外泌体miR-155-PPARγ/PGC-1α介导的代谢重编程调控口腔鳞癌相关成纤维细胞促血管生成表型的分子机制

我们前期研究表明，肿瘤外泌体既介导CAFs代谢重编程又能诱导促血管生成表型，但二者之间是否存在共同的分子开关并不清楚。miRNAs具有广泛的基因调节功能，是介导肿瘤-基质细胞对话的重要信使。因此，本课题提出“外泌体miR-155/PGC-1α通过介导CAFs代谢重编程调控口腔鳞癌CAFs促血管生成表型”，重点探讨：①口腔鳞癌外泌体调控CAFs代谢重编程及促血管生成表型；②miR-155对调控CAFs代谢重编程的调控；③PPARγ/PGC-1α对CAFs代谢重编程及促血管生成表型的门控作用；④miR-155调控CAFs中PPARγ/PGC-1α和ROS的机制；⑤ROS/PFKFB3介导的代谢重编程在miR-155诱导CAFs促血管生成表型中的机制。本课题对阐明口腔鳞癌外泌体介导的代谢重编程调控CAFs促血管生成表型的全新分子机制，以及筛选针对CAFs的新型治疗靶标均具有重要意义。

Exosomes are important messengers of intercellular communication that mediate tumor-stromal cell interactions. Our previous studies confirmed that tumoral exosomes mediated metabolic reprogramming of cancer-associated fibroblasts (CAFs) and induced their pro-angiogenic phenotype via transferring miR-155, but the association between the metabolic reprogramming and pro-angiogenic phenotype acquisition of CAFs is unclear. In conjunction with other findings, we propose that "exosomal miR-155 regulates the pro-angiogenic phenotype of oral squamous cell carcinoma (OSCC)-CAFs by mediating their metabolic reprogramming". This project aimed mainly to investigate: ⅰ) roles of OSCC-exosome in the regulation of metabolic reprogramming and pro-angiogenic phenotype of CAFs;ⅱ) roles of exosome-mediated miR-155 transmission in the regulation of CAFs activation and metabolic reprogramming; ⅲ) gating effect of PPARγ/PGC-1α on metabolic reprogramming and pro-angiogenic phenotype acquisition of CAFs in OSCC; iv) mechanisms underlying the regulation of PPARγ/PGC-1α expression and ROS levels in CAFs by OSCC-exosomal miR-155; v) mechanisms underlying the regulation of miR-155-mediated pro-angiogenic phenotype acquisition by ROS/PFKFB3-mediated metabolic reprogramming. This study links exosome-mediated intercellular communication, miRNA-governed gene regulation, metabolic reprogramming, and pro-angiogenic phenotype of CAFs and explore the role of exosome-mediated metabolic reprogramming in regulating the pro-angiogenic phenotype acquisition of CAFs in OSCC.