Institute of Biology, Faculty of Exact and Natural Sciences, University of Antioquia, Calle 67 #53-108, 050010 Medellín, Colombia.
Department of Pathology, Faculty of Medicine, University of Antioquia, Cra. 51d #62-29, 050010 Medellín, Colombia.
Exp Mol Pathol. 2021 Oct;122:104673. doi: 10.1016/j.yexmp.2021.104673. Epub 2021 Aug 8.
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.
最近的研究结果表明，在体外培养的胶质母细胞瘤进展细胞和小鼠肿瘤中，SHH/GLI 和 PI3K/Akt/mTORC1 信号之间存在协同串扰，但尚不清楚这种情况是否也发生在人类胶质瘤中。因此，我们旨在研究这些通路的关键蛋白在不同人类胶质瘤中的表达情况。通过免疫组织化学方法检测了胶质瘤和对照脑组织中 PTEN、磷酸化 Akt（Ser473）、磷酸化 S6K1（Thr389）、SHH、GLI1、GLI2 和 GLI3 的表达。根据胶质瘤类型、胶质瘤分级和细胞类型确定每种蛋白的表达模式；使用每种蛋白的相对表达量进行统计分析。我们发现，两种信号通路的蛋白表达在正常脑组织和胶质瘤组织之间存在差异。例如，正常星形胶质细胞的蛋白表达模式与反应性和肿瘤性星形胶质细胞不同。有趣的是，我们在少突胶质细胞中检测到 GLI3 的表达模式和有丝分裂性肿瘤细胞中磷酸化 S6K1 的表达模式反复出现。我们还根据胶质瘤类型确定了细胞信号的差异：少突胶质细胞瘤和室管膜瘤与 SHH/GLI 蛋白的表达有关。最后，我们发现高级别胶质瘤与 GLI1 和 GLI2 的表达呈统计学相关，并且 GLI1、GLI2、磷酸化 Akt 和磷酸化 S6K1 在生存时间较短的患者中表达更高，这表明这些细胞信号的激活影响胶质瘤的发生和患者的生存。总之，我们的结果表明，PI3K/Akt/mTORC1 和 SHH/GLI 通路的蛋白在人类胶质瘤中根据肿瘤类型和分级而不同表达，并表明这些信号网络的激活与胶质瘤的进展相关。
