Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF.
Gene Expr
; 17(4): 313-326, 2017 11 27.
Article
em En
| MEDLINE
| ID: mdl-28915934
ABSTRACT
Autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF) is a rare but fatal genetic disease characterized by progressive cyst development in the kidneys and liver. Liver cysts arise from aberrantly proliferative cholangiocytes accompanied by pericystic fibrosis and inflammation. Yes-associated protein (YAP), the downstream effector of the Hippo signaling pathway, is implicated in human hepatic malignancies such as hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma, but its role in hepatic cystogenesis in ARPKD/CHF is unknown. We studied the role of the YAP in hepatic cyst development using polycystic kidney (PCK) rats, an orthologous model of ARPKD, and in human ARPKD/CHF patients. The liver cyst wall epithelial cells (CWECs) in PCK rats were highly proliferative and exhibited expression of YAP. There was increased expression of YAP target genes, Ccnd1 (cyclin D1) and Ctgf (connective tissue growth factor), in PCK rat livers. Extensive expression of YAP and its target genes was also detected in human ARPKD/CHF liver samples. Finally, pharmacological inhibition of YAP activity with verteporfin and short hairpin (sh) RNA-mediated knockdown of YAP expression in isolated liver CWECs significantly reduced their proliferation. These data indicate that increased YAP activity, possibly through dysregulation of the Hippo signaling pathway, is associated with hepatic cyst growth in ARPKD/CHF.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proliferação de Células
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Células Epiteliais
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Proteínas Reguladoras de Apoptose
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Doenças Renais Policísticas
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article