ROS介导的ABL1调控胃癌相关性抑郁的分子机制研究

Depression affects clinical treatment and the long-term prognosis of patients .The ROS level is related closely to the development of depression. Our preliminary work showed that morbidity of depression among patients with gastric cancer (GC) exceeded 50%. GC patients with depression had shorter survival time, and had serious redox imbalance as well as increased ROS levels. The gene chip of the tissue samples showed that oxidavive stress/ROS associated gene proto oncogene ABL1 increased accompaning with the maladjustment of proinflammatory cytokines. It is demonstrated that ABL1 activate NF-kB, subsequently promoting the secretion of proinflammatory cytokines in tumor cells such as IL-6, which accounts for depressive like behavior. Therefore, we put forward the hypothesis the development of depression in the gastric adenocarcinoma is involved in ROS mediated ABL1 pathway through mediating the expression of proinflammatory cytokines. Here, we will establish GC patient derived xenograft (PDX) mouse models with depression, treating ABL1-/- mices with chronic mild stress and Helicobacter pylori +MNNG. Then, we will explore the role of ABL1 in GC associated depression and progress of GC by analyzing mice behaviors, hippocampus iconography of mice models,miR-21, proinflammatory cytokines and 5-HT. The project aims to clarify the molecular mechanism of GC-related depression by investigating ROS mediated ABL1 pathway. The research focuing on ROS / ABL1 of gastric cancer as the breakthrough point will help us to find new clinical ways to treat other cancers with depression. Taking ABL1 as the starting point, this project will enable us to explore the pathogenesis of tumor associated depression in-depth, and pave the way for clinical therapy of depression.

抑郁影响肿瘤临床治疗及预后，活性氧自由基（ROS）与抑郁的发生密切相关。我们前期工作发现胃癌抑郁症状发生率超过50%，生存期短。胃癌抑郁患者ROS水平异常增高，与氧化应激/ROS密切相关的原癌基因ABL1异常高表达，IL-6等多种炎症因子表达失调。研究表明ABL1能激活NF-κB，促进肿瘤细胞分泌导致抑郁样行为产生的IL-6等炎症因子。由此假设：ROS介导的ABL1通过调控炎症因子的表达导致胃癌相关性抑郁。本课题构建胃癌PDX小鼠抑郁模型、ABL1基因敲除小鼠模型，胃癌细胞ABL1上/下调小鼠模型，通过对比观察小鼠行为学、肿瘤生物特征、ROS/ABL1相关基因表达、miR-21、炎症因子及5-HT等指标的变化来阐明抑郁和胃癌进展的关系，探索ROS介导的ABL1调控胃癌相关性抑郁的分子机制。本课题以ABL1为切入点研究肿瘤抑郁的发病机制，为靶向于ABL1的心理治疗药物研发提供理论依据。

1.背景：随着胃癌患者生存期的延长，越来越多的胃癌患者出现抑郁症状。抑郁的出现不仅影响胃癌患者的生活质量，而且与胃癌患者较短的生存期以及治疗耐受相关。然而，胃癌与抑郁之间相互作用的分子机制目前仍不明确；此外，对于胃癌伴抑郁患者，临床上缺乏潜在的诊断及预后生物标记物。研究证实活性氧自由基（reactive oxygen species，ROS）参与胃癌和抑郁的病理生理过程，且参与炎症信号通路调控。那么ROS及炎症信号通路是否参与胃癌与抑郁之间的相互作用呢？在本研究中，我们设计相关实验探究胃癌和抑郁之间相互作用的分子机制；寻找胃癌伴抑郁患者潜在的诊断和预后生物标记物。.2.主要研究内容：（1）通过临床标本分析氧化应激和炎症标志物与胃癌伴抑郁患者临床特征之间的相关性；（2）通过胃癌细胞系和相应的动物模型探究胃癌与抑郁之间相互作用的潜在分子机制；（3）通过蛋白质谱分析胃癌伴抑郁患者异常表达的蛋白寻找胃癌伴抑郁患者潜在的诊断和预后生物标志物。.3.重要结果：（1）胃癌伴抑郁患者预后不良，处于高氧化应激状态；胃癌患者炎症水平与抑郁和TNM分期具有相关性。（2）ROS通过激活ABL1调控胃癌细胞中炎症信号通路；ROS/ABL1/炎症信号通路参与胃癌进展。（3）胃癌与抑郁能够相互促进，高氧化应激状态下肿瘤组织和海马组织中ABL1激活的炎症信号通路参与胃癌和抑郁的相互作用。（4）中性粒细胞脱颗粒相关蛋白ELANE与胃癌患者预后相关，在胃癌伴抑郁患者肿瘤组织和血清中均升高，是胃癌伴抑郁患者潜在的诊断和预后生物标志物。.4.关键数据及意义：（1）对胃癌PDX小鼠进行行为学检测发现荷瘤能够诱发小鼠抑郁样行为，伴小鼠血清氧化应激指标ROS和8-OHdG的增高以及ABL1和炎症信号通路在小鼠海马组织中的激活。表明胃癌和抑郁能够相互促进。（2）高表达的ELANE和VIM与胃癌患者较短的生存期相关。通过ELISA确认与胃癌不伴抑郁患者相比，CXCL1和ELANE在胃癌伴抑郁患者血清中显著升高。因此是胃癌伴抑郁患者潜在生物标志物。