BRD7 转录调控模式及参与鼻咽癌发生发展的功能和机制研究

BRD7 is a potential tumor suppressor and nuclear transcription factor in nasopharyngeal carcinoma (NPC) cloned by our lab, and involved in the carcinogenesis process of NPC by regulating multiple pathways such as Ras/MEK/ERK, Rb/E2F and Wnt/β-catenin. However, the role of BRD7 as a tumor-suppressive transcription factor and regulation mechanism involved in the carcinogenesis of NPC is still short of strong direct evidences. This work is firstly aimed to screen and identify target genes directly regulated by BRD7 and locate the DNA binding site (Motif) of BRD7. Secondly, we want to study the mode of BRD7 regulating target genes, and from them to identify the most critical genes involved in the function of BRD7 suppressing the carcinogenesis of NPC. Thirdly, we plan to screen the component of BRD7 protein complex, and identify the transcription co-factors of activator or inhibitor involved in the function of BRD7 suppressing the carcinogenesis. Next, we plan to investigate the regulation mode of BRD7 and the mechanism of BRD7 involved in carcinogenesis in vivo by using the BRD7 conditional knockout mouse model and chemical carcinogen induced cancer model based on this. Finally, we intend to investigate the expression association and clinic significance of BRD7, BRD7 co-factors, target genes and key genes in the pathways of BRD7 involved. All the above study will lay a solid foundation for the role of BRD7 as a tumor-suppressive transcription factor and regulation mechanism of BRD7 involved in the carcinogenesis of NPC.

BRD7是我室自主克隆的鼻咽癌抑瘤基因及潜在核转录因子，通过对Ras/MEK/ERK、Rb/E2F和Wnt/β-catenin等信号通路的调节参与鼻咽癌发生发展，但“BRD7抑瘤性转录因子”的角色及其参与鼻咽癌发病的转录调控机制仍然缺乏强有力的直接证据。为此，本课题拟筛选和鉴定BRD7直接调控的靶基因，确定BRD7的DNA结合域（Motif）；研究BRD7对靶基因的调控模式，确定BRD7抑瘤途径中关键的靶基因；鉴定BRD7蛋白复合体的组分，确定BRD7抑瘤途径中的共激活/拮抗因子；利用BRD7剔除小鼠模型及以此为基础构建小鼠肿瘤模型，体内探讨BRD7转录调控模式及在肿瘤发生发展中的作用；利用自制的鼻咽癌组织芯片，确定BRD7、BRD7共激活/拮抗因子、靶基因、信号通路中关键靶分子之间表达的相关性及临床意义，为BRD7“抑瘤性转录因子”的角色及参与鼻咽癌发病的转录调控机制奠定基础。

BRD7是我室自主克隆的鼻咽癌抑瘤基因及潜在核转录因子，但BRD7作为抑瘤性转录因子的角色及其参与鼻咽癌发病的转录调控机制仍然缺乏强有力的依据。通过该项目的研究，筛选和确定了BRD7潜在的靶基因及DNA结合域；证实BIRC2是BRD7直接调控的靶基因及鼻咽癌中重要的癌基因，BRD7作为转录调控因子直接结合在BIRC2的增强子区域，负性调控BIRC2的表达及对鼻咽癌恶性表型的抑制；确定BRD7能在转录水平负性调控miR-141的表达，证实BRD7通过负性调控miR-141/ PTEN/AKT信号轴的活性抑制鼻咽癌细胞增殖和肿瘤生长；发现BRD7的表达与c-Myc的活化形成一个双负反馈环，通过负性调控miR-141介导的PTEN/AKT信号轴共同参与鼻咽癌的发生发展；发现YY1在鼻咽癌中发挥抑癌基因功能，极有可能作为c-Myc转录复合体的一个新的组分，通过负性调控c-Myc/miR-141/PTEN/AKT信号轴活性共同参与鼻咽癌的发生发展；在BRD7剔除小鼠模型的基础上进一步构建了DSS诱导的急性炎症模型和AOM/DSS诱导的结直肠炎癌模型，发现BRD7在小鼠早期急性炎症中发挥抑炎功能、中晚期促进结直肠炎癌的发生发展，这是BRD7功能的新发现，为后续进一步完善BRD7在炎症和肿瘤中的作用提供了重要的线索；同时，从临床水平发现 BRD7、YY1与鼻咽癌的发生发展、预后及miR-141 的表达呈负相关，支持BRD7、YY1及c-Myc/miR-141轴在鼻咽癌的发生发展中发挥重要功能；这些研究结果为阐明BRD7参与鼻咽癌发生发展的转录调控机制及临床分子诊疗提供了重要的实验基础和理论依据。