Activation of the developmental pathway neurogenin-3/microRNA-7a regulates cholangiocyte proliferation in response to injury.
Hepatology
; 60(4): 1324-35, 2014 Oct.
Article
em En
| MEDLINE
| ID: mdl-24925797
ABSTRACT
UNLABELLED The activation of the biliary stem-cell signaling pathway hairy and enhancer of split 1/pancreatic duodenal homeobox-1 (Hes-1/PDX-1) in mature cholangiocytes determines cell proliferation. Neurogenin-3 (Ngn-3) is required for pancreas development and ductal cell neogenesis. PDX-1-dependent activation of Ngn-3 initiates the differentiation program by inducing microRNA (miR)-7 expression. Here we investigated the role Ngn-3 on cholangiocyte proliferation. Expression levels of Ngn-3 and miR-7 isoforms were tested in cholangiocytes from normal and cholestatic human livers. Ngn-3 was knocked-down in vitro in normal rat cholangiocytes by short interfering RNA (siRNA). In vivo, wild-type and Ngn-3-heterozygous (+/-) mice were subjected to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding (a model of sclerosing cholangitis) or bile duct ligation (BDL). In the liver, Ngn-3 is expressed specifically in cholangiocytes of primary sclerosing cholangitis (PSC) patients and in mice subjected to DDC or BDL, but not in normal human and mouse livers. Expression of miR-7a-1 and miR-7a-2 isoforms, but not miR-7b, was increased in DDC cholangiocytes compared to normal ones. In normal rat cholangiocytes, siRNA against Ngn-3 blocked the proliferation stimulated by exendin-4. In addition, Ngn-3 knockdown neutralized the overexpression of insulin growth factor-1 (IGF1; promitotic effector) observed after exposure to exendin-4, but not that of PDX-1 or VEGF-A/C. Oligonucleotides anti-miR-7 inhibited the exendin-4-induced proliferation in normal rat cholangiocytes, but did not affect Ngn-3 synthesis. Biliary hyperplasia and collagen deposition induced by DDC or BDL were significantly reduced in Ngn-3(+/-) mice compared to wild-type. CONCLUSION:
Ngn-3-dependent activation of miR-7a is a determinant of cholangiocyte proliferation. These findings indicate that the reacquisition of a molecular profile typical of organ development is essential for the biological response to injury by mature cholangiocytes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ductos Biliares
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Transdução de Sinais
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Colestase
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MicroRNAs
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Proliferação de Células
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Fatores de Transcrição Hélice-Alça-Hélice Básicos
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Lesão Pulmonar Aguda
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Proteínas do Tecido Nervoso
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Hepatology
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Itália