miR-24 Inhibition Increases Menin Expression and Decreases Cholangiocarcinoma Proliferation

Laurent Ehrlich, Chad Hall, Julie Venter, David Dostal, Francesca Bernuzzi, Pietro Invernizzi, Fanyin Meng, Jerome P. Trzeciakowski, Tianhao Zhou, Holly Standeford, Gianfranco Alpini, Terry C. Lairmore, Shannon Glaser

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12 Scopus citations

Abstract

Menin (MEN1) is a tumor-suppressor protein in neuroendocrine tissue. Therefore, we tested the novel hypothesis that menin regulates cholangiocarcinoma proliferation. Menin and miR-24 expression levels were measured in the following intrahepatic and extrahepatic cholangiocarcinoma (CCA) cell lines, Mz-ChA-1, TFK-1, SG231, CCLP, HuCCT-1, and HuH-28, as well as the nonmalignant human intrahepatic biliary line, H69. miR-24 miRNA and menin protein levels were manipulated in vitro in Mz-ChA-1 cell lines. Markers of proliferation and angiogenesis (Ki-67, vascular endothelial growth factors A/C, vascular endothelial growth factor receptors 2/3, angiopoietin 1/2, and angiopoietin receptors 1/2) were evaluated. Mz-ChA-1 cells were injected into the flanks of nude mice and treated with miR-24 inhibitor or inhibitor scramble. Menin expression was decreased in advanced CCA specimens, whereas miR-24 expression was increased in CCA. Menin overexpression decreased proliferation, angiogenesis, migration, and invasion. Inhibition of miR-24 increased menin protein expression while decreasing proliferation, angiogenesis, migration, and invasion. miR-24 was shown to negatively regulate menin expression by luciferase assay. Tumor burden and expression of proliferative and angiogenic markers was decreased in the miR-24 inhibited tumor group compared to controls. Interestingly, treated tumors were more fibrotic than the control group. miR-24–dependent expression of menin may be important in the regulation of nonmalignant and CCA proliferation and may be an additional therapeutic tool for managing CCA progression.

Original languageEnglish (US)
Pages (from-to)570-580
Number of pages11
JournalAmerican Journal of Pathology
Volume187
Issue number3
DOIs
StatePublished - Mar 1 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Ehrlich, L., Hall, C., Venter, J., Dostal, D., Bernuzzi, F., Invernizzi, P., Meng, F., Trzeciakowski, J. P., Zhou, T., Standeford, H., Alpini, G., Lairmore, T. C., & Glaser, S. (2017). miR-24 Inhibition Increases Menin Expression and Decreases Cholangiocarcinoma Proliferation. American Journal of Pathology, 187(3), 570-580. https://doi.org/10.1016/j.ajpath.2016.10.021