LncRNA DSCAS竞争性结合miR-646-3p介导survivin和Bcl-2的表达调控 肺鳞癌细胞顺铂敏感性

Lung cancer is one of the most malignant tumors with high morbidity and mortality worldwide. Platinum-based chemotherapy is the main treatment for lung squamous cell carcinoma, however, clinical response is often limited by the inherent or acquired chemotherapeutic drug resistance. Long non-coding RNA (lncRNA) has been reported to be differentially expressed in tumor tissues and may be associated with chemoresistance. In our previous study, we found that lncRNA DSCAS may be associated with chemosensitivity to cisplatin in lung squamous cell carcinoma, and preliminary validation was carried out. We then hypothesized that lncRNA DSCAS may regulate the cisplatin sensitivity of lung squamous cell carcinoma cells by competitively binding to miR-646-3p in the form of ceRNA, and mediating the expression of survivin and Bcl-2, which are known as apoptosis related genes. This study aims to analyze the expression of lncRNA DSCAS and its relationship with cisplatin resistance at the tissue level; and to observe effects of lncRNA DSCAS on sensitivity to cisplatin and on proliferation, apoptosis in lung squamous cell carcinoma by regulating the expression of lncRNA DSCAS bidirectionally both in cells and animals. Finally, the mechanism of cisplatin sensitivity is supposed to be explored. We expect this study to provide theoretical and experimental evidence for resistance of platinum-based chemotherapy in lung squamous cell carcinoma.

肺癌是目前世界范围内发病率和死亡率均居前列的恶性肿瘤之一，含铂两药化疗作为肺鳞癌的主要治疗方案，其临床疗效经常受到化疗药物的固有及获得性耐药的限制。长链非编码RNA（lncRNA）在肿瘤组织中存在差异性表达并可能与化疗耐药相关。本课题组前期的基因芯片筛选发现lncRNA DSCAS可能与肺鳞癌顺铂化疗敏感性相关，并进行了前期验证，提出lncRNA DSCAS可能通过ceRNA形式竞争性结合miR-646-3p，进而介导凋亡相关基因survivin及Bcl-2的表达，调控肺鳞癌细胞的顺铂敏感性的假说。本课题拟在组织水平分析lncRNA DSCAS的表达及其与顺铂耐药的相关性；在细胞及动物体内双向调控lncRNA DSCAS表达，观察其对肺鳞癌细胞顺铂敏感性及增殖、凋亡的影响；并对其调控顺铂敏感性的分子机制进行分析验证，以期为肺鳞癌铂类化疗耐药提供理论和实验依据。

（1）肺癌作为我国癌症死亡率首位病因的癌种，总体5年生存率不到20%，严重威胁着人类的生命健康。本课题基于前期基因芯片结果，筛选出研究对象lncRNA DSCAS在肺鳞癌组织中呈异常高表达。本课题研究结果显示，在肺鳞癌组织和细胞中，lncRNA DSCAS呈显著高表达，且在顺铂不敏感组织中的表达水平高于顺铂敏感肺鳞癌组织；肺鳞癌细胞中下调lncRNA DSCAS表达可抑制肺鳞癌细胞的增殖、迁移和侵袭能力，并可能增加其对顺铂的敏感性；反之，上调lncRNA DSCAS表达则可促进肺鳞癌增殖、侵袭等，减弱细胞对顺铂的敏感性；体内实验证实在顺铂作用下下调lncRNA DSCAS可抑制裸鼠移植瘤的增殖。相关机制研究提示调控lncRNA DSCAS表达可通过结合miR-646-3p影响凋亡相关因子Bcl-2、Survivin的表达及肺鳞癌细胞对顺铂敏感性。该课题为肺鳞癌的调控机制、铂类化疗耐药机制提供了理论和实验依据。.（2）课题组利用高通量测序、数据库挖掘等方式，对于其他非编码RNA在肺肿瘤中的调控机制，如PGAM1/miR-3614-5p/TGF-β信号通路、荜茇酰胺/miR-34b-3p通路等也进行了功能及机制探索。