Abstract
Abstract The interferon (IFN) pathway controls the cellular response to viral infection and double-stranded RNA. We have found that this pathway provides a novel checkpoint for enhanced expression of miRNAs. The IFN pathway is abrogated in fibroblasts from Li-Fraumeni Syndrome (LFS) patients during spontaneous cellular immortalization, a necessary step in carcinogenesis. Interferon stimulated genes (ISGs) were down-regulated by epigenetic silencing during immortalization and some of these same ISGs were activated by replicative senescence. Bisulfite sequencing of the promoter regions of IFN-regulatory transcription factors (IRF5 and IRF7) revealed that IRF7 but not IRF5 was epigenetically silenced by methylation of CpG islands in immortal LFS cells. The re-activation of ISGs by those transcription factors is sufficient to inhibit cell proliferation and induce a senescence-related phenotype in immortal LFS cells. Similar epigenetic silencing of IRF7 also results in disruption of IFN pathway in ∼30% lung cancer cells and primary tissues. Examination of innate immunity status in normal bronchial epithelial cell line Beas2B, its ras transformed derivative BVK cells and tumor-generating clones reveals increasing loss of functional IFN pathway as cells become more cancerous. Furthermore, microarray profiling of differentially expressed microRNAs (miRNAs) in LFS cell lines revealed most miRNAs were up-regulated in IFN-pathway-defective MDAH087-10 fibroblasts compared to MDAH087-N cells with relatively normal IFN signaling. Overexpression of Dicer, a critical enzyme in miRNA biogenesis, promoted cell growth and colony formation in MDAH087-10 cells. However, double-stranded miRNA produced by Dicer enhanced the expression of ISGs in MDAH087-N cells resulting in significant cell death and reduced cell growth. In addition, manipulation of the IFN pathway in immortal LFS fibroblasts through transcription factor IRF7 reversed their response to Dicer overexpression due to altered activation of the IFN pathway. Dicer-overexpressing MDAH087-N cells contained lower levels of miRNA than vector control, and conversely much higher miRNA expression was detected in Dicer transfected MDAH087-10 cells. The higher miRNA tolerance in immortal LFS fibroblasts with a disrupted IFN pathway indicates for the first time that the IFN pathway as mediated through the transcription factor IRF7 must be disrupted to permit miRNA up-regulation to occur in early carcinogenesis. This IFN pathway appears to provide a checkpoint for miRNA level tolerance and its abrogation by epigenetic silencing leads to cellular immortalization and early events in tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4002. doi:10.1158/1538-7445.AM2011-4002
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