15-LOX-1 Regulation of Resolving Generation to Modulate Colon Cancer

15-LOX-1 调节分解生成以调节结肠癌

• 批准号: 9187612
• 负责人: Imad Shureiqi
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187612
• 关键词: ALOX15 gene; Affect; Apoptosis; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Attenuated; Azoxymethane; B cell differentiation; Breeding; Cancerous; Cell Differentiation process; Cell Proliferation; Cell Respiration; Cells; Chemoprevention; Chemopreventive Agent; Colitis; Colon Carcinoma; Colorectal Cancer; Cyclin D1; Data; Development; Diet; Diffusion; Down-Regulation; Enzyme Immunoassay; Enzymes; Epithelial Cells; Event; FDA approved; Figs - dietary; Fish Oils; Formulation; Future; Generations; Genetic; Goals; Health; Human; Hyperlipidemia; Incidence; Integration Host Factors; Interleukin-1 beta; Intervention; Intestines; Knock-out; Knockout Mice; LOX gene; Length; Lentivirus Vector; Leukocytes; Lipoxygenase 1; Measures; Mediating; Messenger RNA; Metabolism; Molecular; Molecular Target; Mus; Mutation; Omega-3 Fatty Acids; Organoids; Pathway interactions; Patients; Pharmacologic Substance; Phase; Premalignant; Preventive; Production; Proteins; Regulation; Research; Shapes; Signal Pathway; Signal Transduction; Staging; Subfamily lentivirinae; TNF gene; Testing; Transgenic Organisms; Work; base; beta catenin; c-myc Genes; cancer chemoprevention; colon tumorigenesis; colonic crypt; dietary supplements; feeding; gain of function; improved; liquid chromatography mass spectrometry; loss of function; mouse model; novel; prevent; reconstitution; small hairpin RNA; tumor; tumorigenesis

Our long-term goal is to develop novel interventions to prevent colorectal tumorigenesis (CRT). The effects of fish oil and its omega-3 fatty acid derivatives DHA and EPA on CRT are controversial: some studies show promotion and others suppression. We found in preliminary studies that fish oil promoted while EPA inhibited colitis-associated CRT. Whether these differences are applicable to sporadic CRT is unknown. This is clinically important because DHA and EPA are widely used as dietary supplements and FDA-approved treatments. 15- lipoxygenase-1 (15-LOX-1) is a critical enzyme for DHA and EPA oxidative metabolism to generate resolvins and their precursors (e.g., 18-HEPE and RvEs, 17-HDHA and RvEs). 15-LOX-1 and resolvins suppress im- portant pathways (e.g., TNF-α, IL-1β) that potentiate aberrant Wnt/beta-catenin (Wnt/B-catenin) signaling, which is a driver of CRT. 15-LOX-1 expression is commonly lost early during human CRT. Whether 15-LOX-1 expression loss reduces resolvin production from DHA and EPA and reduces the effects of DHA and EPA on CRT is unknown. Our preliminary data show that intestinally targeted 15-LOX-1 expression (15-LOX-1-Gut mice) enhanced resolvin production, suppressed APC mutation-driven B-catenin activation and CRT, attenuat- ed DHA-induced CRT promotion, and enhanced EPA-induced CRT suppression. We hypothesize that 15-LOX- 1 expression in colonic epithelial cells is critical for DHA and EPA to generate resolvins and modulate Wnt/B- catenin signaling and CRT. Aims 1 and 2 will determine the effects of 15-LOX-1 gain (aim 1) and loss of func- tion (aim 2) in colonic epithelial cells on resolvin generation from DHA and EPA, CRT, and B-catenin signaling. For aim 1, we will use 15-LOX-1-Gut mice. For aim 2, we will breed mice with intestinal 12-S-LOX transgenic expression with 12/15-LOX knockout mice to target 12-S-LOX reconstitution to intestinal epithelial cells. In both aims, mice will be fed control, DHA, or EPA diet and treated with AOM to induce CRT. Groups will be com- pared for resolvins and their precursors, CRT, cell proliferation and apoptosis, TNF-α, IL-1β, and activated B- catenin levels, and Wnt/B-catenin target gene (c-Myc, Cyclin D1, Axin2) mRNA levels. We will also evaluate the effect of 15-LOX-1 gain of function (aim 1) and downregulation (aim 2) in human colonic cancerous and normal organoids isolated from patients' colonic crypts and cultured with various concentrations of EPA and DHA on resolvin generation, cell proliferation, cell differentiation, and Wnt/B-catenin signaling. Aim 3 will de- termine the temporal effects of 15-LOX-1 expression in colonic epithelial cells and in leukocytes on resolvin generation and CRT. 15-LOX-1 transgenic expression will be targeted to intestinal epithelial cells and induced at either initiation or progression phases of AOM-induced CRT (subaim 3A) or targeted to leukocytes prior to AOM-induced CRT (subaim 3B). Mice will be fed DHA or EPA diets and compared for end points described for aims 1 and 2. Our findings will direct efforts to develop interventions to prevent CRT based on understanding of the host factors (e.g., 15-LOX-1) that affect DHA and EPA modulation of CRT.

我们的长期目标是开发新的干预措施来预防结直肠肿瘤的发生。的影响