N-Glycosylation-Defective IL6 Alternatively Activates the SRC-YAP-SOX2 Axis to Drive Metastasis and EGFR TKI Resistance

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 found 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 induced EMT and migration in vitro and metastasis in vivo, which were suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secreted 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Cheng-I Daniel Yao  

LAB HEAD: Chun-Hung Lin

PROVIDER: PXD051771 | Pride | 2025-01-18

REPOSITORIES: Pride