Inflammatory myofibroblastic tumors (IMT) harbor mutations in nonsense-mediated RNA decay gene UPF1.

  • Major finding: Inflammatory myofibroblastic tumors (IMT) harbor mutations in nonsense-mediated RNA decay gene UPF1.

  • Mechanism: UPF1 mutations disrupt nonsense-mediated RNA decay, increasing NIK levels and immune infiltration.

  • Impact: UPF1 mutations may be diagnostic for IMT and restoring NMD may have therapeutic potential.

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Inflammatory myofibroblastic tumors (IMT) are rare, often locally invasive tumors characterized by myofibroblast proliferation and inflammatory cell infiltration. However, the molecular events that promote IMT tumorigenesis are largely unknown. Lu and colleagues identified somatic mutations in UPF1, an ATP-dependent RNA helicase critical for nonsense-mediated RNA decay (NMD), a highly conserved and selective RNA degradation pathway responsible for degrading a subset of mRNAs. Thirteen of 15 patients with IMP had a mutation in UPF1, and almost all of the mutations were clustered in exon 10 and intron 10. Introduction of the IMT UPF1 mutations in a minigene resulted in the appearance of an alternatively spliced transcript lacking exons 10 and 11 that was also identified in a patient with UPF1-mutant IMT. UPF1 mutations corresponded with reduced UPF1 protein expression in tissue from patients with IMT, indicating that loss of exons 10 and 11 may destabilize UPF1. The suppression of UPF1 expression suggested a role for NMD in IMT, and increased levels of endogenous NMD substrates were observed in IMT tissue compared with normal tissue from the same patient. Further, expression of NIK, a proinflammatory activator of NF-κB, was increased in UPF1-mutant IMT, and NIK was demonstrated to be an NMD substrate. NF-κB activation results in generation of chemokines, and, consistent with UPF1-mediated upregulation of NIK, UPF1 depletion increased the levels of chemokines including IL8, CCL20, and CXCL1. Altogether, these data are consistent with a model in which NMD normally destabilizes NIK to suppress the chemokine response, and mutations in UPF1 increase NIK and NF-κB–induced chemokine expression, promoting immune cell infiltration and IMT. Moreover, these data suggest that UPF1 mutations may serve as IMT diagnostic biomarkers and that therapies directed at restoring NMD might be beneficial in patients with IMT.

Lu J, Plank TD, Su F, Shi X, Liu C, Ji Y, et al. The nonsense-mediated RNA decay pathway is disrupted in inflammatory myofibroblastic tumors. J Clin Invest 2016 Jun 27 [Epub ahead of print].

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.