Soluble epoxide hydrolase as a novel target of colitis-induced carcinogenesis

可溶性环氧化物水解酶作为结肠炎诱发癌变的新靶点

基本信息

批准号：
8309390
负责人：
Guang-Yu Yang
金额：
$ 30.41万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309390
关键词：
3-nitrotyrosine Abbreviations Acids Acute Adamantane Anemia Animals Anti-Inflammatory Agents Anti-inflammatory Arachidonate 5-Lipoxygenase Arachidonic Acids Benzoic Acids Biology Bronchitis Carcinoma Cell Line Cells Chemopreventive Agent Chronic Colitis Colon Carcinoma Development Dietary Iron Disease Down-Regulation Dysplasia Effectiveness Enzymes Epoxide hydrolase Epoxy Compounds Esters Event Genes Goals Health Hemorrhage Human Hydrolase Gene Hydrolysis Hypertension Immunochemistry In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-10 Kidney Knock-out Knockout Mice LOX gene Lauric Acids Lead Lipopolysaccharides Malignant Neoplasms Mediating Metabolism Microsomal Epoxide Hydrolase Modeling Mucinous Mus NF-kappa B Neutrophil Infiltration Oxidative Stress PPAR gamma PTGS2 gene Pathway interactions Patients Pharmacology Physiological Positioning Attribute Prevention Risk Factors Rodent Model Role Signal Transduction Smoking Sodium Dextran Sulfate Specificity Specimen Supplementation Ulcer Ulcerative Colitis Vascular Cell Adhesion Molecule-1 base carcinogenesis cyclooxygenase 2 inhibitor/antagonist iron supplementation macrophage molecular pathology mouse model neutrophil novel novel strategies prevent water channel

项目摘要

DESCRIPTION (provided by applicant): The overarching goal for this project is to provide an efficient agent for the prevention of colitis-induced cancer. Chronic colitis is a well-recognized risk factor of colon cancer; an increase in colitis-induced aberrant arachidonic acid (AA) metabolites is a key event leading to cancer development. Epoxyeicosatrienoic acids (EETs) are AA metabolites with anti-inflammatory activity; under physiological conditions, EETs are quickly inactivated as they are converted to their corresponding dihydroxyeicosatrienoic acids (DHETs) by the enzyme soluble epoxide hydrolase (sEH) (1, 2). The inhibition of sEH prevents the complete hydrolysis of the epoxide, reducing the conversion of EETs to DHETs. Our preliminary studies have shown that 1) sEH inhibitors AUDA- nBE and t-AUCB significantly inhibit colitis and ulcer formation by suppressed macrophage/neutrophile activity as well as decreased iNOS expression and its mediated nitrotyrosine formation. 2) AUDA-nBE induced PPAR- gamma activity and inhibited NF-kB signaling. iNOS, COX2, 5-LOX, nitro-oxidative stress and VCAM-1 was also inhibited in vitro cell lines (15). 3) Long-term administration of t-AUCB inhibited development of colitis- induced dysplasia and carcinoma in rodent models. Our hypothesis is targeting sEH as a novel approach for the prevention of colitis-induced carcinogenesis is through inhibiting sEH significantly to reduce the conversion of EETs to their corresponding DHETs. The proposed mechanism for the inhibition of inflammation is by suppressing inflammatory cell recruitment, modulating the arachidonic acid metabolite profile and further targeting the PPAR-gamma and NF-kB pathways to lead to an inhibition of COX-2, 5-LOX, iNOS, as well as VCAM-1. The following specific aims are performed: 1) Determine the role of sEH in colitis-induced carcinogenesis using sEH knockout mice in our novel DSS-induced carcinogenesis model, and a spontaneous colitis-carcinogenesis model in double-knockout (sEH and IL-10) mice. 2) Determine the effectiveness of the highly potent and selective sEH inhibitor as a chemopreventive agent against colitis-induced carcinogenesis in both DSS- induced and spontaneous colitis-carcinogenesis mouse models. 3) Determine the mechanism for the inhibition of colitis-induced carcinogenesis by sEH inhibitors in specimens from animals used in the aforementioned two specific aims as well as from in vitro cell lines and conditional PPAR-gamma knockout mice. PUBLIC HEALTH RELEVANCE: Chronic inflammation is one of the most important factors contributing to human cancer. Chronic colitis is a well-recognized risk factor of colon cancer. The goal for this project is to provide an efficient compound for prevention of colitis-induced colon cancer. Epoxyeicosatrienoic acids (EETs) are AA metabolites with anti- inflammatory activity. The inhibition of sEH prevents the complete hydrolysis of the epoxide, reducing the conversion of EETs to DHETs. Thus, EET-sEH inhibition would be efficient pathway for anti-colitis induced carcinogensis. In this project, we are in unique position to investigate the mechanism based prevention of colitis-driven carcinogenesis using potent and selective sEH inhibitor and sEH gene knockout mice combined with unique mouse models molecular pathology and pharmacology approaches.

描述（由申请人提供）：该项目的总体目标是提供一种有效的药物来预防结肠炎诱发的癌症。慢性结肠炎是公认的结肠癌危险因素。结肠炎引起的异常花生四烯酸（AA）代谢物的增加是导致癌症发展的关键事件。环氧二十碳三烯酸 (EET) 是具有抗炎活性的 AA 代谢物；在生理条件下，EET 会被可溶性环氧化物水解酶 (sEH) 转化为相应的二羟基二十碳三烯酸 (DHET)，从而迅速失活 (1, 2)。 sEH 的抑制可防止环氧化物完全水解，从而减少 EET 向 DHET 的转化。我们的初步研究表明，1) sEH 抑制剂 AUDA-nBE 和 t-AUCB 通过抑制巨噬细胞/中性粒细胞活性以及减少 iNOS 表达及其介导的硝基酪氨酸形成，显着抑制结肠炎和溃疡形成。 2)AUDA-nBE诱导PPAR-γ活性并抑制NF-kB信号传导。 iNOS、COX2、5-LOX、硝基氧化应激和 VCAM-1 在体外细胞系中也受到抑制 (15)。 3)长期施用t-AUCB可抑制啮齿动物模型中结肠炎诱导的不典型增生和癌症的发展。我们的假设是将 sEH 作为预防结肠炎诱发癌变的新方法，即通过显着抑制 sEH 来减少 EET 转化为相应的 DHET。所提出的抑制炎症的机制是通过抑制炎症细胞募集、调节花生四烯酸代谢物谱并进一步靶向 PPAR-gamma 和 NF-kB 途径来抑制 COX-2、5-LOX、iNOS，如以及 VCAM-1。执行以下具体目标：1) 在我们的新型 DSS 诱导癌变模型中使用 sEH 敲除小鼠，以及双敲除自发性结肠炎癌变模型（sEH 和 IL-10）确定 sEH 在结肠炎诱导癌变中的作用老鼠。 2) 确定高效、选择性 sEH 抑制剂作为化学预防剂在 DSS 诱导和自发性结肠炎癌变小鼠模型中对抗结肠炎诱导癌变的有效性。 3)确定sEH抑制剂在上述两个特定目标中使用的动物标本以及体外细胞系和条件性PPAR-gamma敲除小鼠标本中抑制结肠炎诱导的癌发生的机制。公共卫生相关性：慢性炎症是导致人类癌症的最重要因素之一。慢性结肠炎是公认的结肠癌危险因素。该项目的目标是提供一种有效的化合物来预防结肠炎诱发的结肠癌。环氧二十碳三烯酸 (EET) 是具有抗炎活性的 AA 代谢物。 sEH 的抑制可防止环氧化物完全水解，从而减少 EET 向 DHET 的转化。因此，EET-sEH 抑制将是抗结肠炎致癌的有效途径。在这个项目中，我们处于独特的地位，利用有效和选择性的 sEH 抑制剂和 sEH 基因敲除小鼠，结合独特的小鼠模型分子病理学和药理学方法，研究基于机制的预防结肠炎驱动的致癌作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dysplastic lesions in inflammatory bowel disease: molecular pathogenesis to morphology.

炎症性肠病中的发育异常病变：从分子发病机制到形态学。

DOI：
10.5858/arpa.2012-0086-ra
发表时间：
2013-03-01
期刊：
Archives of pathology & laboratory medicine
影响因子：
4.6
作者：
K. Matkowskyj;Z. Chen;M. Rao;Guang
通讯作者：
Guang

Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase.

通过抑制可溶性环氧化物水解酶增强α-3环氧多不饱和脂肪酸谱来抑制胰腺癌生长。

DOI：
发表时间：
2019-07
期刊：
影响因子：
2
作者：
Xia, Rong;Sun, Leyu;Liao, Jie;Li, Haonan;You, Xiaoming;Xu, Dandan;Yang, Jun;Hwang, Sung Hee;Jones, Ryan D;Hammock, Bruce;Yang, Guang
通讯作者：
Yang, Guang

Epoxyeicosatrienoic acids and soluble epoxide hydrolase: potential therapeutic targets for inflammation and its induced carcinogenesis.

环氧二十碳三烯酸和可溶性环氧化物水解酶：炎症及其诱发癌变的潜在治疗靶点。