Abstract
Background
Liver transplantation remains the primary treatment for primary sclerosing cholangitis
(PSC). Mdr2−/− mice provide a reliable in vivo model of PSC and develop characteristic biliary inflammation and fibrosis. We tested
the hypothesis that the tumor suppressor protein menin is implicated in the progression
of liver fibrosis and that menin expression can be regulated in the liver via microRNA-24
(miR-24).
Materials and methods
Menin expression was measured in human PSC and Mdr2−/− mice. Twelve-week-old FVB/NJ wild-type (WT) and Mdr2−/− mice were treated with miR-24 Vivo-Morpholino to knockdown miR-24 expression levels.
Liver fibrosis was evaluated by Sirius Red staining and quantitative polymerase chain
reaction (qPCR) for genes associated with liver fibrosis, such as fibronectin 1, collagen type
1 alpha 1, transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin. Studies
were also performed in vitro using immortalized murine cholangiocyte lines treated with miR-24 hairpin inhibitor
and mimic.
Results
Menin gene expression was increased in Mdr2−/− mice and late-stage human PSC samples. Treatment of FVB/NJ WT and Mdr2−/− mice with miR-24 Vivo-Morpholino increased menin expression, which correlated with
increased expression of fibrosis genes. In vitro, inhibition of miR-24 also significantly increased the expression of fibrosis genes.
Conclusions
Inhibition of miR-24 increases menin and TGF-β1 expression, subsequently increasing
hepatic fibrosis in FVB/NJ WT and Mdr2−/− mice. Modulation of the menin/miR-24 axis may provide novel targeted therapies to
slow the progression of hepatic fibrosis into cirrhosis in PSC patients by altering
TGF-β1 expression.
Keywords
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Article info
Publication history
Published online: May 11, 2017
Accepted:
May 3,
2017
Received in revised form:
April 3,
2017
Received:
February 2,
2017
Footnotes
This article is being submitted in conjunction with the Academic Surgical Congress.
Identification
Copyright
© 2017 Elsevier Inc. All rights reserved.
