Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 6, Pages 2058-2062Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0409756102
Keywords
beta-catenin; colon cancer; nuclear receptors
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Funding
- NIDDK NIH HHS [1-P01-DK59820-01, P01 DK059820] Funding Source: Medline
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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 Apc(Min/+) 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.
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