Tristetraprolin抑制细胞衰老相关分泌表型提高胃癌新辅助化疗敏感性的作用及机制研究

新辅助化疗是提高局部进展期胃癌手术根治率的重要手段，但对耐药患者则会延误手术时机，因此有必要寻找一种能预判其疗效的生物标志物以区分获益与非获益人群。 细胞衰老相关分泌表型（SASP）导致化疗耐药，而Tristetraprolin（TTP）可抑制SASP相关产物表达。我们前期研究提示：胃癌新辅助化疗效果与TTP及SASP相关因子表达密切相关。由此推测：TTP可通过抑制SASP提高胃癌新辅助化疗敏感性，其极可能成为提示新辅助化疗敏感性的生物标志物。本项目拟在此基础上，首先通过回顾性研究进一步明确胃癌TTP表达与新辅助化疗效果的正相关性，然后证实TTP通过抑制SASP提高化疗敏感性的作用及机制，最后分析临床胃癌TTP表观遗传学改变、基因多态性等与新辅助化疗效果之间的关系，并进行临床验证。 本课题将阐明TTP提高胃癌新辅助化疗敏感性的作用及机制，明确其为预测胃癌新辅助化疗临床疗效的关键生物标志物.

Neoadjuvant chemotherapy is an important means to improve surgical cure rate of locally advanced gastric cancer，but for patient who is resistant to chemotherapy it will delay the timing of surgery. It is necessary to find a biomarker to distinguish the patients who can benefit from the neoadjuvant chemotherapy. Cell senescence-associated secretory phenotype (SASP) cause resistance to chemotherapy, and Tristetraprolin (TTP) inhibits expression of SASP-related products. Our previous studies have shown that the effect of neoadjuvant chemotherapy is closely related with TTP and SASP-related factors expression in gastric cancer. So we put forward the hypothesis that TTP can improve gastric neoadjuvant chemotherapy effcet by suppression SASP, and TTP may be distinguished as neoadjuvant chemotherapy biomarkers. So based on our previous studis，we will first do retrospective studies to further clarify the relationshio of TTP expression and neoadjuvant chemotherapy effect, then by in vitro studies we will confirmed that TTP enhance chemosensitivity by inhibiting SASP and exploring its mechanisms. At last we will analyze the relationship between the TTP epigenetic changes, gene polymorphism and neoadjuvant chemotherapy effect. This study will clarify the role and mechamism that Tristetraprolin enhances sensitivity of neoadjuvant chemtherapy in the gastric cancer by inhibition of cell senescence-associated secretory phenotype, and the significance of TTP as biomarkers for predicting clinical effect of neoadjuvant chemotherapy in gastric cancer.