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Cited by 250Liver Diseases and ImmunityMicroRNA in disease regulationDrug Transport and Resistance Mechanisms

Up-regulation of microRNA 506 leads to decreased Cl−/HCO3 − anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis

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Banales, Jesús M., Sáez, Elena, Úriz, Miriam, Sarvide, Sarai, Urribarri, Aura D., Splinter, Patrick, Tietz Bogert, Pamela S., Bujanda, Luis +3 more·2012·Hepatology
DOI 10.1002/hep.25691PMC PMC3406248
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Abstract

Cl−/HCO Symbol anion exchanger 2 (AE2) participates in intracellular pH homeostasis and secretin-stimulated biliary bicarbonate secretion. AE2/SLC4A2 gene expression is reduced in liver and blood mononuclear cells from patients with primary biliary cirrhosis (PBC). Our previous findings of hepatic and immunological features mimicking PBC in Ae2 -deficient mice strongly suggest that decreased AE2 expression might be involved in the pathogenesis of PBC. Here, we tested the potential role of microRNA 506 (miR-506) — predicted as candidate to target AE2 mRNA — for the decreased expression of AE2 in PBC. Real-time quantitative polymerase chain reaction showed that miR-506 expression is increased in PBC livers versus normal liver specimens. In situ hybridization in liver sections confirmed that miR-506 is up-regulated in the intrahepatic bile ducts of PBC livers, compared with normal and primary sclerosing cholangitis livers. Precursor-mediated overexpression of miR-506 in SV40-immortalized normal human cholangiocytes (H69 cells) led to decreased AE2 protein expression and activity, as indicated by immunoblotting and microfluorimetry, respectively. Moreover, miR-506 overexpression in three-dimensional (3D)-cultured H69 cholangiocytes blocked the secretin-stimulated expansion of cystic structures developed under the 3D conditions. Luciferase assays and site-directed mutagenesis demonstrated that miR-506 specifically may bind the 3′untranslated region (3′UTR) of AE2 messenger RNA (mRNA) and prevent protein translation. Finally, cultured PBC cholangiocytes showed decreased AE2 activity, together with miR-506 overexpression, compared to normal human cholangiocytes, and transfection of PBC cholangiocytes with anti-miR-506 was able to improve their AE2 activity. Conclusion: miR-506 is up-regulated in cholangiocytes from PBC patients, binds the 3′UTR region of AE2 mRNA, and prevents protein translation, leading to diminished AE2 activity and impaired biliary secretory functions. In view of the putative pathogenic role of decreased AE2 in PBC, miR-506 may constitute a potential therapeutic target for this disease. (HEPATOLOGY 2012)

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Authors
Banales, J. M., Sáez, E., Úriz, M., Sarvide, S., Urribarri, A. D., Splinter, P., Tietz Bogert, P. S., Bujanda, L., Prieto, J., Medina, J. F., & LaRusso, N. F.
Affiliations
  • Centro de Investigación Biomédica en Red (ES)
  • Mayo Clinic (US)
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2012-08
Volume
56
Issue
2
Pages
687-697
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.25691
PMC
PMC3406248
OpenAlex
W2067983267
Cited by
250
References
5
Citations by year
2026: 9 · 2025: 16 · 2024: 19 · 2023: 20 · 2022: 17 · 2021: 10 · 2020: 25 · 2019: 16 · 2018: 17 · 2017: 24 · 2016: 9 · 2015: 26 · 2014: 24 · 2013: 11 · 2012: 6
FWCI
13.57
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1126 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Mayo Foundation for Medical Education and Research
  • European Association for the Study of the Liver
  • National Institutes of Health (DK 24031)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 24031, R01DK024031, P30DK084567)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
primary biliary cirrhosis, cholangiocytes, 3' untranslated region, microRNA target regulation, intracellular pH homeostasis, secretin stimulation, primary sclerosing cholangitis, biliary epithelium, miRNA microarray, miRNA expression profiling
MeSH terms
Bicarbonates, Bile Ducts, Intrahepatic, Chlorides, Computer Simulation, Epithelium, Humans, Liver Cirrhosis, Biliary, RNA, Messenger, Protein Biosynthesis, Up-Regulation, Antiporters, Anion Transport Proteins, Chloride-Bicarbonate Antiporters, MicroRNAs, Cell Line, Tumor, Primary Cell Culture, SLC4A Proteins

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