具核梭杆菌调节lncRNA HOTTIP表达促进胃癌耐药的分子机制及临床价值研究

化疗耐药是困扰胃癌临床治疗的难点，也是影响患者复发和预后的重要因素，如何对其及时、有效评估一直是临床关注的焦点。前期工作中，我们发现胃内菌群，尤其具核梭杆菌（Fn），可调节lncRNA HOTTIP表达，抑制顺铂引起的自噬，参与胃癌细胞耐药的发生。据此，本项目提出假说：Fn通过调节自噬导致化疗耐药，可能与HOTTIP/miR-216a-5p/Bcl-2轴有关。现拟：扩大临床样本数，并采用体内裸鼠移植瘤模型和体外细胞功能实验，进一步评价Fn在判断胃癌化疗后复发和耐药中的价值；同时，基于高通量测序中HOTTIP的ceRNA作用网络，验证HOTTIP、miR-216a-5p和Bcl-2的相互作用，阐述自噬在Fn导致胃癌耐药中的分子机制；进而，通过唾液Fn DNA检测，为临床化疗疗效监测提供潜在指标。本研究不仅有助于进一步丰富胃癌复发耐药的分子理论，而且为疗效监测提供了新的思路和检测手段。

Chemoresistance, closely involved in the recurrence and prognosis of gastric cancer, is one of the unsolved problems that perplex the clinical treatment. How to evaluate chemoresistance timely and effectively has always been in focus of clinical practices. In the previous studies, we found that gastric microbiota, especially F. nucleatum, regulated the expression of lncRNA HOTTIP, resulting in inhibition of autophage caused by cisplatin, and promotion the chemoresistance of gastric cancer cells. Based on the previous observations, we proposed a hypothesis that F. nucleatum might regulate autophage and chemoresistance through a HOTTIP/miR-216a-5p/Bcl-2 axis. According to the hypothesis, we plan to further explore the role of F. nucleatum in chemoresistance evaluation of gastric cancer though pathological samples, in vivo xenograft tumor model and in vitro functional assays. Meanwhile, based on the ceRNA network of HOTTIP established through high throughput sequencing, we would investigate the interactions among HOTTIP, miR-216a-5p and Bcl-2, trying to demonstrate the molecular mechanisms of autophage in F. nucleatum-regulated chemoresistance. Moreover, we would propose potential markers for clinical monitoring by analyzing the DNA of F. nucleatum in saliva of gastric cancer patients. Our study would provide important supplements for the molecular mechanisms in the recurrence and chemoresistance of gastric cancer, and propose novel method for therapeutic efficiency monitoring.