Interactions between polycyclic aromatic hydrocarbons and genetic variants in the cGAS–STING pathway affect the risk of colorectal cancer

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-09-17 DOI:10.1007/s00204-024-03862-8
Jieyu Zhou, Dongzheng Li, Menghuan Xu, Tianru Zhu, Zhengyi Li, Zan Fu, Meilin Wang, Shuwei Li, Dongying Gu
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Abstract

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.

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多环芳烃与 cGAS-STING 通路中的遗传变异之间的相互作用会影响罹患结直肠癌的风险
cGAS-STING 通路在激活肿瘤免疫细胞方面起着至关重要的作用。多环芳烃(PAHs)是具有潜在致癌性的环境污染物,暴露于这种物质与结直肠癌的发生有关。然而,cGAS-STING 通路中的遗传因素以及基因与环境的相互作用对结直肠癌的影响仍未得到充分研究。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和基因-环境交互作用的影响。我们根据 RNA-seq 数据分析了候选基因的表达模式。我们进行了分子生物学实验,研究多环芳烃暴露对候选基因表达和结直肠癌进展的影响。我们在 cGAS-STING 通路中发现了与结直肠癌风险相关的易感位点 rs3750511。我们还发现 TRAF2 rs3750511 与多环芳烃暴露之间存在负交互作用。单细胞RNA-seq分析显示,与正常组织相比,TRAF2在结直肠癌组织中的表达明显升高,尤其是在T细胞中。暴露于 BPDE 会增加 TRAF2 的表达和结直肠癌细胞的恶性表型。处理还进一步增加了 TRAF2 下游基因 NF-κB 的表达,降低了 Caspase8 的表达。我们的研究结果表明,rs3750511 基因变异会影响 TRAF2 的表达,从而通过与多环芳烃的相互作用增加罹患结直肠癌的风险。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。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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