慢性镉胁迫诱导机体肝癌发生的DNA甲基化修饰效应

Regional metal exposure is taken for a vital cue for tumorigenesis. In the preliminary study we mainly analysed the effects of endogenous genes on liver tumorigenesis in Baiyin reach of Yellow river. Etiologically, tumorigenesis mainly related to exogenetic genovariation induced by environmental hazards. It's the hot topic to study exogenetic genovariation in animal and human body induced by long-term and low dose of cadmium stress. Current studies were mainly restricted to genotoxicity of cadmium, the role of epigenetic genes and miRNA induced by cadmium in tumorigenesis was unfortunately poorly emphasized, which is also the defect in our preliminary study. To deeply analyse the exogenetic molecular pattern of liver tumorigenesis induced by chronic Cd exposure, the roles of DNA methylation modification will be studied. Firstly, the mutagenicity and oncogenicity of cadmium exposure in liver tumorigenesis were explored in models of animal and liver cell lines stressed by Cd. Finally, the selected markers were validated by local people stressed by long-term and low dose of cadmium for conforming the early biomarkers to liver tumorigenesis. It may be beneficial to health risk assessment of local people suffering cadmium exposure.

区域性长期低剂量镉暴露常与肿瘤等多种疾病发生密切相关。本课题组前期研究主要针对黄河白银段镉暴露与肝癌发生的关系及引起内源性基因改变的部分特性进行研究。但肿瘤的发生尤其是肝细胞肝癌的发生从病因学分析，主要与周围环境的有害物质（重金属、病毒）的长期暴露密切相关，其中长期低剂量镉暴露引起机体的毒理作用备受关注并成为罪魁祸首。目前国内外研究多局限于镉暴露的遗传毒性，对其诱导肝癌发生的表观遗传修饰效应研究尚未深入，这也是我们前期研究的局限性所在。为深入探索慢性镉胁迫与肝癌发生的关系及外源性特性，本项目拟从DNA甲基化修饰效应入手，建立动物及细胞慢性镉胁迫模型，研究慢性镉胁迫与肝癌发生的关系；通过DNA甲基化检测及甲基化芯片筛选出特异性强的甲基化修饰基因，并在慢性镉胁迫区域人群中验证筛选出的基因在肝癌发生中的机制，阐明慢性镉胁迫可能诱导肝癌发生的表观遗传修饰效应，为区域性肝癌高危人群的防治奠定基础。

重金属Cd 被列为一级环境致癌物，长期低剂量Cd 暴露常与肿瘤等多种疾病发生密切相关。国内外研究多局限于Cd 暴露的遗传毒性，本项目对其诱导肝癌发生的表观遗传修饰效应进行深入探讨，分析DNA甲基化在Cd 诱导肝癌发生过程中的重要作用。通过慢性Cd 胁迫区域人群调查，发现Cd 暴露增加了远期发生肝脏疾病的风险；通过建立动物慢性Cd 胁迫模型，研究慢性Cd 胁迫与肝癌发生的关系，利用全基因组甲基化检测及转录组测序，发现脂质稳态在其中发挥重要作用，同时肝癌发生相关信号通路（PI3K/AKT、MAPK、RAS 信号通路）也出现了差异的DNA甲基化修饰效应；通过建立慢性Cd 胁迫细胞模型对筛选到慢性 Cd 胁迫诱导肝癌发生相关的特异性 DNA 甲基化修饰基因进行分子水平验证。阐明DNA甲基化在慢性Cd 胁迫诱导肝癌潜在机制，为区域性Cd 暴露人群肝病和肿瘤的防治奠定了基础。