LTβR调控p53-GSDMD触发的细胞焦亡在胃癌放疗抵抗中的作用与机制

放疗在中晚期及复发胃癌的治疗中具有重要地位，放疗抵抗是绝大多数胃癌患者放疗失败的主要原因。前期研究发现淋巴毒素β受体（LTβR）能通过抑制胃癌细胞焦亡导致放疗抵抗，并发现此过程由LTβR抑制p53触发的焦亡关键执行蛋白gasdermin的活化所介导；此外还发现gasdermin家族成员GSDMD表达受LTβR调控。基于此，提出如下假说：胃癌中高表达的LTβR在电离辐射下通过抑制p53活性使胃癌细胞获得非caspase依赖的由GSDMD介导的细胞焦亡的抗性，产生放疗抵抗，导致治疗失败。本项目拟在细胞、组织和动物模型中通过一系列生物化学与细胞生物学方法阐明LTβR-p53调控GSDMD介导胃癌细胞焦亡影响放疗抵抗的分子机理，明确LTβR、gasdermin作为胃癌放疗增敏、诊断和预后判断分子靶标的潜在价值，同时为胃癌的治疗提供新的理论依据与策略。

Radiotherapy plays an important role in the treatment of advanced and recurrent gastric cancer. Radio-resistance is the main cause of radiotherapy failure in most patients with gastric cancer. Our previous study found that lymphotoxin beta receptor (LTβR) may play a role of radio-resistance by inhibiting the pyroptosis of gastric cancer cells. This process depends on the activation of gasdermin mediated by p53. In addition, as a key executive protein of pyroptosis, the expression of gasdermin D (GSDMD) was negatively correlated with LTβR. Hence, we proposed that LTβR can promote the radio-resistance in gastric cancer via inhibiting p53-GSDMD triggered pyroptosis independent on caspase, which leads to treatment failure. We will intend to further clarify the molecular mechanism of LTβR regulating p53-GSDMD triggered pyroptosis and influencing radio-resistance through a series of biochemistry and cell biology methods via gastric cancer cells, gastric cancer tissues and gastric cancer animal models. Besides, this study will investigate the potentiality of LTβR and GSDMD as molecular targets for the radio-sensitization, diagnosis and prognosis of gastric cancer. The results of this study will provide new theoretical basis and strategy for the prevention and treatment of gastric cancer.