IFN-γ induces epithelial-to-mesenchymal transition of cancer cells via an unique microRNA processing

Interferon-γ (IFNγ) is a potent cytokine in modulating tumor immunity and tumoricidal effects. We demonstrate a new function of IFNγ in inducing epithelial-to-mesenchymal transition (EMT) in normal and cancer cells from different cell types. IFNγ activates JAK-STAT signaling pathway leading to the transcription of IFN-stimulated genes (ISGs), such as interferon-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor microRNAs (pre-miRNA) that include pre-miR-363 from the miR-106a-363 cluster, as well as pre-miR-101 and pre-miR-128 with a similar 59-end structure with pre-miR-363. Noticeably, these suppressive miRNAs have similar functions by targeting EMT transcription factors in prostate cancer (PCa) cells. We further demonstrated that IFIT5 plays a critical role in IFNγ-induced cell invasiveness in vitro and lung metastasis in vivo. Clinically, IFIT5 is highly elevated in high-grade PCa and its expression inversely correlates with these suppressive miRNAs. Altogether, this study unveils pro-tumorigenic role of the IFN pathway via a new mechanism of action, which certainly raises concern about its clinical application.