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MicroRNA-26a promotes cholangiocarcinoma growth by activating β-catenin.

Abstract：

BACKGROUND & AIMS:MicroRNAs (miRNAs) have been implicated in the development and progression of human cancers. We investigated the roles and mechanisms of miR-26a in human cholangiocarcinoma. METHODS:We used in situ hybridization and quantitative reverse transcriptase polymerase chain reaction to measure expression of miR-26a in human cholangiocarcinoma tissues and cell lines (eg, CCLP1, SG231, HuCCT1, TFK1). Human cholangiocarcinoma cell lines were transduced with lentiviruses that expressed miR-26a1 or a scrambled sequence (control); proliferation and colony formation were analyzed. We analyzed growth of human cholangiocarcinoma cells that overexpress miR-26a or its inhibitor in severe combined immune-deficient mice. Immunoblot, immunoprecipitation, DNA pull-down, immunofluorescence, and luciferase reporter assays were used to measure expression and activity of glycogen synthase kinase (GSK)-3β, β-catenin, and related signaling molecules. RESULTS:Human cholangiocarcinoma tissues and cell lines had increased levels of miR-26a compared with the noncancerous biliary epithelial cells. Overexpression of miR-26a increased proliferation of cholangiocarcinoma cells and colony formation in vitro, whereas miR-26 depletion reduced these parameters. In severe combined immune-deficient mice, overexpression of miR-26a by cholangiocarcinoma cells increased tumor growth and overexpression of the miR-26a inhibitor reduced it. GSK-3β messenger RNA was identified as a direct target of miR-26a by computational analysis and experimental assays. miR-26a-mediated reduction of GSK-3β resulted in activation of β-catenin and induction of several downstream genes including c-Myc, cyclinD1, and peroxisome proliferator-activated receptor δ. Depletion of β-catenin partially prevented miR-26a-induced tumor cell proliferation and colony formation. CONCLUSIONS:miR-26a promotes cholangiocarcinoma growth by inhibition of GSK-3β and subsequent activation of β-catenin. These signaling molecules might be targets for prevention or treatment of cholangiocarcinoma.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Zhang J,Han C,Wu T

doi

10.1053/j.gastro.2012.03.045

subject

Has Abstract

pub_date

2012-07-01 00:00:00

pages

246-56.e8

issue

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(12)00493-3

journal_volume

143

pub_type

杂志文章

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MicroRNA-26a promotes cholangiocarcinoma growth by activating β-catenin.