以EMT相关miR-205-5p为靶点治疗顺铂耐药鼻咽癌的机制研究

Nasopharyngeal carcinoma (NPC) is a common tumor with high degree of malignancy in China. The incidence rate is increasing year by year, and the prognosis is poor, this mainly due to its molecular mechanism is not clear and patients are prone to drug resistance. Therefore, it is of great significance to strengthen the basic and clinical research of NPC. Our previous study showed that the sensitivity of NPC cells to cisplatin was decreased, which was related to the occurrence of epithelial-mesenchymal transition (EMT); It was also found that the high expression of miR-205-5p and PTEN gene were related to the occurrence and the process of drug resistance, but the specific mechanism is unknown. This project aims to regulate the expression of EMT related miR-205-5p, and then regulating the expression of targeting PTEN. To investigate the mechanism of EMT related miR-205-5p as a target in the treatment of cisplatin resistant NPC, and further clarify the relationship between PTEN and PI3K/Akt signaling, so as to increase the curative effect of cisplatin and improve drug resistance, and in order to provide a new theoretical and experimental basis for the clinical treatment of NPC.

鼻咽癌是我国恶性程度很高的常见肿瘤，发病率有逐年上升趋势，且预后较差，主要是由于其发生的分子机制不清楚及患者易出现耐药状况。因此，加强鼻咽癌的基础和临床研究意义重大。我们课题组前期研究表明，鼻咽癌细胞对化疗药物顺铂治疗的敏感性降低，可能与鼻咽癌细胞发生EMT过程有关；同时还发现miR-205-5p特异性高表达，且其和PTEN基因与鼻咽癌的发生和耐药过程有关，但具体机制不详。本项目拟通过调控顺铂耐药鼻咽癌细胞株中EMT相关 miR-205-5p的表达，进而调节其靶基因PTEN等的表达，探讨以EMT相关miR-205-5p为靶点治疗顺铂耐药鼻咽癌的机制，进一步阐明PTEN与PI3K/Akt信号传递关系，从而提高化疗药物顺铂的疗效、改善耐药状况，以期为开辟鼻咽癌的临床治疗途径提供新的理论和实验依据。

近年来，上皮-间质转化（EMT）被证实与肿瘤耐药、转移、免疫逃逸等一系列恶性进程相关，EMT的出现几乎成了癌症进一步恶化的标志。微小RNA（microRNA，miRNA）是一类内源性非编码小RNA，其通过对转录后翻译水平的调节参与各种生物学进程，如增殖、代谢、分化以及耐药等。课题组前期研究发现鼻咽癌细胞对化疗药物顺铂的敏感性降低，顺铂耐药鼻咽癌细胞发生了EMT进程，且细胞内的miR-205-5p特异性高表达，但这三者之间的调控机制尚不明确。本项目通过RNA干扰技术对细胞内miR-205-5p的表达进行特异性调节，并与临床常用化疗药物合用，研究其对细胞增殖、凋亡、迁移和侵袭等的影响，揭示miR-205-5p与细胞耐药、EMT之间的调控机制。结果发现下调miR-205-5p增强鼻咽癌细胞对顺铂和3-溴丙酮酸的敏感性，其机制可能与下调Mcl-1和Bcl-2表达，上调Bak和Bax的表达有关。此外，miR-205-5p能够促进EMT进程，而下调miR-205-5p逆转EMT进程，进而调节其靶基因PTEN的表达，且其调控机制与PI3K/Akt信号通路有关，阐明了miR-205-5p-PTEN-PI3K/Akt信号传递的关系。因此，miR-205-5p可能是克服肿瘤耐药的有效靶点，其对增加鼻咽癌细胞对化疗药物的敏感性及降低癌细胞转移风险具有指导意义。这也为探明肿瘤耐药的发病机理与病因奠定了实验基础，为后期研究做好铺垫。