NKG2C调控NF-κB磷酸化诱导TAMs极化参与α干扰素抗肝癌侵袭转移的作用机制研究

Based on animal experiment and clinical randomized controlled trials, we have evidenced that interferon alpha (IFN-α) can effectively inhibit the metastasis and recurrence of hepatocellular carcinoma (HCC). Currently, IFN-α has served as one of the effective clinical drugs for HCC patients; However, some HCC patients are not sensitive to IFN-α therapy and the specific mechanism is still not clear. Thus, to explore the exact anti-tumor mechanism of IFN-α has become an urgent need for clinical. In our previous work, we have confirmed that IFN-α can inhibit the metastasis and recurrence of HCC by regulating tumor-associated macrophages (TAMs) polarization through NKG2C-NF-κB signal. This study will establish in vivo and in vitro model of human HCC immune microenvironment to investigate the NKG2C-related key molecule pathway involved in the regulation of IFN-α-induced TAMs polarization. In addition, we will validate the functions of above key molecules by gene transfection and small RNA interference, further elucidating the anti-tumor mechanism of IFN-α, and finally establish molecular model to predict the outcome of IFN-α therapy in HCC patients by our clinical specimen database established previously. Our study will provide the experimental basis for improving the outcomes of IFN-α in HCC.

通过动物及临床随机对照实验，本课题组在国际上率先证实了α干扰素能有效抑制肝癌转移复发。目前，α干扰素是为数不多的临床治疗肝癌有效药物，但存在个体敏感性差异，总体疗效不尽如人意。因此，探明α干扰素抗肝癌的确切机制及寻找筛选治疗敏感人群分子标志，已成为临床迫切需求。前期工作中，我们在证实α干扰素诱导肿瘤相关巨噬细胞（TAMs）极化抗肝癌基础上，筛选α干扰素作用的关键靶分子NKG2C并发现其调控NF-κB磷酸化修饰过程。本研究拟建立模拟人体肝癌免疫微环境的体内及体外模型，通过肝癌细胞及TAMs原代分选纯化及生物芯片等技术，以NKG2C作为α干扰素调控靶点，探讨NKG2C介导TAMs极化对α干扰素抗肝癌作用的影响，并对其具体机制进行初步研究。课题将验证α干扰素靶向作用NKG2C诱导TAMs极化抗肝癌的假说，并最终在已建立的临床标本库基础上构建其疗效预测分子模型，为提高α干扰素疗效提供实验依据。

转移复发限制肝癌术后患者生存率进一步提高，临床匮乏有效药物。通过动物及临床随机对照实验，本课题组在国际上率先证实了α干扰素能有效抑制肝癌转移复发。目前，α干扰素是为数不多的临床治疗肝癌有效药物，但存在个体敏感性差异，总体疗效不尽如人意。因此，探明α干扰素抗肝癌的确切机制及寻找筛选治疗敏感人群分子标志，已成为临床迫切需求。前期工作中，我们在证实α干扰素诱导肿瘤相关巨噬细胞（TAMs）极化抗肝癌基础上，筛选α干扰素作用的关键靶分子NKG2C并发现其调控NF-κB磷酸化修饰过程。本研究拟建立模拟人体肝癌免疫微环境的体内及体外模型，通过肝癌细胞及TAMs原代分选纯化及生物芯片等技术，以NKG2C作为α干扰素调控靶点，探讨NKG2C介导TAMs极化对α干扰素抗肝癌作用的影响，并对其具体机制进行初步研究。课题将验证α干扰素靶向作用NKG2C诱导TAMs极化抗肝癌的假说，并最终在已建立的临床标本库基础上构建其疗效预测分子模型，为提高α干扰素疗效提供实验依据。