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microRNA-192 suppresses the expression of the farnesoid X receptor
Univ Zurich, Univ Zurich Hosp, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Univ Munich, Grosshadern Hosp, Dept Gen Visceral Transplantat Vasc & Thorac Surg, Munich, Germany..
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2016 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 310, no 11, G1044-G1051 p.Article in journal (Refereed) PublishedText
Abstract [en]

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 OST alpha-OST beta 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.

Place, publisher, year, edition, pages
2016. Vol. 310, no 11, G1044-G1051 p.
Keyword [en]
miR-192, farnesoid X receptor, bile-acid transporters, drug-induced liver injury, colonic adenocarcinoma
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:uu:diva-299049DOI: 10.1152/ajpgi.00297.2015ISI: 000377433200017PubMedID: 27079614OAI: oai:DiVA.org:uu-299049DiVA: diva2:948794
Available from: 2016-07-13 Created: 2016-07-13 Last updated: 2016-07-13Bibliographically approved

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Boström, AdrianSchiöth, Helgi B.Mwinyi, Jessica
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