项目名称： HRH4遗传变异对组胺H4受体调控非小细胞肺癌EMT过程及恶性进展的影响及机制研究

项目编号： No.81460560

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 何功浩

作者单位： 昆明理工大学

项目金额： 45万元

中文摘要： 受体功能研究是药理学研究领域的核心科学问题，但影响和调控受体功能的因素却错综复杂。随着基因组学研究深入，遗传因素对受体功能的影响为受体功能研究提供了新的思路。申请者前期研究发现组胺H4受体（HRH4）编码基因及蛋白在多种非小细胞肺癌细胞系中均有表达并在上皮细胞间质化（EMT）过程中发挥重要作用，而HRH4基因rs11662595多态性与肺癌患者临床分级、转移程度、复发率及死亡率均显著相关。基于此，申请者合理推测：rs11662595不同基因型对HRH4基因表达产物的功能有显著影响，进而极有可能改变肺癌细胞EMT过程。为系统证明上述推断，本项目拟从分子、细胞及组织水平研究rs11662595不同基因型影响HRH4功能的机制，阐明rs11662595多态性影响肺癌恶性进展的具体机理，期望深入理解遗传因素对HRH4功能影响，为以HRH4为靶点的抗肿瘤药物开发及肺癌个体化防治提供新的理论基础。

中文关键词： 组胺H4受体；遗传变异；非小细胞肺癌；上皮细胞间质化

英文摘要： To elucidate receptor function is one of the core scientific issues in pharmacological field. However, the factors that affect or modulate receptor function are rather complicate and not fully clarified yet. With the development of genomic research, genetic factor is gradually acknowledged as a novel and important factor affecting receptor function, which provides us new insight into this area. According to our previous investigation, the histamine H4 receptor (HRH4) mRNA and protein were expressed and exerted inhibitory effect on the epithelial-to-mesenchymal transition (EMT) progress in many kinds of non-small cell lung cancer (NSCLC) cell lines. Moreover, we also found that the polymorphism of rs11662595 in HRH4 gene was significantly associated with the clinical grade, degree of metastasis, and recurrence and death rate in NSCLC patients. Based on these findings, we rationally hypothesize that genotypes of rs11662595 may affect the gene and protein expression of HRH4 and hence affect the EMT progress of NSCLC. In order to systematically prove this hypothesis, we plan to explore the underlying mechanisms of how polymorphism of rs11662595 affects the function of HRH4 at the molecular, cellular and organizational level and demonstrate how this polymorphism affects the malignant progression of NSCLC. The accomplishment of this study will provide us in-depth understanding of the genetic effects on HRH4 function, and also provide novel rationales for personal prevention and treatment of NSCLC and new strategies for anti-cancer drug development that target HRH4.

英文关键词： histamine H4 receptor;genetic variation;non-small cell lung cancer;epithelial-to-mesenchymal transition