Neddylation通路活化上调CCL2表达促进肺癌微环境巨噬细胞招募的机制研究

Lung cancer severely endangers human health, which is urgent to clarify its pathogenesis and explore new therapeutic strategies. We found that the Neddylation pathway is over-activated in lung cancer, and negatively related to the prognosis of patients significantly. Moreover, inactivation of Neddylation pathway inhibits the NF-κB pathway and down-regulates the expression of its target gene CCL2. In view of the CCL2 function in promotion of tumor associated macrophages (TAM) infiltration and inhibition of the anti-tumor immune response, we hypothesized that the activation of Neddylation pathway can activate the NF-κB pathway and the CCL2 expression, and promote the infiltration of TAM and development of lung cancer. On the contrary, inactivation of Neddylation pathway to down-regulate the CCL2 expression can stimulate the immune response against lung cancer. To test this hypothesis, this project will study the mechanism of NF-κB/CCL2 pathway activation and TAM infiltration by Neddylation modification, and to evaluate the anti-cancer effect in inhibition of NF-κB/CCL2 pathway and TAM infiltration by targeting Neddylation pathway. Our study will help to further clarify the mechanism of Neddylation pathway in the development of lung cancer, and provide a new scientific basis for the treatment of lung cancer.

肺癌严重危害人类健康，亟待阐明其发生机理，探索新型治疗策略。我们前期研究发现Neddylation通路在肺癌内过度活化，且与患者预后呈显著负相关；灭活Neddylation通路可抑制NF-κB通路并下调其靶基因CCL2表达。鉴于CCL2促进肿瘤相关巨噬细胞（TAM）浸润并抑制机体抗肿瘤免疫应答，我们提出假说：Neddylation通路活化激活NF-κB通路上调CCL2表达，促进TAM浸润和肺癌发生发展；相反，灭活Neddylation通路下调CCL2表达可激发抗肺癌免疫应答。为检验该假说，本项目将研究Neddylation修饰激活NF-κB/CCL2通路、促进TAM肺癌内浸润的机制，进而评价靶向Neddylation修饰抑制NF-κB/CCL2通路和TAM浸润的抗肺癌作用。该项目有助于进一步阐明Neddylation通路调控肺癌发生发展的分子机制，为靶向此通路抗肺癌治疗提供新的科学依据。

肺癌严重危害人类健康，亟待阐明其发生机理，探索新型治疗策略。我们前期研究发现Neddylation通路在肺癌内过度活化，且与患者预后呈显著负相关；灭活Neddylation通路可抑制NF-κB通路并下调其靶基因CCL2表达。鉴于CCL2促进肿瘤相关巨噬细胞（TAM）浸润并抑制机体抗肿瘤免疫应答，我们提出假说：Neddylation通路活化激活NF-κB通路上调CCL2表达，促进TAM浸润和肺癌发生发展；相反，灭活Neddylation通路下调CCL2表达可激发抗肺癌免疫应答。为检验该假说，本项目重点研究Neddylation通路活化对NF-κB/CCL2通路、TAM浸润的调控作用，Neddylation通路通过NF-κB转录激活CCL2表达的调控机制， Neddylation通路控通过调控CCL2表达介导肺癌内巨噬细胞浸润的作用与机制，以及研究Neddylation/NF-κB/I-κBα/CCL2通路与巨噬细胞浸润在肺癌组织样本中的相关性及临床病理学意义。我们发现，NEDD8与CCL2在肺癌内均显著高表达，且两者表达呈显著正相关；Neddylation通路过度活化通过激活NF-κB转录上调CCL2并进而诱导肺癌微环境巨噬细胞招募；相反地，利用小分子抑制剂MLN4924靶向灭活Neddylation通过诱导I-κBα积聚，从而导致NF-κB转录活性被抑制/CCL2下调来发挥抗肿瘤效应。该项目的成功完成充分阐明了Neddylation在肺癌过度活化通过调控肿瘤微环境的促癌分子机制，为靶向Neddylation通路抗肺癌治疗提供新的科学依据。