Data from Role of Hedgehog Signaling in Malignant Pleural Mesothelioma

Abstract

<div>Abstract<p><b>Purpose:</b> The aim of this study was to assess the activity of hedgehog signaling pathway in malignant pleural mesothelioma (MPM).</p><p><b>Experimental Design:</b> The expression of hedgehog signaling components was assessed by quantitative PCR and <i>in situ</i> 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 <i>GLI1</i> silencing on cell growth and hedgehog signaling. <i>In vivo</i> effects of SMO antagonists were determined in an MPM xenograft growing in nude mice.</p><p><b>Results:</b> A significant increase in <i>GLI1</i>, <i>sonic hedgehog</i>, and <i>human hedgehog interacting protein</i> gene expression was observed in MPM tumors compared with nontumoral pleural tissue. SMO antagonists inhibited <i>GLI1</i> expression and cell growth in sensitive primary cultures. This effect was mimicked by <i>GLI1</i> silencing. Reduced survivin and YAP protein levels were also observed. Survivin protein levels were rescued by overexpression of <i>GLI1</i> or constitutively active <i>YAP1.</i> Treatment of tumor-bearing mice with the SMO inhibitor HhAntag led to a significant inhibition of tumor growth <i>in vivo</i> accompanied by decreased Ki-67 and nuclear YAP immunostaining and a significant difference in selected gene expression profile in tumors.</p><p><b>Conclusions:</b> An aberrant hedgehog signaling is present in MPM, and inhibition of hedgehog signaling decreases tumor growth indicating potential new therapeutic approach. <i>Clin Cancer Res; 18(17); 4646–56. ©2012 AACR</i>.</p></div>