IL-8 drives EMT and malignant progression in chronic obstructive pulmonary disease-associated lung cancer via STAT3 signaling

Chronic obstructive pulmonary disease (COPD) increases the risk of lung cancer (LC), but the underlying mechanisms remain unclear. Interleukin-8 (IL-8), a proinflammatory cytokine, has been implicated in tumor progression and epithelial–mesenchymal transition (EMT). This study explored how IL-8 contributes to COPD-associated LC progression. A COPD-like microenvironment was established using cigarette smoke extract (CSE)-exposed HBEC3-KT bronchial epithelial cells co-cultured with A549 or 95D LC cells. IL-8 expression was assessed by qRT-PCR, ELISA, and Western blotting. Gain- and loss-of-function experiments were conducted to examine IL-8’s effects on migration, invasion, and EMT markers. STAT3 signaling involvement was evaluated using the inhibitor Stattic. Conditioned medium from CSE-treated HBEC3-KT cells was applied for functional verification. Immunohistochemical analysis of LC tissues from patients with and without COPD validated clinical relevance. IL-8 expression was markedly elevated in CSE-treated and co-culture systems, peaking in co-cultured cells. IL-8 overexpression enhanced, whereas silencing attenuated, the migratory, invasive, and EMT phenotypes of A549 and 95D cells. Mechanistically, IL-8 activated STAT3 phosphorylation, and inhibition of STAT3 abolished IL-8–induced EMT. Conditioned medium from CSE-treated epithelial cells promoted EMT and invasiveness, effects reversed by IL-8 depletion. Clinically, COPD-related LC tissues exhibited increased IL-8 and N-cadherin, alongside reduced E-cadherin expression. IL-8 acts as a critical mediator connecting COPD-associated inflammation to EMT and tumor aggressiveness via STAT3 activation. Therapeutically targeting IL-8 signaling may offer new strategies for managing COPD-related LC.