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)-d, 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-d. 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-d mRNA and protein expression. PPAR-d over-expression in colonic epithelial cells promoted CAC tu-morigenesis in mice and increased IL-6 expression and STAT3 phosphorylation, whereas concomitant 15-LOX-1 expression in colonic epithelial cells (15-LOX-1-PPAR-d-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 ± 0.25in15-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.
Original language | English (US) |
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Pages (from-to) | 2359-2370 |
Number of pages | 12 |
Journal | FASEB Journal |
Volume | 29 |
Issue number | 6 |
DOIs | |
State | Published - Jun 1 2015 |
Keywords
- 15-LOX-1
- CAC
- IL-6 expression
- PPAR-δ
- STAT3 phosphorylation
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics
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