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是导致人类结直肠癌（CRC）发生和/或进展的原因。然而，微生物群成员与结肠癌发生之间的分子联系尚不清楚。人结肠厌氧细菌，产肠毒素脆弱类杆菌（ETBF），是B的分子亚型。fragilis产生一种称为B的有效金属蛋白酶毒素。脆壁毒素（BFT）。ETBF通过诱导选择性的前致癌性结肠内Th 17免疫应答，在小鼠模型中是结肠肿瘤发生的有效诱导剂。ETBF结肠肿瘤发生需要BFT表达。BFT通过与定位于结肠上皮细胞（CEC）的特异性受体结合来激活CEC中的几种前致癌信号通路。然而，BFT CEC受体及其与BFT诱导的致癌信号传导、结肠炎和结肠肿瘤发生的关系仍有待阐明。通过差减阵列和shRNA技术，G蛋白偶联受体（GPCR）GPR 35被鉴定为BFT受体。该提案将测试以下假设：已知在结肠中高度表达且先前与胃癌诱导相关的GPR 35是被BFT劫持的CEC受体，并且是结肠癌发生的关键贡献者，从而提供了常见微生物群成员与CRC发病机制之间的直接分子联系。我们将测试这一假设，并使用敲除和敲入CEC策略加上GPR 35和β-arrestin KO小鼠模型进一步确定GPR 35如何有助于BFT诱导的CEC致癌信号传导。GPRC代表了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GPR 35或其亚型在结肠癌发生中的作用可能会促进人类CRC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.