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RESEARCH PRODUCT
SOCS3 transactivation by PPARγ prevents IL-17-driven cancer growth.
Aziz HichamiHélène BugautValentin DerangèreFanny ChalminFrançois GhiringhelliMadijd ChikhFederica GilardiLionel ApetohSylvain LadoireCaroline PotBernhard RyffelCédric RébéBéatrice DesvergneAngélique ChevriauxFrédérique VégranHélène BergerMélanie BruchardGrégoire Mignotsubject
CD4-Positive T-LymphocytesCancer ResearchAngiogenesisMammary Neoplasms Experimental/genetics/pathology/prevention & controlSuppressor of Cytokine Signaling Proteinsddc:616.07BioinformaticsTransactivationMice0302 clinical medicineTumor Burden/drug effects/geneticsSOCS3Docosahexaenoic Acids/administration & dosage/pharmacologyPromoter Regions GeneticMice Knockout0303 health sciencesMice Inbred BALB CChemistryReverse Transcriptase Polymerase Chain ReactionInterleukin-17InterleukinCell DifferentiationCell biologyTumor BurdenOncology030220 oncology & carcinogenesisFemaleRNA InterferenceInterleukin 17Th17 Cells/drug effects/metabolismTranscriptional ActivationDocosahexaenoic AcidsBlotting WesternMice NudeCD4-Positive T-Lymphocytes/drug effects/metabolismProinflammatory cytokine03 medical and health sciencesSuppressor of Cytokine Signaling Proteins/genetics/metabolismCell Line TumorAnimalsTranscription factor030304 developmental biologyMammary Neoplasms ExperimentalPromoter Regions Genetic/geneticsDietMice Inbred C57BLPPAR gammaInterleukin-17/metabolismCell cultureSuppressor of Cytokine Signaling 3 ProteinCell Differentiation/drug effectsPPAR gamma/agonists/genetics/metabolismTh17 Cellsdescription
Abstract Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARγ are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory T-helper (TH)17 cells. Accordingly, TH17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPARγ by DHA. Furthermore, naïve CD4 T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into TH17 cells. In two different mouse models of cancer, DHA prevented tumor outgrowth and angiogenesis in an IL-17–dependent manner. Altogether, our results uncover a novel molecular pathway by which PPARγ-induced SOCS3 expression prevents IL-17–mediated cancer growth. Cancer Res; 73(12); 3578–90. ©2013 AACR.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2013-06-13 | Cancer research |