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1.
J Invest Dermatol ; 138(8): 1805-1815, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29751003

RESUMO

Deficient expression of SATB1 hampers thymocyte development and results in inept T-cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides, the most frequent variant of cutaneous T-cell lymphoma. Here, we report on a disease stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. STAT5 inhibited SATB1 expression through induction of microRNA-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32), whereas increased SATB1 expression had the opposite effect, indicating that the microRNA-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5 and its upstream activator JAK3 triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic JAK3/STAT5/microRNA-155 pathway, SATB1, and cytokines linked to CTCL severity and progression, indicating that SATB1 dysregulation is involved in cutaneous T-cell lymphoma pathogenesis.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/genética , MicroRNAs/metabolismo , Micose Fungoide/genética , Neoplasias Cutâneas/genética , Linfócitos T/imunologia , Linhagem Celular Tumoral , Estudos de Coortes , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Interleucina-5/imunologia , Interleucina-5/metabolismo , Interleucina-9/imunologia , Interleucina-9/metabolismo , Janus Quinase 3/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/imunologia , Micose Fungoide/imunologia , Micose Fungoide/patologia , Estadiamento de Neoplasias , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T/metabolismo
2.
Oncotarget ; 7(29): 45730-45744, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27329723

RESUMO

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.


Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , Linfoma Cutâneo de Células T/metabolismo , MicroRNAs/biossíntese , Fator de Transcrição STAT5/metabolismo , Neoplasias Cutâneas/metabolismo , Feminino , Humanos , Linfoma Cutâneo de Células T/genética , Masculino , MicroRNAs/genética , Fator de Transcrição STAT5/genética , Neoplasias Cutâneas/genética
3.
Blood ; 127(10): 1287-96, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26738536

RESUMO

Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region ß chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis.


Assuntos
Enterotoxinas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interleucina-17/biossíntese , Proteínas de Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Síndrome de Sézary/metabolismo , Linfócitos T/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Humanos , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Síndrome de Sézary/patologia , Linfócitos T/patologia
4.
Oncotarget ; 6(24): 20555-69, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26244872

RESUMO

Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.


Assuntos
Janus Quinase 3/metabolismo , Linfoma Cutâneo de Células T/genética , MicroRNAs/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Neoplasias Cutâneas/genética , Linhagem Celular Tumoral , Genes Supressores de Tumor , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/genética , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologia , MicroRNAs/administração & dosagem , MicroRNAs/biossíntese , MicroRNAs/genética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT5/genética , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Transfecção
5.
Anticancer Res ; 34(10): 5277-86, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25275020

RESUMO

Eosinophil granulocytes have been implicated in anticancer immunity but recent data indicate that eosinophils can also promote cancer. Herein, we studied eosinophils in skin lesions from 43 patients with mycosis fungoides (MF). The presence of eosinophils correlated with disease stage: 78% of patients with advanced disease displayed eosinophil infiltration, whereas this was only seen in 11% of patients with patches (p<0.01), and in 48% of those with plaque disease. Importantly, 72% of patients with positive staining for phospho-signal-transducer-and-activator-of-transcription (pY-STAT3) in malignant T-cells also stained positively for eosinophils, whereas this was only observed in 28% of pY-STAT3-negative patients (p<0.01). Notably, malignant T-cells expressed eosinophilic activation and trafficking factors: High-mobility group BOX-1 protein (HMGB1) and interleukin 5 (IL5). STAT3 siRNA profoundly inhibited IL5 but not HMGB1 expression. In conclusion, these data suggest that malignant T-cells orchestrate accumulation and activation of eosinophils supporting the notion of STAT3 being a putative target for therapy.


Assuntos
Eosinófilos/patologia , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Fator de Transcrição STAT3/metabolismo , Biópsia , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Imuno-Histoquímica , Interleucina-5/genética , Interleucina-5/metabolismo , Micose Fungoide/genética , Micose Fungoide/imunologia , Interferência de RNA , Fator de Transcrição STAT3/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
6.
Cell Cycle ; 13(8): 1306-12, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24621498

RESUMO

Skin lesions from mycosis fungoides (MF) patients display an increased expression of interleukin-15 (IL-15), IL-17F, and other cytokines implicated in inflammation and malignant cell proliferation in cutaneous T-cell lymphoma (CTCL). In the leukemic variant of CTCL, Sézary syndrome (SS), IL-2 and IL-15 trigger activation of the Jak-3/STAT3 pathway and transcription of IL17A gene, whereas it is unknown what causes IL-15 expression, Jak3/STAT3 activation, and production of IL-17F in MF. Here, we studied the expression and regulation of IL-15 and its relation to IL-17F in MF cell lines and skin lesions from 60 MF patients. We show that: (1) the spontaneous IL-15 mRNA expression is resistant to Jak3 and STAT3 inhibitors at concentrations that profoundly inhibit STAT3 activation and IL-17F mRNA expression; (2) anti-IL-15 antibody blocks STAT3 activation induced by exogenous IL-15 in non-malignant MF T cells, whereas the spontaneous STAT3 activation and IL-17F expression in malignant T cells is not inhibited; (3) patients display heterogeneous IL-15/IL-17F mRNA expression patterns in skin lesions; and (4) IL-15 expression (in contrast to IL-17F) is not associated with progressive disease. Taken together, these findings indicate that IL-15 and IL-17F are differentially regulated and expressed in MF. We propose that IL-15 and IL-17F are markers for different inflammatory environments and play distinct roles in the development and progression of MF.


Assuntos
Interleucina-15/metabolismo , Interleucina-17/metabolismo , Linfoma Cutâneo de Células T/metabolismo , Micose Fungoide/metabolismo , Neoplasias Cutâneas/patologia , Linhagem Celular Tumoral , Humanos , Interleucina-15/genética , Interleucina-17/genética , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/patologia , Fator de Transcrição STAT3/metabolismo , Neoplasias Cutâneas/metabolismo
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