title: Effects of gut-targeted 15-LOX-1 transgene expression on colonic tumorigenesis in mice.
abstract: 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.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Zuo
authors.forename: Zhanglong
authors.initials: Z
authors.lastname: Peng
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Wu
authors.forename: Micheline J
authors.initials: MJ
authors.lastname: Moussalli
authors.forename: Xiu L
authors.initials: XL
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jan
authors.initials: J
authors.lastname: Parker-Thornburg
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Morris
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fischer
authors.forename: Imad
authors.initials: I
authors.lastname: Shureiqi
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D001397:Azoxymethane; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003106:Colon / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D015151:Immunoblotting; D007413:Intestinal Mucosa / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002273:Carcinogens; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D001093:Arachidonate 15-Lipoxygenase; D052247:Nitric Oxide Synthase Type II; D001397:Azoxymethane