CYP2A13 upregulation contributes to lung tumorigenesis upon NNK exposure

Lung cancer remains one of the most prevalent and deadly malignant neoplasms worldwide, with smoking being a primary risk factor. Among the numerous carcinogens in tobacco smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent. The carcinogenic effects of NNK are believed to be mediated through its metabolic activation by CYP2A13 in the lungs, leading to DNA adduct formation and subsequently lung cancer development. However, whether NNK exerts its carcinogenic effects by upregulating CYP2A13 expression and the mechanisms by which NNK upregulates CYP2A13 remain unclear. In this study, we demonstrated that CYP2A13 was overexpressed in human lung adenocarcinoma and NNK exposure significantly upregulated the expression of CYP2A13 in bronchial epithelial cells. Mechanistically, NNK exposure enhanced both transcription and stabilization of CYP2A13 mRNA. Further exploration showed that elevated transcription of CYP2A13 was mediated by the activation of the p-PP2A-C/p-JNK/p-c-Jun signaling axis, while CYP2A13 mRNA stability was driven through the S6/TRIM25/Dicer/miR-7108-3p axis. These findings not only provide critical insights into the mechanisms underlying NNK-induced lung carcinogenesis, but also identify potential therapeutic targets, including PP2A, TRIM25, and miR-7108-3p, for further exploration.