IFN Induces miR-21 through a Signal Transducer and Activator of Transcription 3-Dependent Pathway as a Suppressive Negative Feedback on IFN-Induced Apoptosis

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 20; pp. 8108 - 8116
• Main Authors: CHUAN HE YANG, JUNMING YUE, MEIYUN FAN, PFEFFER, Lawrence M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.10.2010
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - genetics; Biological and medical sciences; DNA Primers; DNA, Complementary - genetics; Feedback; Fibroblasts - physiology; Gene Silencing; Humans; Interferons - pharmacology; Male; Medical sciences; Mice; Mice, Knockout; MicroRNAs - genetics; Pharmacology. Drug treatments; Prostatic Neoplasms - genetics; Signal Transduction - physiology; STAT3 Transcription Factor - metabolism; Transcription Factor RelA - deficiency; Transcription Factor RelA - genetics; Tumors; Gene silencing; Signal transduction; RNA interference; Activator; Feedback; Cell death; Cytokine; Transcription factor STAT3; Micro RNA; Interferon; Apoptosis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-2579

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.