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Cigarette smoke contains numerous toxic compounds that can induce oxidative stress and DNA damage. While smoking is a well-established driver of lung cancer initiation, the biological consequences of continued exposure after tumor establishment remain poorly understood. This study investigated the genomic and phenotypic effects of chronic cigarette smoke exposure in established lung cancer cells.

Human lung adenocarcinoma A549 cells were chronically exposed to cigarette smoke extract to model sustained exposure. Cellular proliferation and migration assays were performed to evaluate phenotypic changes. Transcriptomic profiling was used to examine alterations in gene expression related to cell cycle regulation and DNA repair pathways. Whole-genome sequencing was conducted to identify mutational signatures associated with genomic instability. Tumor growth and histological features were further evaluated using xenograft models.

Chronic cigarette smoke extract exposure increased the clonogenic capacity and migratory behavior of A549 cells and induced phenotypic features consistent with partial epithelial-mesenchymal transition. Transcriptomic analysis revealed disruption of cell cycle regulation and reduced expression of homologous recombination DNA repair genes, including RAD51. Whole-genome sequencing identified mutational signatures associated with oxidative damage, mismatch repair deficiency, and homologous recombination defects. These alterations were accompanied by increased tumor growth and cellular atypia in xenograft models.

Chronic cigarette smoke exposure may enhance genomic instability and promote aggressive phenotypes in established lung cancer cells, suggesting that continued smoking after cancer development may contribute to tumor progression.