舌鳞癌VEGF通过YAP/TAZ通路介导施万细胞去分化迁移促进神经周侵袭的机制研究

舌鳞癌神经周侵袭（perineural invasion, PNI）导致疼痛、伸舌困难等神经功能障碍，是预后不良的重要危险特征。研究发现施万细胞（Schwann cell, SC）去分化是肿瘤PNI的起始步骤，但舌鳞癌PNI发生的具体机制尚不清楚。本课题组前期发现VEGF激活YAP/TAZ通路促进SC去分化，故提出舌鳞癌VEGF通过YAP/TAZ通路介导SC去分化启动PNI的假说。本课题首先明确舌鳞癌VEGF与SC去分化具有相关性；然后在体外dSC-DRG模型中将SC与肿瘤细胞共培养，通过计数PNI细胞占比和比较疼痛分子表达以评估PNI程度；最后在动物PNI模型中监测大鼠行为学神经功能和其他PNI表型，进一步探究VEGF促进SC去分化对舌鳞癌细胞PNI的影响，继而深入阐释YAP/TAZ通路参与该过程的分子机制，以期为降低舌鳞癌局部复发、提高治疗预后及减轻患者神经症状提供基础实验证据支持。

Perineural invasion (PNI) of tongue squamous cell carcinoma is an important risk feature of poor prognosis which leads to multiple neurological dysfunction such as pain and difficulty in tongue extension. Studies have shown that Schwann cell (SC) dedifferentiation is the initial step of tumor PNI, but the mechanism of PNI in tongue squamous cell carcinoma remains unclear. Our group found that VEGF can activate the YAP/TAZ pathway to promote SC dedifferentiation, so we proposed the hypothesis that VEGF mediates SC dedifferentiation through the YAP/TAZ pathway to initiate PNI in tongue squamous carcinoma. This study first confirmed the correlation between VEGF and SC dedifferentiation in tongue squamous cell carcinoma. Then, SCs were co-cultured with tumor cells in dSC-DRG model in vitro, and PNI was evaluated by caculating the proportion of PNI cells and comparing the expression of pain molecules. Finally, the effect of VEGF-promoted SC dedifferentiation on PNI of tongue squamous carcinoma cells was further investigated in an animal PNI model by monitoring behavioral neurological function and other PNI phenotypes, and then the molecular mechanism of YAP/TAZ pathway involved in this process was further elucidated, in order to provide basic experimental evidence to reduce local recurrence, improve treatment prognosis and relieve neurological symptoms of patients.