长链非编码RNA RP11-350N15.6促进肺鳞癌顺铂耐药的机制研究

RP11-350N15.6 is a novel long noncoding RNA that conserved in mammals and highly expressed in cisplatin-resistant squamous cell lung cancer cells identified by lncRNA microarray. Our previous study found RP11-350N15.6 was overexpressed in cisplatin-resistant squamous cell lung cancer patients and RP11-350N15.6 knockdown significantly increased cellular sensitivity to cisplatin in squamous cell lung cancer. Furthermore, bioinformatic analysis and experiments suggested that RP11-350N15.6 may promote histone H3K56 acetylation and transcriptional activation of FGFR1-STAT3 by recruiting CBP/p300, followed by RP11-350N15.6 overexpression and resistance to cisplatin in squamous cell lung cancer. We intend to verify this hypothesis via in vitro and in vivo experiments based on specimens of patients, tumor-bearing mice and squamous cell lung cancer cells with overexpression and knockdown strategies. Our research would elucidate RP11-350N15.6 promoting cisplatin-resistance with a positive feedback loop including FGFR1-STAT3 in squamous cell lung cancer. This study will enrich the understanding of cisplatin-resistance from the perspective of lncRNA, and therefore provide theoretical information for targeted therapy of squamous cell lung cancer.

人RP11-350N15.6是我们采用lncRNA芯片筛选到的、哺乳动物中保守的、一条差异高表达于肺鳞癌耐顺铂细胞中、功能未知的lncRNA。前期发现：①耐药病例中RP11-350N15.6明显高表达；②敲低RP11-350N15.6显著增加肺鳞癌细胞对顺铂的敏感性；③生物信息学与实验均提示RP11-350N15.6可能通过募集绑定CBP/p300，促进组蛋白H3K56乙酰化及激活FGFR1的转录，继而通过下游STAT3再反馈激活RP11-350N15.6的表达，最终促成了肺鳞癌对顺铂的耐药。研究拟从组织、动物和细胞三个层面，采用过表达与敲低策略，以FGFR1-STAT3为机制主线，论证RP11-350N15.6异常高表达通过FGFR1-STAT3正反馈导致肺鳞癌顺铂耐药的新机制。研究将揭示lncRNA在肿瘤耐药中的调控作用，对经典耐药理论给予补充，并为肺鳞癌靶向治疗提供新的思路。

我们全面分析LncRNA RP11-350N15.6可作为肺鳞癌顺铂耐药的标志物及其耐药机制。通过RT-PCR, Western Blot等分子实验，我们发现LncRNA RP11-350N15.6 在耐药患者组织和耐药细胞株中高表达，细胞实验说明LncRNA RP11-350N15.6与细胞的增殖生长相关，进而对LncRNA RP11-350N15.6诱导耐药的机制进行探索，发现LncRNA RP11-350N15.6影响FGFR1-STAT3 介导的细胞顺铂耐药性，并且可募集 CBP/p300 对 FGFR1 的转录具有调控作用； 进一步研究发现，RP11-350N15.6 受 FGFR1-STAT3 的反馈调节。研究揭示 lncRNA 在肿瘤耐药中的调控作用，为肺鳞癌靶向治疗提供新的思路。