环境致癌物二羟环氧苯并[α]芘诱导支气管上皮细胞恶性转化的机制  

Mechanism of Malignant Transformation in Bronchial Epithelial Cells Induced by The Environmental Carcinogen B[α]PDE

作　　者：尹张雅 李聪亚 竹俊兰 YIN Zhang-Ya;LI Cong-Ya;ZHU Jun-Lan(Health Science Center,Ningbo University,Ningbo 315211,China;The Precision Medicine Laboratory,Ningbo Beilun District People’s Hospital,Ningbo 315800,China;Department of Laboratory Medicine,Linhai Second People’s Hospital,Taizhou 317016,China)

机构地区：[1]宁波大学医学部,宁波315211 [2]宁波市北仑区人民医院精准医学研究中心,宁波315800 [3]临海市第二人民医院检验科,台州317016

出　　处：《生物化学与生物物理进展》2024年第12期3207-3223,共17页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(82103872);宁波市自然科学基金(2023J026)资助项目。

摘　　要：苯并[α]芘(benzo[α]pyrene, B[α]P)是一种常见的环境致癌物,主要来源于工业生产和生活过程中煤炭、石油和天然气等燃料不完全燃烧产生的烟气等,其在体内经过一系列代谢反应,最终生成活性代谢物二羟环氧苯并[α]芘(B[α]PDE)从而发挥强致癌作用。B[α]PDE与DNA碱基共价结合形成B[α]PDE-DNA加合物,引起DNA碱基突变,诱导支气管上皮细胞恶性转化,最终形成肿瘤。B[α]PDE亦可通过激活相关信号转导通路调控原癌基因、抑癌基因的表达或沉默,干扰DNA修复功能,导致细胞代谢及细胞周期紊乱从而诱导肺癌的发生发展。B[α]PDE也可以通过组蛋白修饰、DNA甲基化、mi RNA、多聚ADP核糖甘油水解酶、代谢重编程、lnc RNA等表观遗传变异来诱导支气管上皮细胞恶性转化。深入研究B[α]PDE诱导支气管上皮细胞恶性转化的机制,可以为潜在的抗肿瘤药物研发靶点研究提供理论依据,有利于指导污染环境及烟雾环境暴露下肺癌的防治措施,也为禁烟控烟的健康中国措施提供理论支持。Benzo[a]pyrene(B[α]P)is a common environmental carcinogen,mainly from the smoke generated by the incomplete combustion of coal,oil and natural gas in the industrial production and living process,which undergoes a series of metabolic reactions in vivo,and ultimately generates the active metabolite,benzopyrene dihydroxy epoxide(B[α]PDE)to exert a strong carcinogenic effect.In this paper,we provide an overview of the mechanisms involved in the malignant transformation of bronchial epithelial cells induced by B[α]PDE in terms of DNA base mutations,DNA repair function,related signaling pathways and epigenetic variations.B[α]PDE covalently binds to DNA bases to form B[α]PDE-DNA adducts,which cause DNA base mutations,inducing malignant transformation of bronchial epithelial cells and ultimate tumor formation.Interestingly,it was found that B[α]PDE-DNA adducts showed a high GC-dependent distribution and the single-nucleotide resolution profile of DNA damage profile was highly similar to that of mutations previously identified in the lung cancer genomes of smokers.B[α]PDE can also regulate the expression or silencing of proto-oncogenes and oncogenes by activating the classical AhR signaling pathway,as well as the PI3K/AKT/mTOR and NF-κB signaling pathways,inducing epithelial-mesenchymal transition(EMT)in bronchial epithelial cells,and interfering with cellular metabolism and the cell cycle,thereby inducing the development of lung cancer.The genes mutated in B[α]PDE-induced malignant transformation of bronchial epithelial cells include the proto-oncogenes RAS,KIF11,and PPP1R13L as well as the oncogenes PHLPP2 and p53.B[α]PDE exposure leads to single nucleotide polymorphisms in the 3'-UTR of DNA repair enzyme gene,which inhibits the transcription of genes encoding proteins related to DNA damage repair,and subsequently affects the cell cycle,proliferation,and apoptosis of tumor cells.B[α]PDE exposure can induce lung carcinogenesis and progression by inducing hypomethylation of specific gene promoter regions to act

关 键 词：B[α]PDE 支气管上皮细胞 恶性转化 肺癌 表观遗传变异 

分 类 号：Q26[生物学—细胞生物学] R73[医药卫生—肿瘤]