title: microRNA-192 suppresses the expression of the farnesoid X receptor.
abstract: Farnesoid X receptor (FXR, NR1H4) plays an important role in the regulation of bile acid homeostasis in liver and intestine and may exert protective effects against certain forms of cancer such as colon carcinoma. However, the role of FXR in cell growth regulation, apoptosis, and carcinogenesis is still controversial. Similar to FXR, microRNA-192 (miR-192) is mainly expressed in the liver and colon and plays an important role in the pathogenesis of colon carcinoma. In this study, we investigated the extent to which FXR is regulated by miR-192. Two in silico-predicted binding sites for miR-192-3p within the NR1H4-3' untranslated region (UTR) were examined in vitro by luciferase reporter assays. Wild-type and mutated forms of the NR1H4-3'UTR were subcloned into a pmirGLO vector and cotransfected into Huh-7 cells with miR-192-3p. To study the effects of miR-192 on the expression of FXR, FXR target genes and cell proliferation, Huh-7 and Caco-2 cells were transfected with miR-192-5p and -3p mimics or antagomirs. In addition, the correlation between FXR and miR-192 expression was studied by linear regression analyses in colonic adenocarcinoma tissue from 27 patients. MiR-192-3p bound specifically to the NR1H4-3'UTR and significantly decreased luciferase activity. Transfection with miR-192 led to significant decreases in NR1H4 mRNA and protein levels as well as the mRNA levels of the FXR-inducible bile acid transporters OSTα-OSTβ and OATP1B3. Significant inverse correlations were detected in colonic adenocarcinoma between NR1H4 mRNA and miR-192-3p expression. In summary, microRNA-192 suppresses the expression of FXR and FXR target genes in vitro and in vivo.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland;
authors.forename: Regina
authors.initials: R
authors.lastname: Krattinger
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, University of Uppsala, Uppsala, Sweden; and.
authors.forename: Adrian
authors.initials: A
authors.lastname: Boström
authors.affiliation: Department of Neuroscience, Division of Functional Pharmacology, University of Uppsala, Uppsala, Sweden; and.
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Neuroscience, Division of Functional Pharmacology, University of Uppsala, Uppsala, Sweden; and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mwinyi
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; gerd.kullak@usz.ch.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
mesh_terms: D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D029362:Organic Anion Transporters, Sodium-Independent; D018160:Receptors, Cytoplasmic and Nuclear; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000099150:Receptor, Farnesoid X-Activated; C546783:MIRN192 microRNA, human; C421209:SLCO1B3 protein, human
keywords: bile-acid transporters; colonic adenocarcinoma; drug-induced liver injury; farnesoid X receptor; miR-192