USP11通过RelB/非经典NF-κB途径调控肿瘤微环境介导的NSCLC侵袭转移

M2型肿瘤相关巨噬细胞（M2）在肿瘤微环境介导的非小细胞肺癌（NSCLC）侵袭转移过程中发挥重要作用。我们预实验表明：在M2中敲低去泛素化酶USP11显著增加非经典NF-κB信号通路下游基因表达，其条件培养基促进NSCLC转移。但USP11调控肿瘤微环境促进NSCLC侵袭转移的机制不清。我们研究发现USP11与转录因子RelB相互作用，抑制USP11增加了RelB的泛素化，但不导致蛋白降解。据此我们推测USP11与RelB结合，通过降低RelB的泛素化，减弱RelB-p52介导的非经典NF-κB信号活性，从而抑制M2介导的NSCLC侵袭转移。本项目拟采用免疫共沉淀、荧光素酶报告基因、RT-PCR、体外去泛素化及构建转移性肺癌动物模型等方法，阐明USP11调控RelB介导的非经典NF-κB调控肿瘤微环境的新机制，加深我们对非经典NF-κB信号通路调控机制的理解，为NSCLC提供新的治疗策略。

M2 tumor-associated macrophages (M2) play important roles in the tumor microenvironment-mediated invasion and metastasis of non-small cell lung cancer (NSCLC). Our preliminary data demonstrated that deubiquitinase USP11 knockdown significantly increased the expression of downstream genes in the non-canonical NF-κB signaling pathway; and the conditioned medium from USP11-knockdown M2 macrophages increased the migratory activity of NSCLC. However, the mechanism of USP11 regulating tumor microenvironment-mediated invasion and metastasis of NSCLC has not yet been elucidated. Further studies demonstrated that USP11 interacted with RelB; USP11 knockdown increased the ubiquitination of RelB, but did not affect the level of RelB protein. We speculate that USP11 interacts with RelB, decreases the ubiquitination of RelB and attenuates RelB-p52-mediated non-canonical NF-κB signaling activity, thereby inhibiting M2-mediated invasion and metastasis of NSCLC. This project intends to adopt methods such as immunoprecipitation, luciferase reporter gene, RT-PCR, in vitro deubiquitination, and construction of metastatic lung cancer animal models. This project is expected to reveal the new mechanism by which USP11 regulates RelB-mediated non-canonical NF-κB to regulate the tumor microenvironment, deepen our understanding of the regulatory mechanism of non-canonical NF-κB signaling pathways, and provide new treatment strategies for NSCLC.