Cigarette Smoking-Regulated PRKCE Is Involved in Bladder Cancer Susceptibility through cGMP/PKG-Dependent Glycolysis

The mechanism by which cigarette smoking affects bladder cancer susceptibility via glucose metabolism remains unclear. We identified bladder cancer-specific glucose metabolism-related genes (GMGs) using Molecular Signatures Database (MSigDB) and a case-control study (580 cases and 1,101 controls) through genetic association and interaction analyses with cigarette smoking. Among 811 GMGs, we observed that PRKCE rs4953292 G > A was significantly associated with increased bladder cancer risk [odds ratio (OR) = 1.19, 95% confidence interval (CI): 1.03-1.37, P _adj = 1.87 × 10^-2] and exhibited an interaction effect with cigarette smoking (P _interaction < 0.05). Smokers with rs4953292 A allele had higher bladder cancer risk than nonsmokers with G allele (P _trend < 9.09 × 10^-3). We performed functional experiments using 4-aminobiphenyl (4-ABP)-treated bladder cancer cells and found that the rs4953292 A allele combined with 4-ABP decreased PRKCE expression levels in bladder cancer cells, which could upregulate PKG and phosphorylate VASP within the cGMP-PKG signaling pathway, enhance glucose uptake, lactate generation, and extracellular acidification rate (ECAR) to reprogram glycolysis, thus promoting bladder cancer susceptibility. This study elucidates that cigarette smoking-regulated PRKCE facilitates bladder cancer susceptibility by mediating glycolytic reprogramming through activating the cGMP-PKG signaling pathway. The findings provide valuable predictors for bladder cancer susceptibility, aiding in prevention strategies.