期刊
CANCER RESEARCH
卷 79, 期 6, 页码 1098-1112出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-2207
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资金
- Harold C. Simmons Cancer Center through an NCI Cancer Center Support Grant [1P30 CA142543]
- Department of Radiology [NIH 1S10RR024757]
- United States Army [W81XWH-11-1-0491, W81XWH-16-1-0474, W81XWH 14 1 0249]
- Ministry of Science and Technology in Taiwan [MOST103-2911-I-005-507]
IFN gamma, a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in patients with prostate cancer after radiation. In this study, we demonstrate that IFN gamma can induce epithelial-to-mesenchymal transition (EMT) in prostate cancer cells via the JAK-STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as IFN-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor miRNAs (pre-miRNA) that includes 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 prostate cancer cells. Depletion of IFIT5 decreased IFN gamma-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade prostate cancer and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a pro-metastatic role of the IFN gamma pathway via a new mechanism of action, which raises concerns about its clinical application.
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