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

Chad Hall, Laurent Ehrlich, Fanyin Meng, Pietro Invernizzi, Francesca Bernuzzi, Terry C. Lairmore, Gianfranco Alpini, Shannon Glaser

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
JournalJournal of Surgical Research
DOIs
StateAccepted/In press - Feb 2 2017

Keywords

  • Hepatic fibrosis
  • Liver
  • Menin
  • MiR-24

ASJC Scopus subject areas

  • Surgery

Fingerprint Dive into the research topics of 'Inhibition of microRNA-24 increases liver fibrosis by enhanced menin expression in Mdr2<sup>-/-</sup> mice'. Together they form a unique fingerprint.

  • Cite this

    Hall, C., Ehrlich, L., Meng, F., Invernizzi, P., Bernuzzi, F., Lairmore, T. C., Alpini, G., & Glaser, S. (Accepted/In press). Inhibition of microRNA-24 increases liver fibrosis by enhanced menin expression in Mdr2-/- mice. Journal of Surgical Research. https://doi.org/10.1016/j.jss.2017.05.020