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Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15

Author

Listed:
  • Huiyuan Zhu

    (Tongji University School of Medicine)

  • Man Li

    (Tongji University School of Medicine)

  • Dexi Bi

    (Tongji University School of Medicine)

  • Huiqiong Yang

    (Tongji University School of Medicine)

  • Yaohui Gao

    (Tongji University School of Medicine)

  • Feifei Song

    (Tongji University School of Medicine)

  • Jiayi Zheng

    (Tongji University School of Medicine)

  • Ruting Xie

    (Tongji University School of Medicine)

  • Youhua Zhang

    (Tongji University School of Medicine)

  • Hu Liu

    (Tongji University School of Medicine)

  • Xuebing Yan

    (Yangzhou University Medical College Affiliated Hospital)

  • Cheng Kong

    (Fudan University Shanghai Cancer Center)

  • Yefei Zhu

    (Tongji University School of Medicine)

  • Qian Xu

    (Tongji University School of Medicine)

  • Qing Wei

    (Tongji University School of Medicine)

  • Huanlong Qin

    (Tongji University School of Medicine
    Tongji University School of Medicine)

Abstract

Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues and contributes to colorectal tumorigenesis in Villin-Cre/KrasG12D+/- mice. Additionally, Parabacteroides distasonis (P. distasonis) competes with F. nucleatum in the G12D mouse model and human CRC tissues with the KRAS mutation. Orally gavaged P. distasonis in mice alleviates the F. nucleatum-dependent CRC progression. F. nucleatum invades intestinal epithelial cells and binds to DHX15, a protein of RNA helicase family expressed on CRC tumor cells, mechanistically involving ERK/STAT3 signaling. Knock out of Dhx15 in Villin-Cre/KrasG12D+/- mice attenuates the CRC phenotype. These findings reveal that the oncogenic effect of F. nucleatum depends on somatic genetics and gut microbial ecology and indicate that personalized modulation of the gut microbiota may provide a more targeted strategy for CRC treatment.

Suggested Citation

  • Huiyuan Zhu & Man Li & Dexi Bi & Huiqiong Yang & Yaohui Gao & Feifei Song & Jiayi Zheng & Ruting Xie & Youhua Zhang & Hu Liu & Xuebing Yan & Cheng Kong & Yefei Zhu & Qian Xu & Qing Wei & Huanlong Qin, 2024. "Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45572-w
    DOI: 10.1038/s41467-024-45572-w
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