在肝癌中lncRNA CASC2通过不同分子通路调控TRAIL敏感性和耐受性的机制研究

TRAIL is considered as a promosing antitumor agent because of its specific cytotoxicity to tumor cells and no side effects on normal cells. Understanding the mechanism of the resistance of hepatocellular carcinoma to TRAIL can be of great value in the treatment of hepatocellular carcinoma. Studies have shown that inhibiting the activation of the NF-κB pathway and amplify the Caspase cascade signaling pathway is the key point to reverse TRAIL resistance. Our group previously reported that lncRNA CASC2 can amplify Caspase cascade signaling pathways through miRNAs. Afterwards, online databases, online tools and preliminary experiments were employed to validate that lncRNA CASC2 could interact with miR-18a, and form a feedback loop together with RIP-1/NF-κB, therefore modulating the resistance to TRAIL. In summary, the present study intends to investigate the molecular mechanism of lncRNA CASC2 modulating the resistance of hepatocellular carcinoma to TRAIL from the levels of tissue, cell, animal and molecules, thus providing new ideas for overcoming the resistance of hepatocellular carcinoma to TRAIL.

TRAIL对肿瘤细胞杀伤的特异性和对正常细胞的几乎无细胞毒作用，被认为是一种很有前景的抗肿瘤药物。探索肝癌TRAIL耐受机制是其能否在肝癌临床治疗普及应用需要解决的难题。研究证实抑制NF-κB通路，激活放大Caspase级联信号通路是逆转TRAIL耐药的关键。本课题组前期报道lncRNA CASC2可通过miRNAs放大Caspase级联信号通路，在后续的预实验以及多个数据库和在线软件分析证明lncRNA CASC2可与miR-18a相互作用并与RIP-1/NF-κB通路形成互反馈环路调控TRAIL耐药。因此，本课题拟从TRAIL耐药机制出发，在组织、细胞、动物和分子四个层面证实lncRNA CASC2调控肝癌TRAIL耐受的分子机制，以期为克服肝癌TRAIL耐受提供新的思路。

TRAIL对肿瘤细胞杀伤的特异性和对正常细胞的几乎无细胞毒作用，被认为是一种很有前景的抗肿瘤药物。探索肝癌TRAIL耐受机制是其能否在肝癌临床治疗普及应用的关键。研究证实抑制NF-κB通路，激活放大Caspase级联信号通路是逆转TRAIL耐药的关键。本项目验证了lncRNACASC2通过调控miR-24、miR-221、miR-18a对肝癌细胞增殖、凋亡以及对Caspase和NF-κB通路的影响；构建了TRAIL耐受的裸鼠成瘤模型以检测lncRNA CASC2对肿瘤生长的影响；验证了lncRNA CASC2与miRNAs的相互靶向作用。并观察NF-κB活化后对lncRNA CASC2表达的影响；收集肝细胞癌患者肿瘤组织、癌旁组织，检测组织样本中各因子表达，分析了各因子表达的相关性。结果发现CASC2过表达可能会抑制小鼠皮下移植肿瘤的生长并可促进HCC细胞凋亡；CASC2通过miR-24/caspase-8和miR-221/caspase-3轴调节caspase级联的激活和NF-κB信号的激活调控癌细胞对TRAIL敏感性和耐药性，而NF-κB与CASC2启动子区域结合，抑制CASC2功能。本课题从TRAIL耐药机制出发，在组织、细胞、动物和分子四个层面证实了lncRNACASC2调控肝癌TRAIL耐受的分子机制，为克服肝癌TRAIL耐受提供了新的思路。