| Autor: |
Zhou, Yi, Zhang, Yaxin, Li, Mingzhou, Ming, Tian, Zhang, Chao, Huang, Chengmei, Li, Jiexi, Li, Fengtian, Li, Huali, Zhao, Enen, Shu, Feng, Liu, Lingtao, Pan, Xingyan, Gao, Yijun, Tian, Lin, Song, Libing, Huang, Huilin, Liao, Wenting |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 100, p1-16, 16p |
| Abstrakt: |
The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating DExD/H-box helicase 6 (DDX60). DDX60 was identified as a KRAS target here and could bind to dsRNAs to protect against RNA-induced silencing complex (RISC)–mediated degradation. Overexpressing DDX60 induced dsRNA accumulation, reactivated IFN signaling, and increased CRC sensitivity to ICI therapy. Mechanistically, KRAS engaged the AKT (also known as protein kinase B)–GSK3β (glycogen synthase kinase-3 beta) pathway to suppress STAT3 phosphorylation, thereby inhibiting STAT3-driven DDX60 transcription. Our findings reveal a role for KRAS in dsRNA homeostasis, suggesting potential strategies to convert "cold" tumors to "hot" and to overcome ICI resistance in CRC with KRAS mutations. Editor's summary: Mutations in the KRAS (Kirsten rat sarcoma viral) oncogene have been linked to impaired IFN responses and limited efficacy of immune checkpoint inhibition (ICI) in colorectal cancer (CRC). Zhou et al. show that oncogenic KRAS promotes double-stranded RNA degradation in CRC cells, which inhibits RIG-I–like receptor (RLR)–mediated signaling, normally needed for antiviral responses and downstream IFN responses. The RNA binding protein DExD/H-box helicase 6 (DDX60) was shown to be suppressed by oncogenic KRAS via AKT-GSK3β-STAT3 signaling, but overexpression of DDX60 could overcome IFN inhibition by oncogenic KRAS by protecting dsRNA from degradation and could sensitize tumors to ICI. —Christiana Fogg [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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