KSR1在慢性非可控性炎症诱导肝癌进展中的作用及机制研究

Chronic non-controllable inflammation is regarded as the seventh characteristic of cancers, briefly, the persistent inflammation promotes tumor growth and metastasis; and tumor microenvironment results in sustained inflammation. Currently, the regulatory network cored by NF-kappa B is one of the key linking inflammation and cancer pathology. We previously found KSR1 phosphorylation and nuclear translocation induced hepatocellular carcinoma (HCC) progression. Furthermore, the co-immunoprecipitation combined with mass spectrometry analysis showed that phosphorylation of KSR1 formed a complex with NKAP (positive regulation of NF-KB signal), but not KSR1, and hepatocellular carcinoma cells treated by a certain concentration of TNF alpha induced the up-regulation of KSR1 phosphorylation and nuclear accumulation. On the basis of the KSR1 presents with activation and cell apoptosis resistance characteristics in inflammatory bowel disease, we speculated that KSR1 phosphorylation and nuclear translocation plays an important role in inflammation mediating HCC progression. So we try to clarify the relationship among inflammatory factors, KSR1 phosphorylation and nuclear translocation of KSR1, and the effect of down-regulation KSR1 on inflammatory factors’ function and biological characteristics of HCC cells; and then we try to reveal p-KSR1 interacting protein, p-KSR1/NKAP complex, and the mutual influence between the nucleation mechanism and functions; thirdly, we will reveal that the clinical significance of KSR1 and KSR1 phosphorylation in HCC patients; Finally,we try to verify the above results in nude mice, thus to provide new targets for clinical intervention of hepatocellular carcinoma progression.

慢性非可控性炎症被视为癌症第七大特征：即肿瘤微环境中持续炎症因素促进肿瘤发生发展。目前以NF-κB为核心的信号网络被证实是连接炎症和癌症病理的关键信号网络之一。我们前期研究发现KSR1磷酸化后核易位促进肝癌进展；免疫共沉淀结合质谱分析显示p-KSR1可与NKAP(正向调控NF-κB信号)形成复合物，而非磷酸化KSR1无此功能；炎症介质TNFα处理肝癌细胞可诱导KSR1磷酸化且向核聚集。基于炎症性肠病常伴KSR1活化且细胞呈凋亡抵抗状态及前期发现，我们推测KSR1在NF-κB为核心的炎症-肿瘤调控网络中起关键作用。本研究旨在细胞水平阐明炎症因子与KSR1磷酸化及核易位关系，三者对肝癌细胞生物学特征影响；分子水平揭示p-KSR1相互作用蛋白、p-KSR1/NKAP复合物间相互影响、入核机制及介导的病理作用；组织水平研究p-KSR1/NKAP与患者预后关系并在裸鼠中验证；为肝癌治疗提供新策略。

慢性非可控性炎症被视为癌症第七大特征：即肿瘤微环境中持续炎症因素促进肿瘤发生发展。目前以NF-κB为核心的信号网络被证实是连接炎症和癌症病理的关键信号网络之一。我们研究发现KSR1磷酸化后核易位促进肝癌进展；免疫共沉淀结合质谱分析显示p-KSR1可与NKAP(正向调控NF-κB信号)形成复合物，而非磷酸化KSR1无此功能；炎症介质TNFα处理肝癌细胞可诱导KSR1磷酸化且向核聚集。本研究阐明炎症因子TNFα与KSR1磷酸化及核易位关系，揭示KSR1磷酸促进TNFα调控的下游通路，丰富了肝癌微环境中炎性细胞因子 TNFα促进肝癌进展的分子机制。直接或者间接靶向KSR1/NKAP通路可作为肝癌治疗的新方向。