RSK4/O-GlcNAc糖基化正反馈环路促进食管鳞癌侵袭转移的作用及机制研究

我国是食管鳞癌（ESCC）高发地区，约有一半患者在确诊时已出现远处转移，治疗效果不佳。研究表明O-GlcNAc糖基化在ESCC转移中发挥着重要作用。申请人前期研究发现RSK4与ESCC侵袭转移密切相关，p-STAT3和OGT是我们筛选到的RSK4调控靶分子。结合前期研究和预实验结果，我们推测在ESCC中存在着RSK4/O-GlcNAc糖基化正反馈环路，即RSK4通过磷酸化STAT3的S727位点促进OGT转录，导致O-GlcNAc糖基化上调；反过来，O-GlcNAc糖基化修饰RSK4，抑制其泛素化降解提高蛋白表达水平，导致O-GlcNAc糖基化进一步升高，最终形成恶性循环，促进ESCC侵袭转移。本课题将综合利用多种细胞和分子生物学技术，深入系统地阐明RSK4/O-GlcNAc糖基化正反馈环路在ESCC侵袭转移中的作用与调控机制，以期为ESCC的临床治疗提供新的研究思路，并提出潜在药物靶位。

China is an area with a high incidence of esophageal squamous cell carcinoma (ESCC). About half of the patients have had distant metastases at the time of diagnosis, and the treatment effect is not good. Studies have shown that O-GlcNAcylation plays an important role in ESCC metastasis. Our previous study found that RSK4 is closely related to the invasion and metastasis of ESCC, and p-STAT3 and OGT are the molecules regulated by RSK4 we screened. Combining the results of previous studies and preliminary experiments, we speculate that there is a positive feedback loop of RSK4/O-GlcNAcylation in ESCC, that is, RSK4 promotes OGT transcription through phosphorylation of STAT3 S727 site, leading to an up-regulation of O-GlcNAcylation; In turn, O-GlcNAcylation modifies RSK4, inhibiting its ubiquitination degradation and increasing protein expression level, leading to a further increase in O-GlcNAcylation, eventually forming a vicious circle, and promoting ESCC invasion and metastasis. This project will comprehensively utilize a variety of cell biology and molecular biology techniques to thoroughly and systematically clarify the role and regulation mechanism of the RSK4/O-GlcNAcylation positive feedback loop in the invasion and metastasis of ESCC, with a view to providing new research ideas for the clinical treatment of ESCC and proposing potential drug targets.