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Defective N-glycosylation of IL6 induces metastasis and tyrosine kinase inhibitor resistance in lung cancer

Author

Listed:
  • Chun-Hua Hung

    (National Cheng Kung University
    National Cheng Kung University
    National Cheng Kung University
    National Cheng Kung University)

  • Shang-Yin Wu

    (National Cheng Kung University
    National Cheng Kung University)

  • Cheng-I Daniel Yao

    (Academia Sinica)

  • Hsuan-Heng Yeh

    (National Cheng Kung University)

  • Chien-Chung Lin

    (National Cheng Kung University
    National Cheng Kung University
    National Cheng Kung University)

  • Chang-Yao Chu

    (National Cheng Kung University)

  • Tzu-Yu Huang

    (National Cheng Kung University)

  • Meng-Ru Shen

    (National Cheng Kung University
    National Cheng Kung University)

  • Chun-Hung Lin

    (Academia Sinica
    National Taiwan University)

  • Wu-Chou Su

    (National Cheng Kung University
    National Cheng Kung University
    National Cheng Kung University
    National Cheng Kung University)

Abstract

The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein find that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induces epithelial-mesenchymal transition (EMT) and migration in vitro and metastasis in vivo, which are suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secrete a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution.

Suggested Citation

  • Chun-Hua Hung & Shang-Yin Wu & Cheng-I Daniel Yao & Hsuan-Heng Yeh & Chien-Chung Lin & Chang-Yao Chu & Tzu-Yu Huang & Meng-Ru Shen & Chun-Hung Lin & Wu-Chou Su, 2024. "Defective N-glycosylation of IL6 induces metastasis and tyrosine kinase inhibitor resistance in lung cancer," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51831-7
    DOI: 10.1038/s41467-024-51831-7
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