title: 15-Lipoxygenase-1 suppression of colitis-associated colon cancer through inhibition of the IL-6/STAT3 signaling pathway.
abstract: The IL-6/signal transducer and activator of transcription 3 (STAT3) pathway is a critical signaling pathway for colitis-associated colorectal cancer (CAC). Peroxisome proliferator-activated receptor (PPAR)-δ, a lipid nuclear receptor, up-regulates IL-6. 15-Lipoxygenase-1 (15-LOX-1), which is crucial to production of lipid signaling mediators to terminate inflammation, down-regulates PPAR-δ. 15-LOX-1 effects on IL-6/STAT3 signaling and CAC tumorigenesis have not been determined. We report that intestinally targeted transgenic 15-LOX-1 expression in mice inhibited azoxymethane- and dextran sodium sulfate-induced CAC, IL-6 expression, STAT3 phosphorylation, and IL-6/STAT3 downstream target (Notch3 and MUC1) expression. 15-LOX-1 down-regulation was associated with IL-6 up-regulation in human colon cancer mucosa. Reexpression of 15-LOX-1 in human colon cancer cells suppressed IL-6 mRNA expression, STAT3 phosphorylation, IL-6 promoter activity, and PPAR-δ mRNA and protein expression. PPAR-δ overexpression in colonic epithelial cells promoted CAC tumorigenesis in mice and increased IL-6 expression and STAT3 phosphorylation, whereas concomitant 15-LOX-1 expression in colonic epithelial cells (15-LOX-1-PPAR-δ-Gut mice) suppressed these effects: the number of tumors per mouse (mean ± sem) was 4.22 ± 0.68 in wild-type littermates, 6.67 ± 0.83 in PPAR-δ-Gut mice (P = 0.026), and 2.25 ± 0.25 in 15-LOX-1-PPAR-δ-Gut mice (P = 0.0006). Identification of 15-LOX-1 suppression of PPAR-δ to inhibit IL-6/STAT3 signaling-driven CAC tumorigenesis provides mechanistic insights that can be used to molecularly target CAC.
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China ishureiqi@mdanderson.org xzuo@mdanderson.org.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Xu
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
authors.forename: Micheline J
authors.initials: MJ
authors.lastname: Moussalli
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
authors.forename: Elias
authors.initials: E
authors.lastname: Elias
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
authors.forename: Haiyan S
authors.initials: HS
authors.lastname: Li
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Watowich
authors.affiliation: Departments of *Gastrointestinal Medical Oncology, Pathology, and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China ishureiqi@mdanderson.org xzuo@mdanderson.org.
authors.forename: Imad
authors.initials: I
authors.lastname: Shureiqi
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001397:Azoxymethane; D015153:Blotting, Western; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate; D015870:Gene Expression; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D015850:Interleukin-6; D047494:PPAR delta; D050796:STAT3 Transcription Factor; D016264:Dextran Sulfate; D001093:Arachidonate 15-Lipoxygenase; D001397:Azoxymethane
keywords: 15-LOX-1; CAC; IL-6 expression; PPAR-δ; STAT3 phosphorylation