miR-24 Inhibition Increases Menin Expression and Decreases Cholangiocarcinoma Proliferation.

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miR-24 Inhibition Increases Menin Expression and Decreases Cholangiocarcinoma Proliferation.

Am J Pathol. 2017 Jan 10;:

Authors: Ehrlich L, Hall C, Venter J, Dostal D, Bernuzzi F, Invernizzi P, Meng F, Trzeciakowski JP, Zhou T, Standeford H, Alpini G, Lairmore TC, Glaser S

Abstract
Menin (MEN1) is a tumor-suppressor protein in neuroendocrine tissue. Because cholangiocytes can take on a neuroendocrine phenotype, 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, Tie1/2, vascular endothelial growth factor receptors 2/3, and Ang1/2) were evaluated. Invasion and migration were evaluated with Boyden chamber and scratch assays. 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.

PMID: 28087162 [PubMed - as supplied by publisher]

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