Gprc5a depletion enhances the risk of smoking-induced lung tumorigenesis and mortality

Abstract Aims Lung cancer remains the leading cause of cancer incidence and mortality. Although cigarette smoke is regarded as a high risk factor for lung tumor initiation, the role of the lung tumor suppressor GPRC5A in smoking-induced lung cancer is unclear. Main methods We obtained two lung cancer cohorts from the TCGA and GEO databases. Bioinformatics analysis showed differential gene expression in the cohorts. Quantitative real-time PCR, Western Blot and Gprc5a −/− mice uncovered the relationship between cigarette smoke and lung cancer in the GPRC5A deletion system in vitro and in vivo. Key findings Bioinformatics analysis showed that the smoking lung cancer patients with low expression of GPRC5A had poor overall survival compared to the patients with high GPRC5A expression. Further analysis revealed that cancer-related stemness pathways such as the Hippo signaling pathway were induced in smoking patients with low GPRC5A expression. Additionally, we detected enriched expression of WNT5A and DLX5 in normal human lung epithelial 16HBE cells and human lung cancer H1299 cells in vitro. A relationship between cigarette smoke extract (NNK) and lung tumor initiation was observed in Gprc5a −/− mice. Significance The lung tumor suppressor gene GPRC5A played a protective role in cigarette smoke-induced lung tumor initiation, providing a target for the prevention of lung cancer development and monitoring of prognosis.