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

• 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
• 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

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预防结肠炎诱发癌症的药物。慢性结肠炎是结肠癌的一个公认的危险因素;结肠炎诱导的异常花生四烯酸（AA）代谢产物的增加是导致癌症发展的关键事件。环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，ESTs）是具有抗炎活性的AA代谢物;在生理条件下，ESTs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（DHSTs），因此ESTs迅速失活（1，2）。sEH的抑制防止了环氧化物的完全水解，减少了E3向DH 3的转化。我们的初步研究已经表明，1）sEH抑制剂AUDA-nBE和t-AUCB通过抑制巨噬细胞/嗜中性粒细胞活性以及降低iNOS表达及其介导的硝基酪氨酸形成来显著抑制结肠炎和溃疡形成。2)AUDA-nBE诱导PPAR-γ活性并抑制NF-κ B信号传导。iNOS、COX 2、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)在啮齿动物模型中，长期给予t-AUCB可抑制结肠炎诱导的发育异常和癌症的发生。我们的假设是靶向sEH作为预防结肠炎诱导的致癌作用的新方法是通过显著抑制sEH来减少E3向其相应的DH 3的转化。所提出的抑制炎症的机制是通过抑制炎性细胞募集、调节花生四烯酸代谢产物谱并进一步靶向PPAR-γ和NF-κ B途径，从而抑制考克斯-2，5-LOX、iNOS以及VCAM-1。1）在我们的新型DSS诱导的癌变模型中使用sEH敲除小鼠，以及在双敲除（sEH和IL-10）小鼠中使用自发性结肠炎癌变模型，确定sEH在结肠炎诱导的癌变中的作用。2)在DSS诱导的和自发性结肠炎致癌小鼠模型中确定高效和选择性sEH抑制剂作为化学预防剂对抗结肠炎诱导的致癌作用的有效性。3)在上述两个特定目的中使用的动物样本以及体外细胞系和条件性PPAR-gamma敲除小鼠样本中，确定sEH抑制剂抑制结肠炎诱导的致癌作用的机制。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。慢性结肠炎是结肠癌的一个公认的危险因素。该项目的目标是提供一种有效的化合物，用于预防结肠炎引起的结肠癌。环氧二十碳三烯酸（Epoxyeicosatrienoicacids，ESTs）是具有抗炎活性的AA代谢物. sEH的抑制防止了环氧化物的完全水解，减少了E3向DH 3的转化。因此，EET-sEH抑制将是抗结肠炎诱导的致癌作用的有效途径。在这个项目中，我们处于独特的地位，研究基于预防结肠炎驱动的致癌作用的机制，使用有效的和选择性的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。

项目成果

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

• 发表时间: 2010-07
• 期刊: American journal of translational research
• 影响因子: 2.2
• 作者: Stephanie Norwood;J. Liao;B. Hammock;Guang-Yu Yang

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: 10.21873/anticanres.13513
• 发表时间: 2019
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Xia,Rong;Sun,Leyu;Liao,Jie;Li,Haonan;You,Xiaoming;Xu,Dandan;Yang,Jun;Hwang,SungHee;Jones,RyanD;Hammock,Bruce;Yang,Guang-Yu
• 通讯作者: Yang,Guang-Yu