β-Trcp介导的转录因子FOXN3泛素化降解促进肺癌放疗抵抗的作用机制研究

放疗抵抗仍然是肺癌局部复发和远处转移的主要原因。转录因子FOXN3被认为是一个潜在的肿瘤抑制蛋白，但其在肺癌放疗抵抗中的作用及调控机制尚未见报道。申请人运用成熟的串联亲和纯化/质谱技术及免疫共沉淀实验发现FOXN3是E3泛素连接酶β-Trcp新的结合蛋白，且β-Trcp可以负向调控FOXN3的蛋白表达水平。初步的功能学实验显示沉默FOXN3促进PI3K/AKT信号通路的活化，肺癌细胞产生放疗抵抗。结合以上预实验结果我们推测：E3泛素连接酶β-Trcp通过与转录因子FOXN3结合并促进其泛素化降解，从而激活下游PI3K/AKT信号通路，最终导致肺癌放疗抵抗。本项目将进一步探索β-Trcp调控FOXN3泛素化降解的分子机制，明确FOXN3在肺癌放疗抵抗中的作用及临床意义，为提高肺癌放射治疗疗效探寻新的分子靶点。

Radioresistance remains the major cause of local relapse and distant metastasis in lung cancer. Transcription factor FOXN3 has been considered a potential tumor suppressor protein. However, the roles and regulatory mechanisms of FOXN3 in lung cancer radioresistance have not yet been elucidated. Using tandem affinity purification/mass spectrometry and immunoprecipitation assay, we show that FOXN3 is a new binding partner and negatively regulated by E3 ubiquitin ligase β-Trcp at the protein level. Preliminary functional experiments demonstrate that FOXN3 silencing activates the PI3K/AKT signaling pathway and leads to lung cancer radioresistance. Therefore, we propose that E3 ubiquitin ligase β-Trcp interacts with and promotes the ubiquitination and degradation of FOXN3, subsequently activating the PI3K/AKT signaling pathway, ultimately resulting in radioresistance in lung cancer. This study will explore the molecular mechanism of how FOXN3 is mechanistically controlled by β-Trcp and investigate the functions and clinical significances of FOXN3 in lung cancer, and provide a new therapeutic target for radiotherapy in lung cancer.