Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation.

Kristina Schoonjans (1) , Laurent Dubuquoy (1) , Joseph Mebis , Elisabeth Fayard (1) , Olivia Wendling , Céline Haby (1) , Karel Geboes , Johan Auwerx (1)

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

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.

Domaines: Biologie moléculaire

Kristina Schoonjans, Laurent Dubuquoy, Joseph Mebis, Elisabeth Fayard, Olivia Wendling, et al.. Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation.. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102 (6), pp.2058-62. ⟨10.1073/pnas.0409756102⟩. ⟨hal-00187750⟩