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

U. Ging Lo, Rey Chen Pong, Diane Yang, Leah Gandee, Elizabeth Hernandez, Andrew Dang, Chung Jung Lin, John Santoyo, Shi Hong Ma, Rajni Sonavane, Jun Huang, Shu Fen Tseng, Loredana Moro, Arnaldo A. Arbini, Payal Kapur, Ganesh Raj, Dalin He, Chih ho Lai, Ho Lin, Jer Tsong Hsieh

Research output: Contribution to journalArticlepeer-review

Abstract

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 5’-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.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Jun 25 2018

Keywords

  • EMT
  • IFIT5
  • Interferon
  • metastasis
  • microRNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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