann, Anders

AU - Iversen, Lars

AU - Litman, Thomas

AU - Geisler, Carsten

AU - Ødum, Niels

AU - Lindahl, Lise M.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Cutaneous T-cell lymphoma

KW - microRNA-93

KW - Mycosis fungoides

KW - p21

KW - SAHA/Vorinostat

KW - Tumor progression

U2 - 10.1159/000505743

DO - 10.1159/000505743

M3 - Journal article

C2 - 32335549

AN - SCOPUS:85084397053

VL - 237

SP - 277

EP - 282

JO - Dermatology

JF - Dermatology

SN - 1018-8665

ER -