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Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression

Author

Listed:
  • Fuping Wen

    (Tongji University School of Medicine)

  • Yi Han

    (Tongji University School of Medicine)

  • Hui Zhang

    (Fudan University)

  • Zhangting Zhao

    (Tongji University School of Medicine)

  • Wenjia Wang

    (Fudan University)

  • Fan Chen

    (University of Chinese Academy of Sciences)

  • Weimin Qin

    (Fudan University)

  • Junyi Ju

    (Tongji University School of Medicine)

  • Liwei An

    (Tongji University School of Medicine)

  • Yan Meng

    (Tongji University School of Medicine)

  • Jie Yang

    (Fudan University)

  • Yang Tang

    (Tongji University School of Medicine)

  • Yun Zhao

    (University of Chinese Academy of Sciences)

  • Huanhu Zhang

    (Shanxi Cancer Hospital)

  • Feng Li

    (Shanxi Cancer Hospital)

  • Wenqi Bai

    (Shanxi Cancer Hospital)

  • Yuanzhi Xu

    (Tongji University School of Medicine)

  • Zhaocai Zhou

    (Fudan University
    Nanjing Medical University)

  • Shi Jiao

    (Fudan University)

Abstract

Extracellular vesicles (EVs) are known to mediate cell communications and shape tumor microenvironment. Compared to the well-studied small EVs, the function of large microvesicles (MVs) during tumorigenesis is poorly understood. Here we show the proteome of MVs in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), and identify olfactomedin 4 (OLFM4) is induced by EBV infection and secreted via MVs to promote tumor progression through Hippo signaling. Specifically, OLFM4 is a target gene of the cGAS-STING pathway, and EBV infection activates cGAS-STING pathway and increases OLFM4 expression. Moreover, MV-carried OLFM4 binds with the extracellular cadherin domain of FAT1, thereby impairing its intracellular interaction with MST1 and leading to YAP activation in recipient cells. Together, our study not only reveals a regulatory mechanism though which viral infection is coupled via MVs with intercellular control of the Hippo signaling, but also highlights the OLFM4-Hippo axis as a therapeutic target for EBV-associated cancers.

Suggested Citation

  • Fuping Wen & Yi Han & Hui Zhang & Zhangting Zhao & Wenjia Wang & Fan Chen & Weimin Qin & Junyi Ju & Liwei An & Yan Meng & Jie Yang & Yang Tang & Yun Zhao & Huanhu Zhang & Feng Li & Wenqi Bai & Yuanzhi, 2024. "Epstein-Barr virus infection upregulates extracellular OLFM4 to activate YAP signaling during gastric cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54850-6
    DOI: 10.1038/s41467-024-54850-6
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