基于lncRNA/CDK6相关信号通路探讨益气活血养阴法增强鼻咽癌放射敏感性的分子机制

Radiotherapy is the main treatment of nasopharyngeal carcinoma (NPC), but radiation resistance is severely restricting its efficacy.The traditional chinese medicine(TCM) Shengmaijianghuangsan,which is formed by the method of supplementing qi-activating blood circulation and nourishing yin, has radiosensitizing effects, but its molecular mechanism is still unknown. CDK6 is closely related with radiosensitivity of NPC through hypomethylation in our previous studies; It’s confirmed that Shengmaijianghuangsan has good radiosensitization effect In vivo. In vitro experiments found for the first time and validate lncRNAs and multiple effective molecules involved in regulating the CDK6, thus it put forward the possibility that lncRNA NR_110088 targetes CDK signal pathways and reverses the radioresistance through hypomethylation. This project aims at inquiring into the relationship between lncRNA/CDK6 and the radiation resistance in the cases of regulating cells, animal model and NPC cases ,and obtain the reliable evidence of Shengmaijianghuangsan acting on NR_110088 to targetedly regulate CDK6 hypomethylation and to reverse the radiation resistance. It can provide powerful scientific evidence to annotate the molecular mechanism of NPC radioresistance and Shengmaijianghuangsan sensitizing, the application of TCM in cancer treatment and the lncRNA in multi-target therapeutic of cancer.

放射治疗是鼻咽癌治疗的主要手段，而放射抗拒严重制约了其疗效，“益气活血养阴”法（生脉姜黄散）对鼻咽癌有放射增敏作用，但其分子机制尚不明了。我们前期承担的国家自然基金项目研究表明，射线诱导的CDK6低甲基化可能是放射抗拒的重要分子基础。体内实验证实生脉姜黄散有良好的放射增敏作用；体外实验发现并验证lncRNA及多个效应分子参与调控CDK6，其中一个lncRNA（NR_110088）可能介导调控CDK6基因启动子甲基化。因此提出NR_110088调控CDK6甲基化水平而逆转放射抗拒的可能性。本项目拟在细胞调控、动物模型及临床病例中探讨lncRNA/CDK6及效应分子与放射敏感性之间的关系，获得生脉姜黄散作用于lncRNA/CDK6相关信号通路并逆转放射抗拒的可靠证据，为诠释鼻咽癌放射抗拒及益气活血养阴法放射增敏的分子机制、应用中药多靶点辅助治疗肿瘤提供有力的科学依据。

放射治疗是鼻咽癌治疗的主要手段，而放射抗拒严重制约了其疗效，本项目对“益气活血养阴”法（生脉姜黄散）的放射增敏作用及其机制进行了研究。研究表明CDK6是与鼻咽癌放射增敏性密切相关的重要分子；体内外实验证实生脉姜黄散可以通过lnc-CDK6(NR_110088)介导DNA甲基化，调控CDK6的表达并影响DNMT1等甲基化相关因子而实现放射增敏；进一步研究明确了lnc-CDK6靶向调控CDK6的上游机制。以上研究获得了生脉姜黄散作用于lncCDK6/CDK6相关信号通路，介导DNA甲基化及其参与鼻咽癌放射增敏的可靠证据。另外，项目还从肠道菌群的角度解释了生脉姜黄散在放射增敏的一些药效作用机制。在此基础上，拓展性研究还表明circRNA通过改变鼻咽癌肿瘤干细胞亚群从而引起放射抗拒，相关后续研究思路正在积极申报中；综上研究成果为诠释中药的放射增敏分子机制及应用lncRNA作为肿瘤治疗的新方向提供有力的科学依据。