Department of Neurosurgery, Aichi Cancer Center Research Institute, Nagoya 466-8550, Japan.
Mol Cancer Res. 2009 Dec;7(12):2022-30. doi: 10.1158/1541-7786.MCR-09-0319. Epub 2009 Nov 24.
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.
I 型干扰素参与双链 RNA 反应。在这里，我们研究了 IFN-β 是否可能在人类肿瘤中诱导或下调细胞 microRNA（miRNA），从而利用 RNA 干扰系统显示抗肿瘤作用。由于其与神经胶质瘤生物学的已知联系，我们专注于受 IFN-β 影响的七种 miRNA 中的 miR-21。我们分析了 IFN-β 处理对神经胶质瘤细胞和颅内神经胶质瘤异种移植物中 miR-21 表达的影响。IFN-β 处理明显降低了神经胶质瘤细胞中的 miR-21 表达，IFN-β 给药抑制了由神经胶质瘤起始细胞衍生的颅内肿瘤的生长。添加 IFN-β 6 小时后，初级 miR-21 基因转录物、前体 miR-21 和成熟 miR-21 的水平降低，表明 miR-21 水平的降低是由于转录抑制。我们进行了报告基因测定以阐明 IFN-β 介导的 miR-21 抑制；添加表达信号转导和转录激活因子 3（STAT3）的载体诱导了 IFN-β 介导的 miR-21 抑制，而 STAT3 抑制剂抑制了 miR-21 抑制。因此，我们的研究结果表明，miR-21 的下调有助于 IFN-β 的抗肿瘤作用，并且 miR-21 的表达受 STAT3 激活的负调控。这些结果强调了理解参与致癌作用的 miRNAs 的转录调控的重要性。
