肺鳞癌缺乏个体化治疗策略，放疗后易残留及复发，阐明肺鳞癌启动细胞(TICs)放疗抵抗机制是改善患者预后的关键。我们发现Yap1介导肺鳞癌TICs放疗抵抗，推测Yap1结合IAP、转录激活Nrf2、下调ROS形成Yap1/IAP-Nrf2-ROS信号轴，是维持肺鳞癌TICs放疗抵抗的内在机制。本项目以自发性肺鳞癌小鼠模型和人源肺鳞癌移植小鼠模型为研究对象，首先，检测各信号节点表达水平，从分子水平验证信号轴调控TICs放疗抵抗；其次，慢病毒过表达、Cas9基因敲除及IAP-Nrf2回复实验，从功能水平验证信号轴维持TICs放疗抵抗；再次，CoIP、ChIP-seq、EMSA技术验证Yap1/IAP、IAP-Nrf2的结合位点，从直接互作分析深度证实信号轴的真实性；最后，从临床病例验证信号轴与肺鳞癌放疗疗效及预后的临床病理意义。研究结果对于加深认识肺鳞癌TICs本质和放疗抵抗机制具有重要意义。

Lung squamous cell carcinoma (LSCC), lack of effective personal therapies, tends to relapse after radiotherapy. To improve the prognosis, the key is to explore the mechanism underlying the radioresistance of lung squamous tumor-initiating cells (TICs). We found that Yap1 mediated lung squamous TICs, thus hypothesizing that the intrinsic mechanism of maintaining the radioresistance of lung squamous TICs is to bind Yap1 to IAP (inhibitor of apoptosis protein), then transcript and activate Nrf2, and downregulate active oxygen species (ROS) to form Yap1/IAP-Nrf2-ROS signaling axis. Establishing mouse models of spontaneous LSCC and Patient Derived Xenograft (PDX) of LSCC, this project aims to 1) explore the role of signaling axis in regulating TICs radioresistance on molecular level by detecting the expression at signal nodes; 2) verify the role of signaling axis in maintaining TICs radioresistance on functional level through overexpression of Lentivirus vector, Crispr/Cas9 knockout and IAP-Nrf2 rescue test; 3) confirm the role of signaling axis from analysis of direct interaction by validating the binding sites of Yap1/IAP, and IAP-Nrf2 using co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP-seq) and electrophoretic mobility shift assay (EMSA); 4) test the clinicopathologic significance of this sinaling axis in the radiotherapeutic effect on LSCC and its prognosis based on clinical cases. The results will be of great significance to further the understanding of the essence and radioresistance of lung squamous TICs.