Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation.
Liver receptor homolog 1 (LRH-1) is an orphan nuclear receptor that synergizes with beta-catenin/T cell factor 4 signaling to stimulate intestinal crypt cell renewal. We evaluated here the impact of haploinsufficiency of LRH-1 on intestinal tumorigenesis by using two independent mouse models of human colon tumorigenesis. Haploinsufficiency of LRH-1 blunts intestinal tumorigenesis in the ApcMin/+ mice, a genetic model of intestinal cancer. Likewise, Lrh-1+/- mice are protected against the formation of aberrant crypt foci in the colon of mice exposed to the carcinogen azoxymethane. LRH-1 gene expression is reduced in tumors that express elevated levels of the proinflammatory cytokine TNF-alpha. Reciprocally, decreased LRH-1 expression in Lrh-1+/- mice attenuates TNF-alpha expression. Compared with normal human colon, expression and subcellular localization of LRH-1 is significantly altered in neoplastic colon. In combination, these data suggest a role of LRH-1 in the initiation of intestinal tumorigenesis both by affecting cell cycle control as well as through its impact on inflammatory pathways.
Schoonjans
Kristina
K
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, 67404 Illkirch, France.
Dubuquoy
Laurent
L
Mebis
Joseph
J
Fayard
Elisabeth
E
Wendling
Olivia
O
Haby
Céline
C
Geboes
Karel
K
Auwerx
Johan
J
D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002453:Cell Cycle / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006579:Heterozygote; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002273:Carcinogens; C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D001397:Azoxymethane