title: IFN induces miR-21 through a signal transducer and activator of transcription 3-dependent pathway as a suppressive negative feedback on IFN-induced apoptosis.
abstract: The microRNA miR-21 is overexpressed in many human cancers, wherein accumulating evidence indicates that it functions as an oncogene. Here, we report that the cytokine IFN rapidly induces miR-21 expression in human and mouse cells. Signal transducer and activator of transcription 3 (STAT3) was implicated in this pathway based on the lack of IFN effect on miR-21 expression in prostate cancer cells with a deletion in the STAT3 gene. STAT3 ablation abrogated IFN induction of miR-21, confirming the important role of STAT3 in regulating miR-21. Chromatin immunoprecipitation analysis showed that STAT3 directly bound the miR-21 promoter in response to IFN. Experiments in mouse embryo fibroblasts with a genetic deletion of the p65 NF-κB subunit showed that IFN-induced miR-21 expression was also dependent on NF-κB. STAT3 silencing blocked both IFN-induced p65 binding to the miR-21 promoter and p65 nuclear translocation. Thus, IFN-induced miR-21 expression is coregulated by STAT3 and NF-κB at the level of the miR-21 promoter. Several cell death regulators were identified as downstream targets of miR-21, including PTEN and Akt. Functional experiments in prostate cancer cells directly showed that miR-21 plays a critical role in suppressing IFN-induced apoptosis. Our results identify miR-21 as a novel IFN target gene that functions as a key feedback regulator of IFN-induced apoptosis.
authors.affiliation: Departments of Pathology and Laboratory Medicine and Physiology and Center for Integrative Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.forename: Junming
authors.initials: J
authors.lastname: Yue
authors.forename: Meiyun
authors.initials: M
authors.lastname: Fan
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D005246:Feedback; D005347:Fibroblasts / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C498144:Rela protein, mouse; D050796:STAT3 Transcription Factor; D051996:Transcription Factor RelA; D007372:Interferons
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