title: Transcriptional regulation of the intestinal nuclear bile acid farnesoid X receptor (FXR) by the caudal-related homeobox 2 (CDX2).
abstract: Farnesoid X receptor (FXR, NR1H4) is a bile acid-activated transcription factor that belongs to the nuclear receptor superfamily. It is highly expressed in the enterohepatic system, where it senses bile acid levels to consequently reduce their synthesis while inducing their detoxification. Bile acids are intestinal tumor promoters and their concentrations have to be tightly regulated. Indeed, reduced expression of FXR in the intestine increases colorectal cancer susceptibility in mice, whereas its activation can promote apoptosis in genetically modified cells. Notably, despite the broad knowledge of the FXR enterohepatic transcriptional activity, the molecular mechanisms regulating FXR expression in the intestine are still unknown. Herein, by combining both gain and loss of function approaches and FXR promoter activity studies, we identified caudal-related homeobox 2 (CDX2) transcription factor as a positive regulator of FXR expression in the enterocytes. Our results provide a putative novel tool for modulating FXR expression against bile acid-related colorectal cancer progression.
authors.affiliation: From the Department of Interdisciplinary Medicine, "Aldo Moro," University of Bari, Bari 70124, Italy, the National Cancer Research Center, IRCCS Oncologico Giovanni Paolo II, 70124 Bari, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Modica
authors.affiliation: the National Cancer Research Center, IRCCS Oncologico Giovanni Paolo II, 70124 Bari, Italy.
authors.forename: Marica
authors.initials: M
authors.lastname: Cariello
authors.affiliation: the Laboratory of Lipid Metabolism and Cancer, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), 66030 Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Morgano
authors.affiliation: INSERM UMR S1113, 67200 Strasbourg, France, and the Université de Strasbourg, Fédération de Médecine Translationnelle, Strasbourg 67081, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gross
authors.affiliation: the National Cancer Research Center, IRCCS Oncologico Giovanni Paolo II, 70124 Bari, Italy.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Vegliante
authors.affiliation: the Laboratory of Lipid Metabolism and Cancer, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), 66030 Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Murzilli
authors.affiliation: the Laboratory of Lipid Metabolism and Cancer, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), 66030 Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Salvatore
authors.affiliation: INSERM UMR S1113, 67200 Strasbourg, France, and the Université de Strasbourg, Fédération de Médecine Translationnelle, Strasbourg 67081, France.
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Freund
authors.affiliation: From the Department of Interdisciplinary Medicine, "Aldo Moro," University of Bari, Bari 70124, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sabbà
authors.affiliation: From the Department of Interdisciplinary Medicine, "Aldo Moro," University of Bari, Bari 70124, Italy, the National Cancer Research Center, IRCCS Oncologico Giovanni Paolo II, 70124 Bari, Italy, antonio.moschetta@uniba.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001665:Binding Sites; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D001647:Bile Acids and Salts; D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C555337:APC protein, human; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse
keywords: Bile Acid; Gene Transcription; Intestine; Lipid Metabolism; Nuclear Receptor