ABSTRACT Lung cancer is among the most common malignancies globally, exhibiting the greatest rates of incidence and death compared to all other cancers. Cigarette smoking is a significant causal factor in lung cancer; yet the molecular mechanisms via which smoking facilitates lung cancer development remain mainly ambiguous. In this study, we used different concentrations of cigarette smoke extract (CSE) to A549 cells. Compared with the control group, the total STAT3 expression remained basically unchanged. However, we found that phosphorylated STAT3 (p‐STAT3), interleukin‐9 (IL‐9), and miR‐155‐5p all increased obviously, while the expression of suppressor of cytokine signaling 1 (SOCS1) decreased greatly. Moreover, the epithelial marker E‐cadherin was downregulated, while the mesenchymal markers Vimentin and α‐SMA were upregulated, indicating the induction of epithelial‐mesenchymal transition (EMT). Interventions with STAT3 siRNA, a miR‐155‐5p inhibitor, or a SOCS1 overexpression plasmid reversed these changes. Similarly, co‐treatment with an IL‐9‐neutralizing antibody attenuated CSE‐induced alterations in p‐STAT3, SOCS1, miR‐155‐5p, and EMT markers. In a nude mouse xenograft model, CSE exposure significantly enhanced tumor growth and EMT phenotypes, whereas IL‐9 neutralization reduced tumorigenicity of CSE‐treated A549 cells. Collectively, these findings demonstrate that cigarette smoke promotes lung cancer progression by inducing EMT through the IL‐9‐regulated STAT3/miR‐155‐5p/SOCS1 feedback loop, providing novel mechanistic insight and potential therapeutic targets for smoking‐related lung cancer.
Li et al. (Fri,) studied this question.