放疗抗拒是导致肺癌局部治疗失败和远处转移的重要因素之一。本课题组既往研究发现Myc抑制蛋白Mxi1在肺癌中低表达并参与调控肺癌的放疗抵抗，但其调控机制尚未完全明确。申请人通过串联亲和纯化和免疫共沉淀的方法发现E2/E3 泛素杂合酶UBE2O可以与Mxi1相互作用且负向调控其蛋白水平，提示UBE2O可能是Mxi1的E3泛素连接酶。初步的功能学实验显示沉默UBE2O可增加肺癌细胞的放疗敏感性。因此我们推测：E2/E3杂合酶UBE2O通过与Myc抑制蛋白Mxi1结合，促进Mxi1的泛素化降解，从而激活Myc的转录活性，最终导致肺癌放疗抵抗。本研究将进一步从分子、细胞及动物水平探求UBE2O泛素化降解Mxi1最终参与肺癌放疗抵抗的机制，同时明确UBE2O在肺癌中的临床及预后意义。本研究的完成有望阐明肺癌放疗抵抗的新机制，同时也可为肺癌放射治疗提供新的治疗靶点。

Radiochemoresistance is considered the main cause of local recurrence and distant metastasis in lung cancer. We have previously demonstrated that Mxi1 is downregulated and enhances the radiosensitivity in lung cancer. However, the mechanisms by which Mxi1 is regulated have not yet been fully understood. Using tandem affinity purification and immunoprecipitation technologies, our preliminary data show that E2/E3 hybrid ubiquitin-protein ligase UBE2O binds to Mxi1 and negatively controls the protein level of Mxi1. Functional assays show that UBE2O silencing enhances radiochemosensitivity in lung cancer cells. Therefore, we hypothesize that UBE2O interacts with Mxi1 and promotes the degradation of Mxi1 via ubiquitin-proteasome pathway, which ultimately results in Myc activation and promotes cell radioresistance in lung cancer. This study will elucidate how Mxi1 is controlled by UBE2O mechanistically and explore the role and clinical value of UBE2O in lung cancer，and may be provide insight into the novel molecular mechanism of radioresistance and a potential therapeutic and radiosensitization target for lung cancer.