The Intestinal Nuclear Receptor Signature With Epithelial Localization Patterns and Expression Modulation in Tumors

Modica, Salvatore; Gofflot, Françoise; Murzilli, Stefania; D’Orazio, Andria; Salvatore, Lorena; Pellegrini, Fabio; Nicolucci, Antonio; Tognoni, G.; Copetti, Massimiliano; Valanzano, Rosa; Veschi, Serena; Mariani-Costantini, Renato; Palasciano, Giuseppe; Schoonjans, Kristina; Auwerx, Johan; Moschetta, Antonio

doi:10.1053/j.gastro.2009.09.060

Cited by 80 publications

(77 citation statements)

References 43 publications

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“…Several nuclear receptors that interact with PGC1α, such as PPAR-γ (Table S2) (33-35), farnesoid X receptors (FXRs) (36), retinoic acid receptors (RARs), and retinoid X receptors (RXRs) (37), modulate both differentiation and apoptotic pathways in the intestine with a potential pharmacological importance in colon cancer (38).…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate

D'Errico

Salvatore

Murzilli

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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138

120

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Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a transcriptional coactivator able to up-regulate mitochondrial biogenesis, respiratory capacity, oxidative phosphorylation, and fatty acid β-oxidation with the final aim of providing a more efficient pathway for aerobic energy production. In the continuously renewed intestinal epithelium, proliferative cells in the crypts migrate along the villus axis and differentiate into mature enterocytes, increasing their respiratory capacity and finally undergoing apoptosis. Here we show that in the intestinal epithelial surface, PGC1α drives mitochondrial biogenesis and respiration in the presence of reduced antioxidant enzyme activities, thus determining the accumulation of reactive oxygen species and fostering the fate of enterocytes toward apoptosis. Combining gain-and loss-offunction genetic approaches in human cells and mouse models of intestinal cancer, we present an intriguing scenario whereby PGC1α regulates enterocyte cell fate and protects against tumorigenesis.colon cancer | medical physiology | metabolism | mitochondria | nuclear receptors

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Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate

D'Errico

Salvatore

Murzilli

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

138

120

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“…Several studies have shown that VDR is expressed by normal and certain tumour colon epithelial cells (Sheinin et al 2000, González-Sancho et al 2006, Modica et al 2010 and is associated with a high degree of cell differentiation (Shabahang et al 1993, Zhao & Feldman 1993. VDR expression is enhanced in early stages of colorectal tumourigenesis (adenomas, polyps), whereas it decreases in advanced stages (Sheinin et al 2000, Larriba & Muñ oz 2005, Matusiak et al 2005.…”

Section: Angiogenesismentioning

confidence: 99%

Vitamin D and colon cancer

Перейра¹,

Larriba²,

Múñoz³

2012

Endocrine-Related Cancer

110

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The most active vitamin D metabolite, 1α,25-dihydroxyvitamin D3(1,25(OH)2D3), is a pleiotropic hormone with wide regulatory actions. Classically, vitamin D deficiency was known to alter calcium and phosphate metabolism and bone biology. In addition, recent epidemiological and experimental studies support the association of vitamin D deficiency with a large variety of human diseases, and particularly with the high risk of colorectal cancer. By regulating the expression of many genes via several mechanisms, 1,25(OH)2D3induces differentiation, controls the detoxification metabolism and cell phenotype, sensitises cells to apoptosis and inhibits the proliferation of cultured human colon carcinoma cells. Consistently, 1,25(OH)2D3and several of its analogues decrease intestinal tumourigenesis in animal models. Molecular, genetic and clinical data in humans are scarce but they suggest that vitamin D is protective against colon cancer. Clearly, the available evidence warrants new, well-designed, large-scale trials to clarify the role of vitamin D in the prevention and/or therapy of this important neoplasia.

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“…The ability of FXR to reduce BA synthesis while inducing BA detoxification is of critical importance because high levels of circulating BA can increase hepatic and intestinal susceptibility to tumorigenesis (28 -31). Notably, the expression of FXR in the gut is restricted to the differentiated compartment of the intestinal epithelium (29,32), and its activation by BAs will result not only in BA detoxification but also in increased apoptosis and consequent removal of genetically modified cells (29,33). Indeed, the protective role of FXR against CRC susceptibility has been demonstrated by our group and others in Fxr knock-out mice, where the first hit for CRC development was made by inactivating Apc mutations (29,33).…”

mentioning

confidence: 89%

Transcriptional Regulation of the Intestinal Nuclear Bile Acid Farnesoid X Receptor (FXR) by the caudal-related Homeobox 2 (CDX2)

Modica

Cariello

Morgano

et al. 2014

Journal of Biological Chemistry

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Background: Farnesoid X receptor (FXR) regulates bile acid (BA) metabolism. High BA levels increase susceptibility to intestinal tumorigenesis. Results: caudal-related homeobox 2 (CDX2) directly binds the FXR promoter and regulates FXR expression. Conclusion: CDX2 transcription factor is a positive regulator of FXR in the gut. Significance: Manipulation of the APC-CDX2-FXR axis could reduce BA toxicity and intestinal tumor susceptibility.

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The Intestinal Nuclear Receptor Signature With Epithelial Localization Patterns and Expression Modulation in Tumors

Cited by 80 publications

References 43 publications

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate

Vitamin D and colon cancer

Transcriptional Regulation of the Intestinal Nuclear Bile Acid Farnesoid X Receptor (FXR) by the caudal-related Homeobox 2 (CDX2)

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