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

Sep 21, 2026

Uploaded by Theodore

N-glycosylated interleukin-6 (IL6), especially at Asn73, promotes JAK-STAT3 signaling by prolonging STAT3 phosphorylation in lung cancer. In contrast, N-glycosylation–defective IL6 (deNG-IL6) shortens STAT3 activation and shifts downstream signaling toward the SRC-YAP-SOX2 axis, triggering EMT and migration in vitro and metastasis in vivo. Targeted inhibitors and shRNAs against SRC, YAP, and SOX2 suppress these effects. Osimertinib-resistant cells release abundant deNG-IL6 via reduced N-glycosyltransferase gene expression, activating SRC-YAP and contributing to drug resistance, supported by transcriptome analyses and patient specimen signals.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages24

Reading Time1 h 0 min

AccessFree to download

Background

IL6-GP130-JAK-STAT3 signaling in lung cancer

EGFR-TKI therapy and mechanisms of acquired resistance

Lineage plasticity and IL6-related pathways

Key findings

N-glycosylated IL6 prolongs STAT3 phosphorylation

deNG-IL6 reprograms signaling to SRC-YAP-SOX2

EMT, migration, metastasis, and inhibition by SRC/YAP/SOX2 targeting

Article [https://doi.org/10.1038/s41467-024-51831-7](https://doi.org/10.1038/s41467-024-51831-7) Defective N-glycosylation ofIL6 induces metastasis and tyrosine kinase inhibitor resistance in lung cancer Received: 25 October 2021 Accepted: 19 August 2024 | Published online: 09 September 2024 | | --- | | Check for updates | Chun-Hua Hung 1,2,3,4, Shang-Yin Wu 1,5, Cheng-I Daniel Yao 6, Hsuan-Heng Yeh2, Chien-Chung Lin5,7,8, Chang-Yao Chu9, Tzu-Yu Huang10, Meng-Ru Shen 11,12, Chun-Hung Lin 6,13 & Wu-Chou Su 1,2,3,5,10 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-glycosylationdefective 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. Interleukin-6 (IL6) is produced by both cancerous and noncancerous human cells and binds to IL6-receptor alpha (IL6Rα, also known as GP80). The IL6-IL6Rα complex then associates with coreceptor GP130, primarily triggering the GP130-JAK-STAT3 signaling1–3 axis to regulate immune responses and cancer pathogenesis4–7. In non-small cell lung cancer (NSCLC), an increase in circulating IL6 is associated with poor survival of patients, and autocrine IL6-mediated GP130-JAK-STAT3 signaling is positively correlated with tumor progression, apoptotic resistance, and drug resistance8–10. In addition to JAK-STAT3, IL6 activates the ERK, AKT, and SRC-YAP pathways via GP130 to regulate diverse biological processes1,11,12. 1Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 2Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan. 3Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 4Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan, Taiwan. 5Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 6Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan. 7Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 8Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 9Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 10Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 11Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 12Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 13Department of Chemistry and Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan. e-mail: [sunnysu@mail. ncku.edu.tw](sunnysu@mail. ncku.edu.tw) Targeted therapy using e

FAQs

How does N-glycosylated IL6 influence STAT3 signaling in lung cancer?

N-glycosylated IL6, particularly at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation.

What signaling changes occur when IL6 lacks N-glycosylation?

N-glycosylation–defective IL6 shortens STAT3 activation and shifts downstream preference to the SRC-YAP-SOX2 axis.

How does deNG-IL6 contribute to osimertinib resistance?

Osimertinib-resistant cells secrete deNG-IL6 due to reduced N-glycosyltransferase expression, leading to strong SRC-YAP activation and supporting drug resistance, corroborated by transcriptome and patient specimen analyses.

Sep 21, 2026

Uploaded by Theodore