Role of hedgehog signaling in malignant pleural mesothelioma.

Détails

ID Serval
serval:BIB_CF8210B9AFAD
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Role of hedgehog signaling in malignant pleural mesothelioma.
Périodique
Clinical Cancer Research
Auteur(s)
Shi Y., Moura U., Opitz I., Soltermann A., Rehrauer H., Thies S., Weder W., Stahel R.A., Felley-Bosco E.
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Statut éditorial
Publié
Date de publication
2012
Peer-reviewed
Oui
Volume
18
Numéro
17
Pages
4646-4656
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Résumé
PURPOSE: The aim of this study was to assess the activity of hedgehog signaling pathway in malignant pleural mesothelioma (MPM).
EXPERIMENTAL DESIGN: The expression of hedgehog signaling components was assessed by quantitative PCR and in situ hybridization in 45 clinical samples. Primary MPM cultures were developed in serum-free condition in 3% oxygen and were used to investigate the effects of smoothened (SMO) inhibitors or GLI1 silencing on cell growth and hedgehog signaling. In vivo effects of SMO antagonists were determined in an MPM xenograft growing in nude mice.
RESULTS: A significant increase in GLI1, sonic hedgehog, and human hedgehog interacting protein gene expression was observed in MPM tumors compared with nontumoral pleural tissue. SMO antagonists inhibited GLI1 expression and cell growth in sensitive primary cultures. This effect was mimicked by GLI1 silencing. Reduced survivin and YAP protein levels were also observed. Survivin protein levels were rescued by overexpression of GLI1 or constitutively active YAP1. Treatment of tumor-bearing mice with the SMO inhibitor HhAntag led to a significant inhibition of tumor growth in vivo accompanied by decreased Ki-67 and nuclear YAP immunostaining and a significant difference in selected gene expression profile in tumors.
CONCLUSIONS: An aberrant hedgehog signaling is present in MPM, and inhibition of hedgehog signaling decreases tumor growth indicating potential new therapeutic approach.
Mots-clé
Adaptor Proteins, Signal Transducing/metabolism, Adult, Aged, Anilides/administration & dosage, Animals, Cell Line, Tumor, Cell Proliferation/drug effects, Female, Gene Expression Regulation, Neoplastic/drug effects, Humans, Inhibitor of Apoptosis Proteins/blood, Lung Neoplasms/drug therapy, Lung Neoplasms/metabolism, Male, Mesothelioma/drug therapy, Mesothelioma/metabolism, Mice, Middle Aged, NIH 3T3 Cells, Phosphoproteins/metabolism, Pleural Effusion, Malignant/drug therapy, Pleural Effusion, Malignant/metabolism, Pyridines/administration & dosage, RNA, Small Interfering, Receptors, G-Protein-Coupled/antagonists & inhibitors, Receptors, G-Protein-Coupled/metabolism, Signal Transduction, Tomatine/administration & dosage, Tomatine/analogs & derivatives, Transcription Factors/antagonists & inhibitors, Transcription Factors/metabolism, Transplantation, Heterologous, Veratrum Alkaloids/administration & dosage
Pubmed
Web of science
Open Access
Oui
Création de la notice
03/08/2014 13:36
Dernière modification de la notice
20/08/2019 15:49
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