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microRNA-192 suppresses the expression of the farnesoid X receptor.

  • Krattinger R Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland;
  • Boström A Department of Neuroscience, Division of Functional Pharmacology, University of Uppsala, Uppsala, Sweden; and.
  • Schiöth HB Department of Neuroscience, Division of Functional Pharmacology, University of Uppsala, Uppsala, Sweden; and.
  • Thasler WE Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich, Germany.
  • Mwinyi J 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.
  • Kullak-Ublick GA Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; gerd.kullak@usz.ch.
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  • 2016-04-16
Published in:
  • American journal of physiology. Gastrointestinal and liver physiology. - 2016
bile-acid transporters
colonic adenocarcinoma
drug-induced liver injury
farnesoid X receptor
miR-192
3' Untranslated Regions
Adenocarcinoma
Caco-2 Cells
Cell Line, Tumor
Cell Proliferation
Colonic Neoplasms
Female
Humans
Male
MicroRNAs
Organic Anion Transporters, Sodium-Independent
Receptors, Cytoplasmic and Nuclear
Solute Carrier Organic Anion Transporter Family Member 1B3
English 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.
Language
  • English
Open access status
bronze
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Persistent URL
https://roar.hep-bejune.ch/global/documents/27646
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