Chemerin-ChemR23通路在肠道炎癌转化中的作用及其相关免疫机制研究

Inflammatory bowel disease (IBD) is a high risk factor for colon cancer. The malignant rate ofof IBD and incidence of colorectal cancer has been increasing over years in China, however, the therapeutic strategy is limited. Thus, it is important to study the immune mechanism underlying the development of colitis into colon cancer. Chemerin is a recently identified inflammation-related protein. ChemR23 is the main functional receptor of Chemerin. Literature and our previous research indicated that Chemerin-ChemR23 pathways regulated a variety of tissue inflammation, and the expression of Chemerin correlated with the prognosis of several types of tumor. By using knockout mice and mouse model of colitis-associated colon cancer, we found that Chemerin deficiency was able to enhance colon infiltration of neutrophils and IL-6 expression in the colitis phase, and result in increased tumor malignant transformation in the later phase. Inhibition of colon infiltration of neutrophil by CXCR2 inhibitor could reduce IL-6 expression and tumor malignant transformation. Therefore, we proposed that Chemerin-ChemR23 axis could suppress the development of colitis-associated colon cancer through regulation of the colon infiltration of neutrophil and IL-6 expression. We expect that our study will facilitate to identify the critical target cell and molecule on which Chemerin act to influence colitis-associated colon cancer, clarify the underlying regulatory mechanism, finally providing new targets and therapeutic strategies to prevent and treat colon cancer.

炎症性肠病（IBD）是肠癌的重要诱因，我国IBD癌变率及肠癌发病率逐年增加，但治疗手段有限，因此，深入研究肠炎癌转化的免疫机制意义重大。Chemerin是新发现的炎症相关蛋白，ChemR23是其主要功能受体。文献报道和申请人所在课题组前期研究表明Chemerin-ChemR23通路调控多种组织炎症，Chemerin表达水平和多种肿瘤预后相关。利用基因敲除小鼠和肠炎癌转化小鼠模型，我们发现Chemerin缺失促进肠炎期中性粒细胞浸润和IL-6生成，肿瘤生成增加；利用CXCR2抑制剂阻断肠炎期中性粒细胞浸润，可下调IL-6生成并减轻炎癌转化。因此，我们假设Chemerin-ChemR23通路可能通过调控中性粒细胞的肠道浸润，影响IL-6的表达，从而抑制肠炎癌转化。我们拟通过本课题研究，鉴定Chemerin影响炎癌转化的关键靶细胞和分子，阐明其相关免疫调节机制，为肠癌的防治提供新靶点和新策略。

肠炎相关肠癌是一类由IBD恶性转化而来的肠癌类型，是炎症促进肿瘤发生的代表性疾病。Chemerin是近年发现的与免疫调节和代谢密切相关的蛋白，参与了多种组织炎症和代谢相关疾病，Chemerin结合不同类型细胞上的ChemR23，会产生多种不同的效应。我们的前期研究表明：Chemerin缺失导致肠炎期肠道中性粒细胞浸润和炎症因子IL-6的高表达。利用CXCR2拮抗剂阻断Chemerin-/-小鼠肠道中性粒细胞的浸润，导致肠道局部IL-6蛋白水平表达下调，肠道肿瘤生成的减弱。进一步研究我们发现Chemerin在肠炎中的作用依赖其上皮细胞上的CMKLR1发挥作用。进一步机制发现，Chemerin蛋白对中性粒细胞的趋化因子CXCL1/CXCL2的表达没有直接调控作用。通过对肠道菌群的分析，我们发现缺失Chemerin会导致小鼠肠道菌群紊乱。将WT小鼠与Chemerin敲除小鼠同窝饲养以后，Chemerin敲除小鼠肠炎减轻，菌群恢复，CXCL1表达下调，中性粒细胞浸润下降，肠道肿瘤生成减弱，提示Chemerin缺失导致的肠道菌群紊乱是其肠炎加重的主要原因。通过以上研究，我们发现了Chemerin作用其肠上皮细胞，协维持肠道菌群平衡，抑制肠道炎症以及肿瘤产生，该研究为Chemerin治疗肠炎癌提供理论基础。