微小RNA在化学致癌物生物转化中的功能

xenobiotic metabolism is an important step in the process of chemical carcinogenesis, but the detail molecular mechanism of that is still unclear. Under the support of last Natural Science Found of China, we have proved miRNAs are involed in the chemical carcinogenesis procedure,and suggested some miRNAs might influece this process by regulating the xenobiotic metabolism. Hence, we decide to use some canonical indirect carcinogens, such as Bap, AFB1 and NNK, to systematically investigate the effect of miRNAs on the biotransformation of these carcinogens in this study.Firstly, the time of the metabolites formation and the degree of genetic damage following the treatment of carcinogens with different doses to the cell models wil be observed and used as the evidences to decide the ultimate conditions of toxicant exposure. Subsequently, the mRNA and miRNA expression profiles will be detected by the technology of sequencing,then, the bioinformatics will be adopted to screen the candidate miRNAs for the functional research. Subsequently, the influence of miRNA in gene expression, enzymes activity, the formation of metabolites and DNA adducts, and DNA damage will be examined in cell models. Finally, the expression and the functional of these candidate miRNAs and their target genes will be confirmed in animal models and population with occuoational exposure. The results of this study can not only reveal the mechanism of miRNAs in xenobionetic metabolism, but also provide a theoretical evidence to that miRNAs can be used as an early biological effect marker in the biological monitoring and risk assessment of chemical carcinogenesis.

外源化学物质代谢活化是化学致癌过程的主要环节，但其分子机制尚未完全明确。在上一个国家自然基金的资助下，我们证实miRNAs参与了化学致癌过程，并推测部分miRNA可能通过影响化学物的代谢转化发挥作用。因此，本研究拟选择间接致癌物BaP，AFB1和NNK，系统的研究miRNAs对致癌物代谢转化的影响。我们将以代谢产物生成的时间和遗传损伤的程度作为染毒条件的选择标准，通过测序技术检测mRNA和miRNA表达谱，利用生物信息学和计算机组学筛选出与代谢相关的候选miRNAs和靶基因，在细胞模型中研究其对代谢相关基因的表达、代谢酶活性、代谢产物、DNA加合物生成和遗传损伤的影响，最后将确定的miRNAs及其靶基因在动物模型和职业暴露人群中验证。本研究结果不仅能揭示miRNAs对化学致癌物生物转化的调控机制，还能将miRNAs作为早期生物效应标志应用于化学致癌的生物监测和危险度评价提供理论依据。

外源化学物质代谢活化是化学致癌过程的主要环节。本研究利用高通量测序技术探讨了微小RNAs在调控致癌物苯并芘，黄曲霉毒素B1，二恶英和1,2-二氯乙烷(1,2-DCE) 代谢活化和发挥毒效应中的作用。结果发现 1. miR-203可以通过调控芳香烃受体AhR的蛋白表达，从而影响苯并芘和二恶英的代谢活化和毒作用效应。2. 黄曲霉毒素B1暴露能诱导肝细胞遗传损伤并激活大鼠肝脏中的p53信号通路和miR-34a-5p的表达升高，miR-34a-5p通过调控细胞周期相关蛋白的表达协助细胞对受损DNA进行修复；血浆中的miR-34a-5p可以作为肝脏遗传损伤的早期效应生物标志。3. 1,2-二氯乙烷染毒能诱导小鼠出现轻微的肝脏损伤并伴有严重的糖脂代谢异常，其作用机制是通过激活Akt信号通路后抑制肝糖原正常分解所造成的，miR-451a可能参与了1,2-DCE诱导的糖脂代谢异常。研究结果阐明了部分miRNAs对化学致癌物生物转化及毒作用效应的调控机制，也为将miRNAs作为早期生物效应标志应用于化学致癌的生物监测和危险度评价提供初步的实验数据。