2. Academic Validation
  3. Defective N-glycosylation of IL6 induces metastasis and tyrosine kinase inhibitor resistance in lung cancer

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

  • Nat Commun. 2024 Sep 9;15(1):7885. doi: 10.1038/s41467-024-51831-7.
Chun-Hua Hung 1 2 3 4,  Shang-Yin Wu 1 5,  Cheng-I Daniel Yao 6,  Hsuan-Heng Yeh 2,  Chien-Chung Lin 5 7 8,  Chang-Yao Chu 9,  Tzu-Yu Huang 10,  Meng-Ru Shen 11 12,  Chun-Hung Lin 6 13,  Wu-Chou Su 14 15 16 17 18
Affiliations

Affiliations

  • 1 Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 2 Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan.
  • 3 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 4 Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan, Taiwan.
  • 5 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 6 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
  • 7 Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 8 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 9 Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 10 Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 11 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 12 Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 13 Department of Chemistry and Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
  • 14 Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. sunnysu@mail.ncku.edu.tw.
  • 15 Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan. sunnysu@mail.ncku.edu.tw.
  • 16 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. sunnysu@mail.ncku.edu.tw.
  • 17 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. sunnysu@mail.ncku.edu.tw.
  • 18 Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. sunnysu@mail.ncku.edu.tw.
PMID: 39251588 DOI: 10.1038/s41467-024-51831-7
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.

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