NCOA3/MTHFD1L通过调控氧化还原稳态诱发舌鳞癌放疗抵抗的机制研究

MTHFD1L是叶酸循环和细胞代谢的关键酶，深入研究其调控肿瘤生长与放疗抵抗的作用机制意义重大。前期研究我们发现：MTHFD1L在舌鳞癌中高表达，与患者不良预后正相关；其调控舌鳞癌细胞的氧化还原稳态，促进肿瘤生长和放疗抵抗；NCOA3可结合MTHFD1L启动子并激活其转录。因此，我们推测NCOA3通过调控MTHFD1L表达影响舌鳞癌细胞的氧化还原稳态，进而调控舌鳞癌的生长和放疗抵抗。本课题将通过体外体内实验，确定NCOA3在MTHFD1L启动子上的结合能力和位点，垂钓发现与NCOA3相互结合的互作蛋白，明确NCOA3调控MTHFD1L表达和氧化还原稳态以及舌鳞癌放疗抵抗中的作用及机制。另外，分析舌鳞癌患者组织标本和临床资料，研究NCOA3和MTHFD1L的表达相关性，确定它们在舌鳞癌治疗和预后等方面的临床意义。本项目将为阐明舌鳞癌发生发展和放疗抵抗机制提供新的理论和实验依据。

MTHFD1L is the key enzyme of folate cycle and cell metabolism. It is of significance to study the mechanism of action of MTHFD1L in regulating tumor growth and radiotherapy resistance. In our previous study, we found that MTHFD1L was highly expressed in tongue squamous cell carcinoma (TSCC) and correlated with a poor prognosis. It regulated redox homeostasis of TSCC cells, and thus promoted tumor growth and radiotherapy resistance. We also found that NCOA3 bound to the promoter of MTHFD1L and activated its transcription. In the study, we proposed that NCOA3 regulated TSCC growth and radiotherapy resistance by affecting the redox homeostasis via regulating the expression of MTHFD1L. In this study, we will identify the binding ability and binding sites of NCOA3 at MTHFD1L, and pull down and discover the proteins interacting with NCOA3, and elucidate the mechanism by which NCOA3 regulated MTHFD1L expression, redox homeostasis, TSCC growth and radiotherapy resistance in vitro and in vivo. In addition, we will also analyze the TSCC tissue samples and clinical data to reveal the correlation between NCOA3 and MTHFD1L expression, thereby identifying the clinical significance of TSCC therapy and prognosis. These results will provide a theoretical and experimental basis for identifying the mechanism involved in TSCC tumorigenesis and radiotherapy resistance.