启动子区-286位SNP突变调控C-反应蛋白基因转录的机制研究

The serum levels of C-reactive protein (CRP) is closely associated with the risk and prognosis of several types of cancers. However, it remains unclear whether CRP directly contributes to tumorigenesis or simply represents a bystander marker of the disease. Our recent work reveal a recurrent promoter mutation at the -286 SNP position of CRP gene in multiple human cancers. As this mutation is associated with enhanced induction of CRP in tumors, our results thus indicate that locally produced CRP, but not liver-derived serum CRP, acts as a potential cancer driver. Nonetheless, it is elusive how the -286 mutation regulates CRP expression. Our preliminary experiments suggest the involvement of changes in levels of promoter methylation, binding of transcription factors and interactions of long non-coding RNAs (lncRNA). This project aims to demonstrate the mechanisms by which the -286 mutation regulate the expression of CRP and to solidify the model that CRP produced in situ and its interactions with local inflammation is essential for its role in the development of cancer.

C-反应蛋白（C-reactive protein, CRP）的血浆水平与包括癌症在内的多种慢性炎症的发病风险及预后等密切相关。但CRP是否直接参与相关病理过程还存在很大争议；主流观点认为CRP很可能只是炎症严重程度的非特异性标识。申请人最近的工作发现，CRP启动子区-286 SNP位点在多种癌症中发生高频体细胞突变且伴随着CRP表达水平的上调，从而指出组织局部产生的CRP在癌变过程中发挥重要作用。然而，目前还不清楚启动子区-286位突变如何调控CRP表达。申请人前期工作提示，这很可能涉及到与-286位突变相关的甲基化水平降低、转录因子结合及长非编码RNA（long non-coding RNA, lncRNA）参与。本项目将对此展开深入研究，阐明-286突变调控CRP表达的机制，推进对CRP在癌变等慢性炎症过程中发挥作用方式的理解，建立局部CRP在慢性炎症调控中发挥作用的新模型。