The modulation of microRNAs by type I IFN through the activation of signal transducers and activators of transcription 3 in human glioma.
Type I IFNs are involved in double-stranded RNA responses. Here, we investigated the possibility that IFN-beta may induce or downregulate cellular microRNAs (miRNA) in human neoplasms and thereby use the RNA interference system to show antitumor effects. Because of its known connection to glioma biology, we focused on miR-21 among seven miRNAs influenced by IFN-beta. We analyzed the effect of IFN-beta treatment on miR-21 expression in glioma cells and intracranial glioma xenografts. IFN-beta treatment reduced miR-21 expression in glioma cells markedly, and IFN-beta administration suppressed the growth of glioma-initiating cell-derived intracranial tumors. The levels of primary miR-21 gene transcripts, precursor miR-21, and mature miR-21 decreased 6 hours after the addition of IFN-beta, indicating that the reduction in miR-21 levels was due to transcriptional suppression. We did reporter assays to elucidate the IFN-beta-mediated suppression of miR-21; the addition of signal transducers and activators of transcription 3 (STAT3)-expressing vectors induced the IFN-beta-mediated suppression of miR-21, whereas STAT3-inhibiting agents inhibited the miR-21 suppression. Thus, the results of our study show that the downregulation of miR-21 contributes to the antitumor effects of IFN-beta and that miR-21 expression is negatively regulated by STAT3 activation. These results highlight the importance of understanding the transcriptional regulation of the miRNAs involved in oncogenesis.
Ohno
Masasuke
M
Department of Neurosurgery, Aichi Cancer Center Research Institute, Nagoya 466-8550, Japan.
Natsume
Atsushi
A
Kondo
Yutaka
Y
Iwamizu
Hidetaka
H
Motomura
Kazuya
K
Toda
Hiroshi
H
Ito
Motokazu
M
Kato
Takenori
T
Wakabayashi
Toshihiko
T
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics*; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016899:Interferon-beta