Role of Hedgehog signaling in malignant pleural mesothelioma
Clinical Cancer Research, 06/27/2012
Shi Y et al. – An aberrant HH signaling is present in MPM and inhibition of HH signaling decreases tumor growth indicating potential new therapeutic approach.
Methods- 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.
- 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.
