p53诱导的外泌体-miRNAs介导头颈肿瘤细胞化疗耐药的机制

项目名称： p53诱导的外泌体-miRNAs介导头颈肿瘤细胞化疗耐药的机制

项目编号： No.81472572

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： 张建军

作者单位： 上海交通大学

项目金额： 75万元

中文摘要： 研究证实，肿瘤相关成纤维细胞（CAF）可以调控肿瘤细胞对化疗的敏感性，但是详细机制尚不明确。外泌体是细胞分泌的一种小囊泡结构，包含多种miRNAs，可以在遗传信息层面介导不同类型细胞之间进行信息交流。我们前期实验结果表明：① CAF与肿瘤细胞共培养时，肿瘤细胞能够有效抵抗顺铂所致的DNA损伤及凋亡发生；② 去除CAF与肿瘤细胞共培养体系中的外泌体后，肿瘤细胞重新恢复了对化疗药物的敏感性；③ 将CAF的p53基因沉默后，CAF释放的外泌体显著减少。基于以上实验结果，我们推断，在化疗药物的DNA损伤压力下，p53功能活化后可调控CAF释放外泌体，而外泌体中与p53相关的miRNAs可能参与介导肿瘤细胞DNA修复及耐药的形成。本研究以CAF来源的外泌体为主要研究对象，研究其在肿瘤化疗抵抗中的作用机制。该问题的解决将为以外泌体为治疗靶点的治疗手段以及以外泌体为药物载体的治疗方式提供科学依据。

中文关键词： C01_口腔肿瘤；肿瘤相关成纤维细胞；外泌体；微小RNA；化疗耐药

英文摘要： Studies have confirmed that the sensitivity of tumor cells to chemotherapy can be regulated by tumor associated fibroblasts (CAF). However, the detailed mechanism remains unclear. Exosomes are small vesicles containing unique RNA and protein cargo, secreted by most cell types in culture. One of their most intriguing roles is intercellular communication-exosomes function as the messengers, delivering various effectors or signaling macromolecules between specific cells. Our previous results showed that : ① Tumor cells can block cisplatin -induced DNA damage when CAF co-cultured with tumor cells; ② After removal of the exosomes from CAF and tumor cells co-culture system, tumor cells restored the sensitivity to chemotherapeutic drugs; ③ After silencing of p53 gene in CAF, exosomes released by CAF significantly reduced. Based on these results, we conclude that the activation of p53 in CAF under the pressure of DNA damage caused by chemotherapy drugs can enhance exosome production. The p53-related exosomes-miRNAs may be involved in DNA repair and chemoresistance. In this study, we choose the tumor microenvironment as our study scopes, and mainly focus on the mechanism of chemoresistance mediated by the exosomes derived from CAF. This study will facilitate to provide some strategies for cancer therapy based on exosomes. In addition, exosomes also can be designed to be a drugs-delivering vector for cancer therapy.

英文关键词： oral cancer;cancer associated fibroblast;exosomes;microRNA;Chemoresistance