VEGFA rs2010963多态性与放射性口腔黏膜炎的关联机制及应用研究

Oral mucositis (OM) is one of the most severe toxicities in cancer patients receiving radiotherapy for head and neck area. OM is significantly associated with severe pain, decreased quality of life and excess medical cost. The key point to reduce OM is to clarify the underlying molecular mechanisms. We observed a significant association between VEGFA rs2010963 polymorphism and severe OM in 365 patients with nasopharyngeal carcinoma (NPC), and this association was validated in another 215 NPC patients cohort. Previous studies found this polymorphism may be related with VEGFA expression, however, the relationship between VEGFA and OM is not clear. As a mediator of angiogenesis, VEGFA could be important in the healing of OM. But on the other hand, VEGFA is correlated with proinflammatory cytokines which could be key factors in the progress of OM. Based on above evidence, we suppose that VEGFA rs2010963 polymorphism might affect the expression of VEGFA, which could be involved in development of OM from two different pathways. To verify this hypothesis, we will construct HaCaT cell lines carried VEGFA rs2010963 GG or CC genotypes firstly. The association between genotypes and VEGFA expression will be identified, and we will then compare the radiosensitivity among cell lines and explore the underlying mechanisms. To verify the activity of VEGFA in the development of OM in vivo, mice model with OM will be construct secondly. We will investigate whether VEGFA is involved in the above two different pathways in the progression of OM. Finally, large samples of NPC patients will be recruited prospectively for building a nomogram for predicting severe OM according to genotypes and clinicopathologic factors of patients. With further validation, this model may provide evidence for individualized radiotherapy.

放射性口腔黏膜炎（oral mucositis，OM）严重影响头颈癌患者的治疗和生活质量，加重其医疗负担。阐明OM的分子机制是预防和干预的关键。申请者前期检测鼻咽癌患者6个辐射作用相关基因的9个多态性位点，发现VEGFA rs2010963多态性与365例训练集和215例验证集患者严重OM均明显相关。研究表明该位点多态性可能在转录后水平影响VEGFA的表达，而后者与OM的关系仍未明确。结合前期研究和文献报道，我们推测该位点多态性通过影响VEGFA表达，从调控血管生成和促进炎症因子释放两种途径影响OM的发生。基于此科学假设，本项目拟构建携带不同基因型的HaCaT细胞株，首先明确该位点多态性与VEGFA表达的关系，同时比较细胞放射敏感性的差异，阐明其潜在的分子机制；建立OM小鼠模型，体内鉴定VEGFA对放射性OM的作用及机制；最终开展大样本、前瞻性的鼻咽癌临床研究，建立放射性OM的预测模型。