MicroRNA-21 Expression in CD4+ T Cells Is Regulated by STAT3 and Is Pathologically Involved in Sézary Syndrome

Abstract

MicroRNAs (miRNAs) are small RNAs that control gene expression, and are involved in the regulation of fundamental biological processes including development, cell differentiation, proliferation, and apoptosis. miRNAs regulate gene expression in normal hematopoiesis, and aberrant miRNA expression might contribute to leukomogenesis. Specifically, miR-21 is abundantly expressed in various tumors including leukemia and lymphoma, and is functionally involved in oncogenic processes. We investigated a role for miR-21 in Sézary Syndrome (SS), a cutaneous T-cell lymphoma (CTCL) with CD4+ tumor cells (Sézary cells) present in the skin, lymph nodes, and peripheral blood. It was shown previously that SS is characterized by constitutively activated signal transducer and activator of transcription 3 (STAT3) signaling. In this study we show by chromatin immunoprecipitation that miR-21 is a direct STAT3 target in Sézary cells. Stimulation of Sézary cells or healthy CD4+ T cells with the common-γ chain cytokine IL-21 results in a strong activation of STAT3, and subsequent upregulation of miR-21 expression. Both pri- and mature miR-21 expression are increased in Sézary cells when compared with CD4+ T cells from healthy donors. Silencing of miR-21 in Sézary cells results in increased apoptosis, suggesting a functional role for miR-21 in the leukomogenic process. Consequently, miR-21 might represent a therapeutic target for the treatment of SS.

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

“…Indeed, in autoimmune uveitis, STAT3 hyperphosphorylation correlates with the activation of CD4 + T cells and the proliferation and survival of CD8 + T cells (64,65), whereas upregulation of Wnt/b-catenin pathway in T cells is involved in relapses (66). Furthermore, Haapaniemi et al (67) have recently described that patients with STAT3 gain-of-function mutations present immunological disorders including autoimmunity and T lymphoproliferation, because activation of STAT3 promotes CD4 + T cell proliferation and inhibits their apoptosis (68,69). These observations strengthen the role of STAT3 in proliferation and activation of T cells and could explain the results obtained with the HOClinduced mouse model of SSc, the increased number of overactivated CD4 + and CD8 + T cells, and the abrogation of this phenomenon by the inhibition of these two pathways with niclosamide.…”

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

“…STAT3 was recently shown to regulate miR-21 expression in malignant T cells. 33,34 As siRNA directed against STAT3 resulted in an almost complete depletion of STAT3 without modulating the expression of BIC and miR-155 ( Fig. 3A and B), it appears that STAT3 and STAT5 have distinct and specialized roles regulating miR-21 and miR-155, respectively.…”

“…Interestingly, miR-21, another oncogenic miRNA that is significantly upregulated in CTCL patients, 17,18 was shown to be modulated by STAT3. 33,34 Much less is known about STAT5, another downstream effector of the IL-2R/JAK3 complex. A previous study indicated that STAT5 is aberrantly activated in CTCL, but only a small number of patients was analyzed, and the pathological relevance was unclear.…”

Analysis of STAT4 expression in cutaneous T-cell lymphoma (CTCL) patients and patient-derived cell lines

“…24,25 Constitutively active STAT3 can increase survival and resistance to apoptosis in malignant T cells, promote sensitization to IL-2 stimulation, 24,29 promote Th2 phenotype in advanced disease and induce expression of miR-21 oncogenic microRNA. 30 STAT3 signaling in CTCL was also shown to upregulate VEGF, 31 the anti-inflammatory cytokine IL-10 32 and a suppressor of cytokine signaling-3 (SOCS). 33 The latter was demonstrated to confer resistance to IFN-a in malignant T cells.…”