MIF/IL8/PI3K/AKT信号通路诱导代谢重编程在鼻咽癌放疗抵抗中的作用及分子机制

Our previous study showed that MIF and IL8 upregulation, and activation of AKT signal pathway in radioresistant nasopharyngeal carcinoma cell lines compared to the radiosensitives. Based on PI3K/AKT signaling as an active pathway which regulates key enzymes in the metabolism of aerobic glycolysis, we hypothesize that activation of MIF/IL8/PI3K/AKT pathway induced metabolic reprogramming in cancer associated fibroblast enhances nasopharyngeal carcinoma radioresistance. In this project, we will analyze the association of MIF and IL8 expression, PI3K/AKT activity and key enzymes in the metabolism of aerobic glycolysis with nasopharyngeal carcinoma radiosensitivity; analyze whether or not aberrant upregulation of MIF via IL8/PI3K/AKT pathway activates key enzymes in the metabolism of aerobic glycolysis; and analyze whether or not paracrined MIF enhances nasopharyngeal carcinoma radioresistance through metabolic reprogramming and protective effect in radiation therapy. Our expected data will not only be helpful to reveal the roles and molecular mechanisms of MIF/IL8/PI3K/AKT signaling in nasopharyngeal carcinoma radioresistance, but also can provide potential targets for the radiosensitization and targeted therapy of nasopharyngeal carcinoma.

申请者前期研究发现，放疗抵抗鼻咽癌细胞系MIF和IL8表达上调，AKT信号活化。文献发现，PI3K/AKT信号参与调控糖代谢重编程关键酶。因此，本项目提出“MIF/IL8/PI3K/AKT信号通路诱导代谢重编程增加鼻咽癌放疗抵抗”的科学假设。为验证假说，本项目分析MIF和IL8表达水平，PI3K/AKT信号活性，有氧糖酵解关键酶表达水平与鼻咽癌放射敏感性的关系；分析异常上调的MIF是否通过IL8/PI3K/AKT信号通路调控有氧糖酵解关键酶，证实旁分泌MIF通过诱导肿瘤相关成纤维细胞代谢重编程和放射损伤保护作用增加鼻咽癌放疗抵抗性。本项目研究可阐明MIF/IL8/PI3K/AKT信号通路诱导肿瘤相关成纤维细胞代谢重编程在鼻咽癌放疗抵抗中的作用，同时也为鼻咽癌的放疗增敏和靶向治疗提供靶标。

肿瘤相关成纤维细胞（CAFs）是肿瘤微环境主要的间质细胞，可通过与肿瘤细胞相互作用诱导肿瘤治疗抵抗，但通过何种具体机制诱导放疗抵抗仍不清楚。体外培养的放疗抵抗鼻咽癌细胞系存在炎症因子MIF和IL8表达上调和分泌增加，可激活细胞PI3K/AKT信号通路。本课题研究发现：放疗抵抗鼻咽癌细胞系通过旁分泌MIF调控CAFs有氧糖酵解关键酶，诱导乏氧条件下的细胞放射损伤保护作用，增加鼻咽癌放疗抵抗性。主要研究内容包括：1）TGF-beta1诱导体外培养成纤维细胞（HFF-1和HGF-1）激活CD74/AKT/NF-kB/mTOR信号；2）放疗抵抗鼻咽癌细胞系（CNE2-IR和HNE1-IR）与成纤维细胞共培养，可激活MIF/CD74/AKT/NF-κB/mTOR信号，调控有氧糖酵解关键酶表达；3）线粒体氧化呼吸链抑制剂阿托伐醌或敲低线粒体柠檬酸转运体SLC25A1可通过抑制有氧糖酵解关键酶表达，抑制共培养CAFs细胞AKT/NF-κB/mTOR信号活性，参与体外放疗增敏。结果提示：以放疗抵抗环境中的CAFs为靶标，抑制有氧糖酵解关键酶，可能具有鼻咽癌体外放疗增敏作用。