Expression of activator proteins of SHH/GLI and PI3K/Akt/mTORC1 signaling pathways in human gliomas is associated with high grade tumors

Recent findings have demonstrated a synergic crosstalk between SHH/GLI and PI3K/Akt/mTORC1 signaling in glioblastoma progression cells in vitro and in tumors in mice, but it is not known if this also occurs in human gliomas. We then aimed to investigate the expression of key proteins of these pathways in different human gliomas. The expression of PTEN, phospho-Akt (Ser473), phospho-S6K1 (Thr389), SHH, GLI1, GLI2 and GLI3 was assessed by immunohistochemistry in gliomas and in control brain tissues. The pattern of expression of each protein was established according to glioma type, glioma grade and to cell type; the relative expression of each protein was used to perform statistical analyses. We found that the expression of proteins of both signaling pathways differs between normal brain and glioma tissues. For instance, normal astrocytes had a different protein expression pattern compared with reactive and tumoral astrocytes. Interestingly, we detected a recurrent pattern of expression of GLI3 in oligodendrocytes and of phospho-S6K1 in mitotic neoplastic cells. We also identified differences of cell signaling according to glioma type: oligodendrogliomas and ependymomas are related with the expression of SHH/GLI proteins. Finally, we detected that high grade gliomas statistically correlate with the expression of GLI1 and GLI2, and that GLI1, GLI2, phospho-Akt and phospho-S6K1 are more expressed in patients with less survival, suggesting that activation of these cell signaling influences glioma outcome and patient survival. In summary, our results show that proteins of PI3K/Akt/mTORC1 and SHH/GLI pathways are differentially expressed in human gliomas according to tumor type and grade, and suggest that the activation of these signaling networks is associated with glioma progression.