IFN-r-induced IFIT5 promotes epithelial-to-mesenchymal transition in prostate cancer via microRNA processing
Menée à l'aide de lignées cellulaires de cancer de la prostate, d'explants dérivés de patients et d'un modèle murin, cette étude met en évidence un mécanisme par lequel la répétition tétratricopeptide induite par l'interféron "IFIT5" favorise la transition épithélio-mésenchymateuse en agissant sur le processus de maturation des microARNs
Interferon-
γ (IFNγ), a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in prostate cancer (PCa) patients after radiation. In this study, we demonstrate that IFNγ can induce epithelial-to-mesenchymal transition (EMT) in PCa cells via the JAK-STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) 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, who share a similar 5'-end structure with pre-miR-363. These suppressive miRNAs exerted a similar function by targeting EMT transcription factors in PCa cells. Depletion of IFIT5 decreased IFNγ-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade PCa and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a pro-metastatic role of the IFNγ pathway via a new mechanism of action, which raises concerns about its clinical application.
Cancer Research 2018