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ALOX15 regulation of colon cancer invasiveness via PI3P-linoleic acid metabolism

ALOX15 通过 PI3P-亚油酸代谢调节结肠癌侵袭性

基本信息

批准号：
10545078
负责人：
Imad Shureiqi
金额：
$ 63.89万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545078
关键词：
ALOX15 gene APC mutation Acids Adenocarcinoma Adverse event Affect American diet Animals Arachidonate 15-Lipoxygenase Automobile Driving Azoxymethane Benign Biological Assay Biological Markers Breeding CD44 gene CDX2 gene Cancer Etiology Cell membrane Cellular Membrane Cessation of life Chemicals Chemopreventive Agent Colon Colon Carcinoma Colonic Polyps Colorectal Colorectal Cancer Complex Consumption Corn Oil Cyclin D1 DNA Sequence Alteration Data Development Diet Disease Doxycycline Endosomes Enzymes Event Genes Goals Human Immunodeficient Mouse In Vitro Incidence Induced Mutation Intake Integration Host Factors Intervention Invaded KRAS2 gene KRASG12D Knowledge LDL-Receptor Related Protein 1 LGR5 gene Lentivirus Linoleic Acids Lipoxygenase 1 Liquid Chromatography LoxP-flanked allele Mass Spectrum Analysis Metabolism Mucous Membrane Mus Mutation Omega-6 Fatty Acids Organoids Phospholipids Polyunsaturated Fatty Acids Prevention strategy Recycling Regulation Reporting Research Resected Resolution Risk Rodent Role Sampling Signal Transduction System Testing Tissues Transfection Transgenic Organisms United States adenoma aldehyde dehydrogenase 1 beta catenin c-myc Genes cancer invasiveness carcinogenesis colon cancer risk colon carcinogenesis dietary dietary excess drinking water gain of function in vivo insight lipoprotein receptor related protein 5 loss of function mouse model novel novel chemoprevention organoid transplantation permissiveness peroxidation phosphatidylinositol 3-phosphate prevent preventive intervention receptor stem cell self renewal stem cells stemness therapy development tumor tumorigenesis villin

项目摘要

Colorectal cancer is the third leading cause of cancer deaths in the United States. The long-term goal of our research is to develop novel interventions to prevent colorectal carcinogenesis (CRC). CRC invasiveness, a critical adverse step during CRC progression, requires a combination of certain genetic mutations (e.g. APC, KRAS and Trp53 mutations), which are the key events to drive CRC. However, CRC progression also requires additional factors which increase aberrant Beta-catenin (B-catenin) activation above levels induced by APC/B- catenin mutations. Linoleic acid (LA), the most commonly consumed omega-6 polyunsaturated fatty acids in humans, increases both chemically (AOM)– and APC mutation– induced CRC tumorigenesis in mice. Nonetheless, human studies have been inconclusive regarding the impact of dietary LA on CRC. Determination of LA's role in CRC is important because American diets are enriched with LA while expression of the main metabolizing enzyme for LA,15-lipoxygenase-1 (ALOX15), is lost in human CRC. Recently, we found that 1) high dietary levels of LA promoted CRC by increasing phosphatidylinositol 3-phosphate (PI3P) containing LA (PI3P_LA), which increases LRP5 membranous recycling and subsequently B-catenin activation; 2) ALOX15- induced conversion of PI3P_LA to PI3P_13-HODE suppresses; LRP5 membranous recycling, B-catenin activation, CRC stemness and LA promotion of CRC, especially formation of large tumors, associated with CRC invasiveness; 3) ALOX15 loss of function (LOF) promotes large CRC tumor formation by azoxymethane in 12/15LOX-KO-12LOX (ALOX15-LOF) mice. Whether loss of ALOX15 expression promotes CRC invasiveness remains unknown. Our preliminary data show that ALOX15-LOF mice increased CRC invasiveness and targeted APC mutation into Lgr5+ colorectal stem cells induced CRC in the mice, which was blocked by transgenic ALOX15 expression. We therefore hypothesize that ALOX15 loss of function promotes CRC invasiveness by increasing PI3P_LA levels, which enhances LRP5 membranous recycling, thus potentiating Wnt/B-catenin signaling and subsequently stemness. Aim 1 will determine the effects of ALOX15 gain of function and ALOX15 LOF on LRP5, B-catenin activation, CRC stemness and invasiveness using CRC mouse models in which CRC invasiveness is promoted by either a combination of APC, KRASG12D and Trp53R172H mutations or Trp53R172H mutation with AOM induced B-catenin and KRAS mutations. Aim 2 will determine the effects of ALOX15 LOF on PI3P-LA, LRP5, B-catenin activation, stemness and invasiveness in human CRCs and examine the effects of ALOX15 re-expression via lentivirus Tet-on inducible system in human CRC-derived organoids on invasiveness in-vitro and in-vivo studies. The proposed studies are expected to provide important mechanistic insights into whether colonic ALOX15 expression as a host factor affects CRC invasiveness risk especially with high dietary LA intake. This gained knowledge could inform subjects with colorectal ALOX15 LOF to avoid high LA intake and spur development of interventions to target ALOX15 for re-expression to prevent invasive CRC.

结直肠癌是美国癌症死亡的第三大原因。我们的长期目标