Neddylation通路上调趋化因子CXCL1表达促进肺癌微环境髓样抑制细胞浸润的机制研究

Neddylation pathway is over-activated in lung cancer and has a significantly negative correlation with the prognosis of patients, suggesting that overactivation of neddylation pathway promotes the occurrence and progression of lung cancer. However, the cancer-promotion mechanisms of neddylation overactivation remain unexplored. We have previously demonstrated that inactivation of neddylation pathway inhibits NF-κB pathway and then down-regulates its target CXCL1, a chemokine which plays an important role in MDSCs infiltration and the progression of lung cancer. Based on these studies, we hypothesize that overactivation of neddylation pathway can up-regulate the expression of CXCL1 by activating NF-κB pathway, promoting the infiltration of MDSCs, and consequently, the progression of lung cancer. To test this hypothesis, we plan to carry out intensive studies to elucidate the mechanism of up-regulation of CXCL1 promoting MDSCs infiltration by neddylation overactivation, and evaluate the anti-lung cancer effect and significance of targeting neddylation pathway on the inhibition of MDSCs infiltration. This study will uncover the potential mechanism of neddylation pathway in regulation of the carcinogenesis and progression of lung cancer, and provide a new scientific basis for treatment of lung cancer.

类泛素化Neddylation修饰通路在肺癌中过度活化，促进肺癌发生发展，但其促癌机理尚未阐明。研究发现，灭活肺癌细胞Neddylation通路抑制转录因子NF-κB活性并显著下调其靶基因趋化因子CXCL1的表达。鉴于CXCL1在促进肿瘤微环境髓样抑制细胞（MDSCs）浸润中的重要作用，我们提出假说：Neddylation通路活化可通过激活NF-κB活性上调CXCL1表达，从而促进肺癌组织中MDSCs的浸润和肺癌发生发展；反之，灭活该通路可以抑制MDSCs的肿瘤内浸润进而发挥抑癌效果。本项目旨在检验该假说，深度揭示Neddylation通路活化促进肺癌组织中MDSCs浸润的机理，证实靶向灭活该通路抑制MDSCs浸润的抗肺癌效应，其成功完成有助于深度阐明类泛素化Neddylation通路活化的促癌机理，为靶向该通路抗肺癌治疗奠定坚实的科学基础。

肺癌是全球发病率和死亡率居首的恶性肿瘤，严重危害人类健康。研究表明，Neddylation修饰在肺癌内过度活化，促进肺癌发生发展，但是该通路活化的促癌机理尚未阐明。在肺癌转移模型中，流式细胞免疫组分分析发现，靶向灭活Neddylation通路（药理学手段（MLN4924）和遗传学手段（下调NEDD8））可以显著抑制肺癌内肿瘤相关巨噬细胞（TAM）的浸润，进而抑制肺癌转移。免疫荧光和mRNA转录组分析发现，灭活Neddylation通路抑制CRL泛素连接酶，导致IκBα降解受阻而积聚，从而阻断NF-κB转位到细胞核分泌趋化因子CCL2，最终抑制肺癌内TAMs的浸润。在肺癌皮下移植瘤模型中，利用MLN4924靶向灭活Neddylation通路可以显著抑制肺癌内髓样抑制细胞MDSC浸润。mRNA转录组测序和荧光定量PCR分析发现，Neddylation通路对MDSC浸润的调控作用是由NF-κB-CXCL5信号轴介导的。我们的研究结果揭示Neddylation通路活化对肺癌组织内TAM和MDSC浸润的调控作用，明确靶向Neddylation通路抑制TAM和MDSC浸润的抗肺癌效果与机制，提示Neddylation通路是肺腺癌患者的良好治疗靶点。