IFN induces miR-21 through a signal transducer and activator of transcription 3-dependent pathway as a suppressive negative feedback on IFN-induced apoptosis.
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.
Yang
Chuan He
CH
Departments of Pathology and Laboratory Medicine and Physiology and Center for Integrative Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Yue
Junming
J
Fan
Meiyun
M
Pfeffer
Lawrence M
LM
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
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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