项目名称： DKC1调控口腔鳞癌程序性细胞死亡的分子机制及其临床意义研究

项目编号： No.81502351

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 孙崇奎

作者单位： 四川大学

项目金额： 20万元

中文摘要： 程序性细胞死亡(PCD)包括细胞凋亡与新近备受关注的细胞程序性坏死，具有清除基因组不稳定细胞，防止细胞癌变的生理意义，此外，如何诱导肿瘤细胞进入PCD途径，是目前肿瘤靶向防治的前沿。先天性角化不良基因DKC1参与端粒酶功能执行，维护细胞基因组的完整和稳定；申请人前期发现DKC1缺失导致端粒缩短、DNA损伤增多；然而，是否会导致肿瘤发生，以及PCD是否参与此过程，尚未见报道。基于此，申请人以口腔鳞癌OSCC为模型，拟①从病例组织、细胞、动物水平多角度验证DKC1与OSCC发生发展的关系；②通过凋亡相关蛋白表达水平的变化,探讨DKC1与细胞凋亡的关系；③构建OSCC程序性坏死模型，检测其调控过程中关键蛋白的表达差异，多种实验手段充分研究DKC1与程序性坏死的关系。通过本研究阐释DKC1在口腔黏膜上皮细胞癌变中的潜在功能，探讨其对PCD的分子调控机制，为OSCC的早期预防和靶向治疗提供新思路。

中文关键词： 口腔鳞癌；先天性角化不良基因；增殖；程序性细胞死亡；程序性坏死

英文摘要： Programmed cell death (PCD) is death carried out in a regulated process, including apoptosis and necroptosis, which was recently coined and seen as programmed necrosis. PCD could eliminate the cells with precarious or incomplete genome under normal physiological conditions, so as to resist tumorigenesis to some extent. Otherwise, it is a frontier and important study to activate programmed cell death pathway in molecular targeted therapy for tumors. DKC1 plays core role in telomerase functions and is very important for genome integrity and stability. In previous studies, we found that depletion of DKC1 would result in telomere shortening, DNA damages increasing. However, it was unclear whether the status would promote tumorigenesis, as well whether the programmed cell death process would be implicated in. Based on the previous studies, we intend to do some further research in Oral Squamous Cell Carcinoma (OSCC) cells. Firstly, we need to identify the function of DKC1 in tumorigenesis and development of OSCC using the clinical tissue samples, cell experiments and animal xenografts. Moreover, we want to uncover the relationship between DKC1 depletion and apoptosis through testing the difference of key proteins associated with apoptosis process. Thirdly, necroptosis model would be induced using OSCC cells, then some proteins which are identified as activation marker for necroptosis will be test. And we will determine the potential function of DKC1 in regulating necroptosis using several experiments for full validation. All what we will do in this project are just supposed to investigate the potential function of DKC1 and the detail molecular mechanism in the process of apoptosis or necroptosis, which might uncover a new way in early diagnosis and targeted therapy for OSCC.

英文关键词： Oral Squamous Cell Carcinoma;DKC1;Proliferation;Programmed cell death;Necroptosis