Program Official

Principal Investigator

Imad
Shureiqi
Awardee Organization

University Of Michigan At Ann Arbor
United States

Fiscal Year
2020
Activity Code
R01
Project End Date

15-LOX-1 regulation of resolving generation to modulate colon cancer

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. 15lipoxygenase-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 important 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, attenuated DHA-induced CRT promotion, and enhanced EPA-induced CRT suppression. We hypothesize that 15-LOX1 expression in colonic epithelial cells is critical for DHA and EPA to generate resolvins and modulate Wnt/Bcatenin signaling and CRT. Aims 1 and 2 will determine the effects of 15-LOX-1 gain (aim 1) and loss of function (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 compared for resolvins and their precursors, CRT, cell proliferation and apoptosis, TNF-α, IL-1β, and activated Bcatenin 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 determine 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.

Publications

  • Tian R, Zuo X, Jaoude J, Mao F, Colby J, Shureiqi I. ALOX15 as a suppressor of inflammation and cancer: Lost in the link. Prostaglandins & other lipid mediators. 2017 Sep;132:77-83. Epub 2017 Jan 13. PMID: 28089732
  • Liu F, Zuo X, Liu Y, Deguchi Y, Moussalli MJ, Chen W, Yang P, Wei B, Tan L, Lorenzi PL, Gao S, Jaoude JC, Mehdizadeh A, Valentin LA, Wei D, Shureiqi I. Suppression of Membranous LRP5 Recycling, Wnt/β-Catenin Signaling, and Colon Carcinogenesis by 15-LOX-1 Peroxidation of Linoleic Acid in PI3P. Cell reports. 2020 Aug 18;32(7):108049. PMID: 32814052
  • Liu Y, Colby JK, Zuo X, Jaoude J, Wei D, Shureiqi I. The Role of PPAR-δ in Metabolism, Inflammation, and Cancer: Many Characters of a Critical Transcription Factor. International journal of molecular sciences. 2018 Oct 26;19. (11). PMID: 30373124
  • Liu Y, Deguchi Y, Wei D, Liu F, Moussalli MJ, Deguchi E, Li D, Wang H, Valentin LA, Colby JK, Wang J, Zheng X, Ying H, Gagea M, Ji B, Shi J, Yao JC, Zuo X, Shureiqi I. Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ. Nature communications. 2022 May 13;13(1):2665. PMID: 35562376
  • Liu Y, Deguchi Y, Tian R, Wei D, Wu L, Chen W, Xu W, Xu M, Liu F, Gao S, Jaoude JC, Chrieki SP, Moussalli MJ, Gagea M, Morris J, Broaddus RR, Zuo X, Shureiqi I. Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion. Cancer research. 2019 Mar 1;79(5):954-969. Epub 2019 Jan 24. PMID: 30679176
  • Zuo X, Deguchi Y, Xu W, Liu Y, Li HS, Wei D, Tian R, Chen W, Xu M, Yang Y, Gao S, Jaoude JC, Liu F, Chrieki SP, Moussalli MJ, Gagea M, Sebastian MM, Zheng X, Tan D, Broaddus R, Wang J, Ajami NJ, Swennes AG, Watowich SS, Shureiqi I. PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice. Gastroenterology. 2019 Jul;157(1):163-178. Epub 2019 Mar 15. PMID: 30885780