The Role of HGF/c-Met/PI3K/AKT Pathway Regulated by α7-nAChR/β2-AR in Nicotine-Promoted Malignant Progression of Nonsmall Cell Lung Cancer A549 Cells

As the most frequently occurring cancer worldwide, lung cancer is notoriously diagnosed at advanced stages, resulting in high mortality rates. The primary factor underlying this persistent global health burden remains tobacco consumption. Nicotine, a key component of cigarette smoke, is one of the major contributing factors to the development of lung cancer, but the molecular mechanisms remain incompletely elucidated. α7-nAChR, β2-AR, and HGF/c-Met are known to contribute to lung cancer development, respectively. However, the specific signaling cascade through which they interact in nicotine-induced malignancy is unclear. In this study, using CCK-8 assays across a range of concentrations (0–5 μM), we determined that 1 μM nicotine treatment for 48 h optimally enhances A549 cell proliferation, establishing this condition for subsequent experiments. This study uncovers nicotine’s role in driving malignant behaviors including proliferation, migration, and invasion in nonsmall cell lung cancer A549 cells. Notably, nicotine potently stimulated migration and invasion, accompanied by upregulation of Cyclin D1 and MMP-2, and downregulation of BAX, BAD, and Caspase-3. Mechanistically, nicotine induced synergistic engagement of α7-nAChR and β2-AR, leading to activation of the HGF/c-Met/PI3K/AKT axis and enhancing the secretion of both HGF and MMP-2. Importantly, we reveal a previously unrecognized bidirectional regulatory loop between α7-nAChR and β2-AR that functionally converges on the HGF/c-Met axis, which acts as a critical signaling hub to drive the downstream PI3K/AKT pathway and facilitate tumor progression. Our findings provide the first evidence of a coordinated α7-nAChR/β2-AR interface regulating HGF/c-Met signaling that orchestrates both intracellular signaling and extracellular secretory programs in nicotine-promoted lung cancer progression. This offers innovative insights for identifying potential antitumor therapeutic targets and presents novel perspectives for the prevention and clinical management of lung cancer, particularly in smokers with nonsmall cell lung cancer.