Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China.
Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
Arch Toxicol. 2024 Dec;98(12):4117-4129. doi: 10.1007/s00204-024-03862-8. Epub 2024 Sep 17.
The cGAS-STING pathway plays an essential role in the activation of tumor immune cells. Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants with potential carcinogenicity, and their exposure is associated with the development of colorectal cancer. However, the impacts of genetic factors in the cGAS‒STING pathway and gene‒environment interactions on colorectal cancer remain understudied. We used logistic regression models and interaction analysis to evaluate the impact of genetic variants on colorectal cancer risk and gene‒environment interactions. We analysed the expression patterns of candidate genes based on the RNA-seq data. Molecular biology experiments were performed to investigate the impact of PAHs exposure on candidate gene expression and the progression of colorectal cancer. We identified the susceptibility locus rs3750511 in the cGAS‒STING pathway, which is associated with colorectal cancer risk. A negative interaction between TRAF2 rs3750511 and PAHs exposure was also identified. Single-cell RNA-seq analysis revealed significantly elevated expression of TRAF2 in colorectal cancer tissues compared with normal tissues, especially in T cells. BPDE exposure increased TRAF2 expression and the malignant phenotype of colorectal cancer cells. The treatment also further increased the expression of the TRAF2 downstream gene NF-κB and decreased the expression of Caspase8. Our results suggest that the genetic variant of rs3750511 affects the expression of TRAF2, thereby increasing the risk of colorectal cancer through interaction with PAHs. Our study provides new insights into the influence of gene‒environment interactions on the risk of developing colorectal cancer.
cGAS-STING 通路在肿瘤免疫细胞的激活中发挥着重要作用。多环芳烃（PAHs）是具有潜在致癌性的环境污染物，其暴露与结直肠癌的发生有关。然而，cGAS-STING 通路中的遗传因素和基因-环境相互作用对结直肠癌的影响仍研究不足。我们使用逻辑回归模型和交互分析来评估遗传变异对结直肠癌风险的影响和基因-环境相互作用。我们根据 RNA-seq 数据分析候选基因的表达模式。进行分子生物学实验，以研究 PAHs 暴露对候选基因表达和结直肠癌进展的影响。我们确定了 cGAS-STING 通路中的易感位点 rs3750511，它与结直肠癌风险相关。还发现了 TRAF2 rs3750511 与 PAHs 暴露之间的负交互作用。单细胞 RNA-seq 分析显示，与正常组织相比，结直肠癌组织中 TRAF2 的表达明显升高，尤其是在 T 细胞中。BPDE 暴露增加了 TRAF2 的表达和结直肠癌细胞的恶性表型。该处理还进一步增加了 TRAF2 下游基因 NF-κB 的表达，并降低了 Caspase8 的表达。我们的结果表明，rs3750511 的遗传变异影响 TRAF2 的表达，从而通过与 PAHs 的相互作用增加结直肠癌的风险。我们的研究为基因-环境相互作用对结直肠癌发病风险的影响提供了新的见解。
