口腔黏膜上皮炎癌转化过程中TLR-9基因过表达的转录调控机制研究

项目名称： 口腔黏膜上皮炎癌转化过程中TLR-9基因过表达的转录调控机制研究

项目编号： No.81472517

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 阮敏

作者单位： 上海交通大学

项目金额： 72万元

中文摘要： 慢性炎症与恶性肿瘤的发生发展关系密切。课题组的前期研究明确了TLR-9可以通过活化AP-1炎性信号通路而促进口腔黏膜上皮的癌变，极有可能是口腔黏膜炎癌转化调控网络中的关键节点之一。然而，对于癌变过程中TLR-9基因过表达的始动调控机制仍未明确。结合文献检索及预初实验，课题组发现TLR-9基因的转录启动子含有多个GC盒、GA重复序列以及多种炎性转录因子结合位点；伴随癌变进程，TLR-9基因的转录启动子活性明显阶梯型增高。由此，课题组推测由GC盒和GA重复序列为代表的顺式调控元件和以AP-1及NF-kB为代表的反式作用因子可能是口腔黏膜上皮炎癌转化过程中TLR-9基因过表达的转录起始调控关键。 ，并希望综合运用生物信息学、基因组学、分子生物学及实验动物学等学科交叉的研究方式，从基因转录调控的角度对口腔黏膜上皮炎癌转变的始动及促进机制进行深入研究，为口腔鳞癌炎性发病机制的探索提供新的启示。

中文关键词： C01_口腔肿瘤；Toll样受体-9；转录调控；病因学

英文摘要： It is well known that chronic inflammation has close relation with tumor occurrence and development.Our previous research identified an gradually evaluated expression of TLR-9 during the malignant transformation of oral mucosa epitheliitis to squamous cell carcinoma via stimulating the production and secretion of the AP-1 activated inflammatory factors，which contributed to the tumor cell proliferation, invasion, immune response increasing and tumor microenvironment formation. Thus, TLR-9 is strongly suspected to be one of the key factors in inflammation-related oral mucosa carcinogenesis. However,little is known about the regulating mechanism on overexpression of TLR-9 gene in detail during this procedure. By further literature review and priliminary experiment,we found that there are many GC box, GA repeated sequence and combining sites of inflammation-related transcription factors, including NF-kappaB and AP-1, in the transcription initiation site of TLR-9 gene. We also found an gradually increased TLR-9 transcription initiation site activity during the transformation of oral mucosa epitheliitis to squamous cell carcinoma. Thus we speculate that cis-acting elements such as GC box, GA repeated sequence, and trans-acting factors such as AP-1and NF-kappaB in the transcription initiation site of TLR-9 gene ,may play a key role in the initiation of oral mucosa inflammation-related carcinogenesis.And this abnormal regulation of TLR-9 gene transcription from mRNA level and subsequent cascade reaction of downstream inflammation-related signal pathway,including the TLR-9/AP-1 positive feedback loop, may involved in the whole procedure of malignant transformation of oral mucosa epitheliitis to squamous cell carcinoma. Based on combined utilization of bioinformatics,genomics,molecular biology,cytobiology and experimental zoology, the present study try to further explore the possible initial and promoting mechanisms in inflammation-related oral mucosa caicinogensis from gene transcription level.We believe this research would provide new information and inspiration in prevention and treatment of inflammation-related oral squamous cell carcinoma in future.

英文关键词： Oral cancer;Toll-like receptor-9;Transcriptional regulation;Etiology