| First Author | Mao F | Year | 2015 |
| Journal | FASEB J | Volume | 29 |
| Issue | 6 | Pages | 2359-70 |
| PubMed ID | 25713055 | Mgi Jnum | J:223360 |
| Mgi Id | MGI:5648709 | Doi | 10.1096/fj.14-264515 |
| Citation | Mao F, et al. (2015) 15-Lipoxygenase-1 suppression of colitis-associated colon cancer through inhibition of the IL-6/STAT3 signaling pathway. FASEB J 29(6):2359-70 |
| abstractText | 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)-delta, 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-delta. 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-delta mRNA and protein expression. PPAR-delta 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-delta-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-delta-Gut mice (P = 0.026), and 2.25 +/- 0.25 in 15-LOX-1-PPAR-delta-Gut mice (P = 0.0006). Identification of 15-LOX-1 suppression of PPAR-delta to inhibit IL-6/STAT3 signaling-driven CAC tumorigenesis provides mechanistic insights that can be used to molecularly target CAC. |
