Editors' ChoiceCancer

Messaging with naked RNA

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Sci. Signal.  01 Aug 2017:
Vol. 10, Issue 490, eaao5132
DOI: 10.1126/scisignal.aao5132

Activated stromal cells release an unshielded RNA in exosomes that induces interferon-stimulated gene expression in breast cancer cells and tumor growth.

Upon detection of cytoplasmic RNA with a feature characteristic of viral RNA, such as a 5′ triphosphate (PPP) end, RIG-I induces the expression of interferon-stimulated genes (ISGs). ISG expression also occurs in some breast tumors, generally in more aggressive triple-negative breast cancers (TNBCs) rather than in less aggressive ER-positive ones, and high ISG expression is correlated with relapse. Nabet et al. (see also Matei et al.) revealed that RIG-I–mediated ISG expression in breast cancer cells is triggered by a naked, noncoding RNA released in exosomes from activated stromal fibroblasts. The expression of NOTCH target genes, including that of MYC, was greater in fibroblast cell lines cocultured with ISG-expressing breast cancer cell lines than in those cocultured with non–ISG-expressing breast cancer cell lines. Myc directly binds to and enhances the transcriptional activity of RNA polymerase III (POL3). In activated stromal fibroblasts, Myc-stimulated POL3 generated RNS7SL1, a signal recognition particle RNA, with a 5′ PPP end. This noncoding RNA was produced in amounts that exceeded the binding capacity of the pool of RNA-binding proteins that normally shield it from detection by RIG-I. The unshielded RNS7SL1 was released from fibroblasts in exosomes and activated RIG-I in breast cancer cells. Injection of unshielded RNS7SL1 complexed with liposomes into breast cancer cell xenografts in mice enhanced tumor growth in a RIG-I–dependent manner. Furthermore, unshielded RNS7SL1 RNA was more abundant in serum exosomes from cancer patients than in those from normal volunteers and in those from patients with TNBC than in those from ER-positive breast cancer patients. Thus, breast cancer cells induce stromal fibroblasts to release an unshielded RNA in exosomes that acts as a danger-associated molecular pattern to activate RIG-I in breast cancer cells and trigger ISG expression that promotes tumor growth.

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