Comparative Effects of Cigarette Smoke and E-Cigarette Vapor on Oral Squamous Cell Carcinoma: Unraveling Distinct Molecular Pathways

Oral squamous cell carcinoma (OSCC) poses a significant global health burden, driven by cigarette smoking and complicated by the rising popularity of e-cigarettes. This study compares the effects of cigarette smoke extract (CSE) and e-cigarette vapor extract (EVE) on OSCC progression using Ca9-22 gingival OSCC cells. CSE significantly increased cell invasion by upregulating the receptor for advanced glycation end-products (RAGE), nuclear factor kappa B (NF-κB), and matrix metalloproteinases (MMP-9, MMP-13), facilitating extracellular matrix degradation and metastasis. Conversely, the effects of EVE varied by flavor and nicotine content. Red Hot EVE (cinnamaldehyde-based) enhanced invasion and NF-κB levels with nicotine while reducing MMP-9 expression, suggesting alternative invasion pathways via MMP-13. Green Apple EVE had a less pronounced impact, indicating flavor-specific bioactivity. These findings reveal distinct mechanisms: CSE drives RAGE-NF-κB-MMP-mediated invasion, whereas EVE elicits variable, flavor-dependent responses, potentially involving nicotinic acetylcholine receptors. Targeted therapies, such as RAGE or NF-κB inhibitors, could mitigate tobacco-related OSCC progression. With e-cigarette use surging among youth, stricter regulations on flavored products and robust public health campaigns are urgently needed. Future research should investigate chronic exposures and diverse OSCC models to refine clinical and regulatory approaches, addressing the evolving landscape of tobacco-related oral cancers.