脑源性巨噬细胞迁移抑制因子经脑肠轴促进结肠癌发生发展的机制研究

Recent studies have discovered that central nervous system disorders can regulate the carcinogenesis and development of gastrointestinal tumors through the brain-gut axis, but its mechanism remains unclear. Central nervous system disorders could cause the abnormal secretion of brain-derived macrophage migration inhibitory factor (MIF) which is a pleiotropic cytokine with the feature of neuroendocrine hormone, and plays an important role in the brain-gut axis. Our previous studies have found that the autism model mice could cause Irritable Bowel Syndrome (IBS) and induce the over-expression of brain-derived neurotrophic factor (BDNF) and inflammatory factors in the colon mucosa by up-regulating the expression of brain-derived MIF. BDNF is highly expressed in colon cancer tissue, and it could promote the growth and metastasis of colon cancer. However, its expression in the peripheral blood of patients with colon cancer is obviously reduced. Thus, we deduce that the brain-derived MIF could promote the carcinogenesis and development of colon cancer by inducing the expression of BDNF via brain-gut axis. Moreover, BDNF could form a bi-directional loop with the enteric nerve to further promote the malignant behavior of colon cancer. Thus, the depression mice model will be established in this study. Various technologies including stereotaxically injection, immunofluorescence and WB will be used to explore the changes of colon microenvironment and its regulatory mechanisms for the development of colon cancer induced by brain-derived MIF via brain-gut axis, which will be a novel theory for the treatments of the digestive system tumor through regulating the central nervous system.

近年研究发现，中枢神经功能紊乱可经脑肠轴调控肠道肿瘤的发生发展，但其作用机制尚不明确。中枢神经功能紊乱可引起脑源性巨噬细胞迁移抑制因子（MIF）分泌异常，而MIF具有神经内分泌激素特性，在脑肠轴通路中发挥重要作用。我们前期研究发现，自闭症模型小鼠可通过上调脑源性MIF诱发肠易激综合征，并可诱导肠粘膜脑源性神经营养因子（BDNF）及炎性因子表达增加。BDNF在结肠癌组织中高表达，可促进肿瘤生长及转移，但其在外周血中的水平却明显降低。因此，我们设想脑源性MIF经脑肠轴诱导BDNF促进结肠癌的发生发展，而且BDNF可与肠神经形成双向作用环路，进一步促进结肠癌的恶性行为。本项目拟通过构建抑郁小鼠模型等，借助脑立体定位注射、免疫荧光、WB等技术，探索脑源性MIF经脑肠轴诱导结肠微环境变化及其对结肠癌发生发展的调控机制，通过调控中枢神经系统，为消化系统肿瘤的治疗研究提供新的理论依据。

近年研究发现，中枢神经功能紊乱可经脑肠轴调控肠道肿瘤的发生发展，但其作用机制尚不明确。中枢神经功能紊乱可引起脑源性巨噬细胞迁移抑制因子（MIF）分泌异常，而MIF具有神经内分泌激素特性，在脑肠轴通路中发挥重要作用。本课题组研究脑源性MIF经脑肠轴通路诱导BDNF促进结肠癌发生发展的相关分子机制。研究过程中发现中枢神经系统功能紊乱导致脑源性MIF表达升高且肠道肿瘤发生率升高。然而脑源性MIF同肠道BDNF表达无明显关联。抑郁小鼠肠道组织蛋白组测序发现PLAGL2及NFIB表达升高明显。PLAGL2及NFIB在肠道肿瘤发生发展过程中发挥着重要的作用，但其机制尚未研究清楚。我们研究表明，上调PLAGL2可通过调节β-catenin/ZEB1进而促进上皮-间质转化并介导结直肠癌转移。NFIB通过AKT通路促进结直肠癌细胞增殖、上皮-间质转化和5-氟尿嘧啶耐药性。中枢神经系统紊乱可影响肠道组织微环境平衡进而参与结直肠癌的发生发展。