Chronic Stress Promotes Lung Adenocarcinoma Progression via α5‐nAChR/FOXM1 Signaling Pathway

ABSTRACT

The α5‐nicotinic acetylcholine receptor (α5‐nAChR) mediates chronic stress‐induced lung adenocarcinoma (LUAD) progression. Forkhead Box M1 (FOXM1) is an oxidative stress‐associated protein that is strongly associated with chronic stress and functions as a cancer‐promoting transcription factor critical to LUAD. Our gene expression profiling demonstrated that CHRNA5 (encoding α5‐nAChR) knockdown suppresses FOXM1 levels. It remains unknown whether and how α5‐nAChR interacts with FOXM1 to promote chronic stress‐induced LUAD progression. In this study, the expression and correlation of α5‐nAChR and FOXM1 in LUAD of mice were investigated through chronic restraint stress (CRS). α5‐nAChR expression was related to FOXM1 expression, low survival rate, staging, and smoking status in both LUAD dataset and tissue microarrays. In vitro experiments demonstrated that α5‐nAChR mediates acetylcholine (ACh)‐induced FOXM1, Ki67, and Sox2 expression via STAT3. α5‐nAChR/FOXM1 signaling contributes to LUAD cell proliferation, migration, and invasion. Furthermore, α5‐nAChR expression was linked to FOXM1 expression in chronic unpredictable mild stress (CUMS) mice tissues. The findings suggested that α5‐nAChR/FOXM1 axis is involved in chronic stress‐promoted LUAD progression.