THE ROLE OF ENDOCANNABINOIDS AND THEIR RECEPTORS IN COLORECTAL CANCER

内源性大麻素及其受体在结直肠癌中的作用

基本信息

批准号：
9095170
负责人：
RAYMOND N. DUBOIS
金额：
$ 32.38万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9095170
关键词：
Agonist Animals Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Attenuated Biological Process CNR1 gene CNR2 gene Cardiovascular system Cell Death Cell Fate Control Cell Survival Cells Chemopreventive Agent Chronic Colonic Neoplasms Colorectal Cancer Combined Modality Therapy Coupled Coxibs DNA Methylation DNA Methylation Inhibition DNA Repair Gene Data Diet Dietary Fats Dinoprostone Dose Endocannabinoids Epithelial Cells Equilibrium FAAH inhibitor Fatty acid glycerol esters G-Protein-Coupled Receptors GTP-Binding Proteins Genes Genetic Growth Human Immune In Vitro Inflammation Inflammatory Instruction Intestinal Polyps Intestines Lead Lipids Malignant Neoplasms Mediating Metabolism Methylation Pathway interactions Play Process Property Prostaglandin-Endoperoxide Synthase Prostaglandins Risk Factors Role Signal Transduction Therapeutic Translational Research Treatment Protocols Tumor Suppressor Proteins adenoma antitumor agent antitumor effect arachidonate base cannabinoid receptor carcinogenesis celecoxib colon carcinogenesis colon tumorigenesis cyclooxygenase 2 fatty acid amide hydrolase genome-wide in vivo lipid mediator mouse model neoplastic cell novel novel strategies prevent promoter receptor research study tumor tumor growth tumor progression

项目摘要

Pro-inflammatory prostaglandin E2 (PGE2) is the most abundant prostaglandin found in human colorectal cancers and plays a predominant role in promoting tumor growth. In contrast to the role of PGE2 in carcinogenesis and inflammation, another of the arachidonate-based bioactive lipids, endocannabinoids, exert potential anti-tumor effects on a wide spectrum of human tumors in vitro and have proven antiinflammatory properties. Opposing effects of PGE2 and endocannabinoids on inflammation and cancer progression prompted us to hypothesize that PGE2 and endocannabinoids coordinately control tumor progression. Endocannabinoids primarily activate two G-protein-coupled cannabinoid receptors CBI and CB2 and are degraded by fatty acid amide hydrolase (FAAH). Based on our preliminary data, cross talk exists between PGE2 and endocannabinoid signaling. PGE2 can downregulate CBI expression via DNA methylation, whereas a selective COX-2 inhibitor restores CBI expression. However, little is known regarding the role of CB1, CB2 and FAAH in colorectal cancer progression. This proposal will examine the following: 1) The role of PGE2 in silencing tumor suppressors, DNA repair genes, and tumor inhibitory genes via DNA methylation during the colon tumor progression. 2) The role of endocannabinoid signaling in colorectal cancer progression by examining the biological functions of FAAH and by evaluating whether a combinational treatment of a CB1 agonist with a demethylating agent or a selective COX-2 inhibitor achieves optimal anti-tumor effects of CBI agonists in vivo. 3) The influence of endocannabinoid signaling on inflammation-associated colorectal tumorigenesis by defining the role of CB1, CB2 and FAAH in the mouse models of inflammation-associated colonic carcinogenesis and by evaluating the relative contributions of the endocannabinoid signaling in epithelial cells versus immune cells. In summary, we expect to generate novel mouse models and new approaches to study the role of PGE2-mediated inflammation, its influence on DNA methylation and suppression of the anti-inflammatory role of the endocannabinoid pathway in the progression of colorectal cancer.

促炎性前列腺素E2（PGE2）是人类结直肠癌中发现的最丰富的前列腺素，在促进肿瘤生长中起主要作用。与PGE2在癌变和炎症中的作用相反，基于蛛网膜酸的生物活性脂质，内源性大麻素，内源性大麻素，在体外对广泛的人类肿瘤发挥了潜在的抗肿瘤作用，并已证明是抗肿瘤的作用特性。 PGE2和内源性大麻素对炎症和癌症进展的相反影响促使我们假设PGE2和内源性大麻素可以协同控制肿瘤的进展。内源性大麻素主要激活两个G蛋白偶联的大麻素受体CBI和CB2，并被脂肪酸酰胺水解酶（FAAH）降解。根据我们的初步数据，PGE2和内源性大麻素信号之间存在串扰。 PGE2可以通过DNA下调CBI表达甲基化，而选择性COX-2抑制剂恢复了CBI的表达。但是，关于CB1，CB2和FAAH在结直肠癌进展中的作用知之甚少。该建议将检查以下内容：1）在结肠肿瘤进展过程中，PGE2在沉默的肿瘤抑制子，DNA修复基因和肿瘤抑制基因中的作用。 2）内源性大麻素信号在结直肠癌的进展是通过检查FAAH的生物学功能，并评估与脱甲基化剂的CB1激动剂的组合治疗是否能够达到CBI激动剂在体内的最佳抗肿瘤作用。 3）内源性大麻素信号传导对与炎症相关的结直肠肿瘤发生的影响，通过定义CB1，CB2和FAAH的作用通过评估上皮细胞与免疫细胞中内源性大麻素信号传导的相对贡献，与炎症相关的结肠癌发生模型。总而言之，我们期望生成新型的小鼠模型和新方法来研究PGE2介导的炎症的作用，其对DNA甲基化的影响以及抑制内源性大麻素途径中抗炎作用的作用结直肠癌的进展。