Role of hedgehog signaling in malignant pleural mesothelioma.
OBJECTIVE
The aim of this study was to assess the activity of hedgehog signaling pathway in malignant pleural mesothelioma (MPM).


METHODS
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.
Laboratory of Molecular Oncology, Clinic and Policlinic of Oncology, Division of Thoracic Surgery, Institute of Surgical Pathology, University Hospital Zürich, Zurich, Switzerland.
Yandong
Y
Shi
Ubiratan
U
Moura
Isabelle
I
Opitz
Alex
A
Soltermann
Hubert
H
Rehrauer
Svenja
S
Thies
Walter
W
Weder
Rolf A
RA
Stahel
Emanuela
E
Felley-Bosco
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D000813:Anilides / Q000008:administration & dosage*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000097:blood; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000378:metabolism; D016066:Pleural Effusion, Malignant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage*; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D000077022:Survivin; D014053:Tomatine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014183:Transplantation, Heterologous; D014704:Veratrum Alkaloids / Q000008:administration & dosage; D000091102:YAP-Signaling Proteins; D000071676:Zinc Finger Protein GLI1
D048868:Adaptor Proteins, Signal Transducing; D000813:Anilides; C107489:BIRC5 protein, human; C400551:GLI1 protein, human; C538724:HhAntag691; D051034:Inhibitor of Apoptosis Proteins; D010750:Phosphoproteins; D011725:Pyridines; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D000077022:Survivin; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000071676:Zinc Finger Protein GLI1; C003677:tomatidine; D014053:Tomatine; C000541:cyclopamine