MDM2基因启动子区40-bp插入/缺失多态性调控MDM2-P53通路在结直肠癌发生中的作用机制研究

Insertion/deletion polymorphisms (Indels) have been found to be pervasively transcribed in the genome and involved gene expression modulation, aberrant allelic frequency of Indels linked to human cancers. Our previous studies have identified a novel polymorphism (rs3730485) within distal promoter of murine double minute2 (MDM2) which was significantly associated with CRC incidence in a Chinese population, but the underlying mechanism remained incompletely known. Reports confirmed that MDM2-P53 pathway involved the development of CRC. The results of our preliminary experiments indicated that del allele of rs3730485 could upregulate MDM2 expression, bioinformatics analysis predicted candidate transcription factors binding to the loci. Therefore, we assumed that rs3730485 could probably modulate MDM2 expression by influence of promoter activity, which in turn regulating MDM2-P53 pathway, thus involved the development of CRC. Based on recent data and CRC patient samples and cell lines, we plan to fully elucidate the mechanism of transcrption factor mediated Indel modulation of MDM2 expression, and explore the Indel associated effect on MDM2-P53 pathway. Our proposal would lay a foundation for further Indels-related diagnosis and therapy of CRC.

插入缺失多态(Indels）在基因组中广泛存在并参与调控基因表达，且与肿瘤发生密切相关。申请者前期研究发现，位于泛素蛋白连接酶MDM2基因启动子区的一个40-bp Indel (rs3730485)与结直肠癌（CRC）易感性显著相关，但机制不明。文献证实，MDM2-P53通路参与CRC发生。预实验证实，在CRC组织中rs3730485等位基因缺失，MDM2 表达上调，软件预测到转录因子可与rs3730485结合。据此推测：rs3730485可能通过影响启动子活性调控MDM2表达，经由MDM2-P53途径参与CRC的发生。本项目拟在前期实验研究的基础上，以CRC组织、外周血和细胞株为对象，采用基因型-表型关联结合功能实验方法，阐明启动子区40-bp Indel调控MDM2表达的机制，探讨Indel对MDM2-P53信号通路的影响，为Indels相关的CRC诊断和治疗提供依据。

插入缺失多态(Indels）在基因组中广泛存在并参与调控基因表达，且与肿瘤发生密切相关。申请者前期研究发现，位于泛素蛋白连接酶MDM2基因启动子区的一个40-bp Indel (rs3730485)与结直肠癌（CRC）易感性显著相关，但机制不明。本研究前期实验研究的基础上，以CRC组织、外周血和细胞株为对象，采用基因型-表型关联结合功能实验方法，首次发现MDM2启动子序列功能性多态rs3730485调控CRC发病风险，多态del等位基因可以破坏GATA-1转录因子的结合，增强MDM2表达，升高CRC患病风险，且多态rs3730485可以通过MDM2-P53通路起作用。本发现为CRC精准医疗提供实验依据，有助于全面揭示CRC发病机制。