circRNA在苯并(a)芘诱导肺癌变发生中的作用及其机制

Epigenetic changes, including altered expression of non-coding RNA, are important mechanisms for environmental chemical carcinogenesis. Our previous research studied the mechanisms of microRNA (miRNA) and long non-coding RNA in chemical carcinogenesis , and we have published 26 relative SCI papers. The function of circular non-coding RNA (circRNA) and its role in miRNA regulation were firstly reported in the Nature in 2013, providing novel insights on the understanding of circRNAs. At present, circRNA in field of toxicology and tumor biology remains unreported. We previously found the aberrant expressions of circRNAs in malignant transformation cells and cancer tissues. Moreover, we also found an interaction exists between several circRNAs and benzo(a)pyrene-induced carcinogenesis related miRNAs. In this project, the co-expression of circRNA and miRNA will be detected in low dose benzo(a)pyrene-induced malignant transformation cell model and carcinogenesis animal model. The bioinformatics analysis assay will be performed to analyze the interaction between circRNAs and miRNAs. The RNAi, gene overexpression and reporter gene expression assays are performed to establish functional research system. Based on these, we aim to systematically identify and validate chemical carcinogenesis related circRNAs and investigate their function. Then we will further investigate their negative regulation role in miRNA. By performing this project, we expect to elucidate the function and mechanism of circRNA in chemical carcinogenesis, which would provide novel biomarkers for cancer early diagnosis and screening, and therapeutic targets for cancer treatment.

包括非编码RNA在内的表观遗传学改变是环境化学致癌重要机制。本课题组对化学致癌小分子(miRNA)和长链非编码RNA等线性RNA机制进行了系列探索，发表SCI论文26篇。2013年Nature杂志首次报道环状非编码RNA(circRNA)功能及其与miRNA作用，刷新了对环状RNA认知。目前毒理学及肿瘤功能学领域无circRNA研究报道。我们前期发现癌变细胞及组织circRNA表达改变，以及苯并(a)芘致癌相关miRNA与circRNA有关联。本项目拟以低剂量苯并(a)芘诱导细胞恶变和肺癌模型，进行circRNA与miRNA共表达检测及相互作用生物信息学分析，以RNAi、过表达和报告基因等技术，建立功能研究体系，筛选癌变相关circRNA及鉴定其功能，并探索对miRNA的负向调控。本项目将揭示环状RNA在化学致癌中作用与机制，同时为肿瘤早期诊断、筛查和治疗提供潜在新标志物和靶点。

本项目以苯并(a)芘诱导建立人支气管上皮细胞恶变模型，进行了环状非编码RNA(circRNA)与微小RNA（miRNA）共表达检测及相互作用的生物信息学分析，以RNA干扰、过表达和报告基因等技术，建立了功能研究体系，筛选了与肺细胞恶变和肺癌变相关的circRNA，鉴定了它们的功能，并探索了circRNA对miRNA的负向调控机制。本研究已按计划目标完成，找到了circ0006916、circNOL10、circRNA100146及circRNA104250等几种与化学致癌物致支气管细胞恶变及肺癌发生有关、具有功能意义的circRNA，鉴定出了miR-522-3p、miR-361-3p、miR-615-5p等几个circRNA调控的miRNA，系统阐明了circRNA在化学物致癌中的作用与机制，为环境化学暴露致癌的风险评估和危险人群筛查及肺癌的分子治疗，提供了新的分子靶点。研究内容发表SCI论文6篇，其中影响因子10以上2篇。课题研究相关内容与之前课题一起，汇集的成果“化学致癌的非编码RNA机制研究”，获2019国家教育部高等学校科学研究优秀成果奖（科学技术）自然科学奖二等奖。课题负责人就本项目研究内容，应邀在中国毒理学大会等全国学术大会上作多次报告。课题负责人获2019年中国毒理学杰出贡献奖。本项目培养博士硕士研究生6人，多位研究生在全国学术会议上获优秀论文奖。