Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25713055
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
15-Lipoxygenase-1 suppression of colitis-associated colon cancer through
inhibition of the IL-6/STAT3 signaling pathway
#MMPMID25713055
Mao F
; Xu M
; Zuo X
; Yu J
; Xu W
; Moussalli MJ
; Elias E
; Li HS
; Watowich SS
; Shureiqi I
FASEB J
2015[Jun]; 29
(6
): 2359-70
PMID25713055
show ga
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)-?, 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-?.
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-? mRNA and protein expression. PPAR-? 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-?-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-?-Gut mice (P = 0.026), and 2.25 ± 0.25 in
15-LOX-1-PPAR-?-Gut mice (P = 0.0006). Identification of 15-LOX-1 suppression of
PPAR-? to inhibit IL-6/STAT3 signaling-driven CAC tumorigenesis provides
mechanistic insights that can be used to molecularly target CAC.
free
free
free
