GPR35: Role in Colonic Inflammation and Oncogenesis

描述（由申请人提供）：对微生物群的炎症反应被认为有助于人类结直肠癌（CRC）的发生和/或进展。然而，微生物群成员与结肠癌发生之间的分子联系尚不明确。人类结肠厌氧细菌，肠产毒素脆弱拟杆菌（ETBF），是脆弱杆菌的一个分子亚型，产生一种强效的金属蛋白酶毒素，称为脆弱杆菌毒素（BFT）。在小鼠模型中，ETBF是一种有效的结肠肿瘤发生诱导剂，通过诱导选择性的结肠癌前致癌性结肠内Th17免疫反应。ETBF结肠肿瘤发生需要BFT的表达。BFT通过与结肠上皮细胞（CEC）的特异性受体结合，激活了结肠上皮细胞（CEC）的几种前致癌信号通路。然而，BFT CEC受体及其与BFT诱导的致癌信号、结肠炎和结肠肿瘤发生的关系仍有待阐明。通过减法阵列和shRNA策略，GPR35是一种G蛋白偶联受体（GPCR），现在被确定为假定的BFT受体。该研究将验证GPR35是BFT劫持的CEC受体，是结肠癌发生的关键因素，从而在常见微生物群成员和CRC发病机制之间提供了直接的分子联系。GPR35已知在结肠中高表达，先前与胃癌诱导有关。我们将验证这一假设，并使用敲除和敲入CEC策略以及GPR35和ß- artin KO小鼠模型进一步定义GPR35如何促进bft诱导的CEC致癌信号传导。GPRCs是人类基因组中最大的细胞表面受体家族，也是新药发现的有力靶点。因此，确定GPR35或其亚型在结肠癌发生中的作用可能会促进人类结直肠癌的预防和/或治疗。

DESCRIPTION (provided by applicant): Inflammatory responses to the microbiota are proposed as contributory to the initiation and/or progression of human colorectal cancer (CRC). However, molecular links between members of the microbiota and colon carcinogenesis are poorly defined. The human colon anaerobic bacterium, enterotoxigenic Bacteroides fragilis (ETBF), is a molecular subtype of B. fragilis that produces a potent metalloprotease toxin called the B. fragilis toxin (BFT). ETBF is a potent inducer of colon tumorigenesis in a murine model through induction of a selective procarcinogenic intracolonic Th17 immune response. ETBF colon tumorigenesis requires BFT expression. BFT activates several procarcinogenic signaling pathways in colonic epithelial cells (CEC) by binding to a specific receptor localized to CECs. However, the BFT CEC receptor and its relationship to BFT-induced oncogenic signaling, colitis and colon tumorigenesis remain to be elucidated. Through subtraction array and shRNA strategies, GPR35, a G protein-coupled receptor (GPCR), is now identified as the putative BFT receptor. This proposal will test the hypothesis that GPR35, known to be highly expressed in the colon and previously linked to gastric cancer induction, is the CEC receptor hijacked by BFT and a critical contributor to colon carcinogenesis, thereby, providing a direct molecular link between a common microbiota member and CRC pathogenesis. We will test this hypothesis and further define how GPR35 contributes to BFT-induced CEC oncogenic signaling using knockout and knock-in CEC strategies plus GPR35 and ß-arrestin KO murine models. GPRCs represent the largest family of cell surface receptors within the human genome and powerful targets for new drug discovery. Thus, establishing a role for GPR35 or its isoforms in colon carcinogenesis may advance the prevention and/or therapy of human CRC.