Abstract

PURPOSE: The aim of this study was to assess the activity of hedgehog (HH) signaling pathway in malignant pleural mesothelioma (MPM). EXPERIMENTAL DESIGN: The expression of HH signaling components was assessed by q-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 HH signaling. In vivo effects of SMO antagonists were determined in a 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 to non tumoral 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 HH signaling is present in MPM and inhibition of HH signaling decreases tumor growth indicating potential new therapeutic approach.