TY - JOUR
T1 - Effects of gut-targeted 15-LOX-1 transgene expression on colonic tumorigenesis in mice
AU - Zuo, Xiangsheng
AU - Peng, Zhanglong
AU - Wu, Yuanqing
AU - Moussalli, Micheline J.
AU - Yang, Xiu L.
AU - Wang, Yan
AU - Parker-Thornburg, Jan
AU - Morris, Jeffrey S.
AU - Broaddus, Russell R.
AU - Fischer, Susan M.
AU - Shureiqi, Imad
N1 - Funding Information:
National Cancer Institute (R01-CA137213 to IS); the American Cancer Society Research Scholar Award (RSG-04-020-01-CNE); University of Texas M. D. Anderson Cancer Center Institutional Bridge Funding and the Caroline Wiess Law Endowment for Cancer Prevention. This study made use of the M. D. Anderson Cancer Center Genetically Engineered Mouse Facility, DNA Analysis Facility, and Research Animal Support Facility—Smithville, Genetic Services, supported by Cancer Center Support Grant (CA016672).
PY - 2012/5/2
Y1 - 2012/5/2
N2 - Expression of 15-lipoxygenase-1 (15-LOX-1) is decreased in many human cancers; however, the mechanistic significance of its decreased expression has been difficult to determine because its mouse homolog 12/15-LOX has opposing functions. We generated a mouse model in which expression of a human 15-LOX-1 transgene was targeted to the intestinal epithelium via the villin promoter. Targeted expression was confirmed by real-time reverse transcription-polymerase chain reaction and immunoblotting. When the 15-LOX-1 transgene was expressed in colonic epithelial cells of two independent mouse lines (B6 and FVB), azoxymethane-inducible colonic tumorigenesis was suppressed (mean number of tumors: wild type [WT] = 8.2, 15-LOX-1+/- = 4.91, 15-LOX-1 +/+ = 3.57; WT vs 15-LOX-1+/- two-sided P = .003, WT vs 15-LOX-1+/+ two-sided P < .001; n = 10-14 mice per group). 15-LOX-1 transgene expression was always decreased in the tumors that did develop. In the presence of expression of the 15-LOX-1 transgene, expression of tumor necrosis factor alpha and its target inducible nitric oxide synthase were decreased and activation of nuclear factor-kappa B in colonic epithelial cells was inhibited.
AB - Expression of 15-lipoxygenase-1 (15-LOX-1) is decreased in many human cancers; however, the mechanistic significance of its decreased expression has been difficult to determine because its mouse homolog 12/15-LOX has opposing functions. We generated a mouse model in which expression of a human 15-LOX-1 transgene was targeted to the intestinal epithelium via the villin promoter. Targeted expression was confirmed by real-time reverse transcription-polymerase chain reaction and immunoblotting. When the 15-LOX-1 transgene was expressed in colonic epithelial cells of two independent mouse lines (B6 and FVB), azoxymethane-inducible colonic tumorigenesis was suppressed (mean number of tumors: wild type [WT] = 8.2, 15-LOX-1+/- = 4.91, 15-LOX-1 +/+ = 3.57; WT vs 15-LOX-1+/- two-sided P = .003, WT vs 15-LOX-1+/+ two-sided P < .001; n = 10-14 mice per group). 15-LOX-1 transgene expression was always decreased in the tumors that did develop. In the presence of expression of the 15-LOX-1 transgene, expression of tumor necrosis factor alpha and its target inducible nitric oxide synthase were decreased and activation of nuclear factor-kappa B in colonic epithelial cells was inhibited.
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U2 - 10.1093/jnci/djs187
DO - 10.1093/jnci/djs187
M3 - Article
C2 - 22472308
AN - SCOPUS:84862217496
SN - 0027-8874
VL - 104
SP - 709
EP - 716
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 9
ER -