Inhibition of microRNA-24 increases liver fibrosis by enhanced menin expression in Mdr2-/- mice.

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.

• Authors: Chad Hall, Laurent Ehrlich, Fanyin Meng, Pietro Invernizzi, Francesca Bernuzzi, Terry C Lairmore, Gianfranco Alpini, Shannon Glaser
• Journal: The Journal of surgical research (J Surg Res) Vol. 217 Pg. 160-169 (09 2017) ISSN: 1095-8673 [Electronic] United States
• PMID: 28602220 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• MEN1 protein, human
• Men1 protein, mouse
• MicroRNAs
• Mirn24 microRNA, mouse
• Proto-Oncogene Proteins
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics)
• Animals
• Cell Line
• Cholangitis, Sclerosing (complications, metabolism)
• Gene Expression
• Humans
• Liver Cirrhosis (etiology, metabolism)
• Mice
• Mice, Knockout
• MicroRNAs (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• ATP-Binding Cassette Sub-Family B Member 4