Our data indicate that upregulation of GLI1 induced by QKI deficiency maintains GSC stemness and enhances the invasiveness of GBM cells, thereby hinting at new options for the treatment of GBM.
Effects of different combinations of VIP-related neuropeptides and of pharmacological and siRNA inhibitors of PKA, Akt, and of the SHH/GLI1 pathways were tested on GBM migration rat C6 and human U87 GBM cell lines using the wound-healing technique.
We generated an antibody specific for phosphorylated PD-1-Y248 and examined PD-1pY248<sup>+</sup> (pPD-1) expression in human T cells. pPD-1 was upregulated by TCR/CD3 + CD28 stimulation and simultaneous PD-1 ligation. pPD-1<sup>+</sup>CD8<sup>+</sup> T cells were identified in human peripheral blood and had impaired effector function. pPD-1<sup>+</sup> T cells were also detected in tumor-draining lymph nodes of tumor bearing mice and in biopsies of patients with glioblastoma multiform.
Hepatic expression of IGFBPrP1, α-smooth muscle actin (α-SMA), transforming growth factor β 1 (TGFβ1), collagen I, MMPs/TIMPs, Sonic Hedgehog (Shh), and glioblastoma family transcription factors (Gli1) were investigated by immunohistochemical staining and Western blotting analysis.
These data suggested that FL34 exerted antitumor activity mediated by the inhibition of GLI1 and that FL34 may be a potential antitumor candidate compound that could be used to develop new antitumor drugs for the treatment of GBM.
After polydatin treatment, the main components of the Shh pathway, including Shh, Patched (Ptc), Smoothened (Smo), and glioblastoma-1 (Gli1), were upregulated at the mRNA and protein levels.
In an orthotopic GBM xenograft mouse model, tGLI1-overexpressing tumors grew more aggressively with increased proliferation and angiogenesis compared with control and GLI1-overexpressing xenografts. tGLI1 was highly expressed in GBM clinical specimens but undetectable in normal brains, whereas GLI1 was expressed in both tissues.
Further investigation found that the expression of the glioblastoma transcription factor (Gli) significantly increased in TGF-β1-stimulated neuroblastoma cells undergoing EMT, accordingly, interfering with Gli1/2 expression inhibited TGF-β1-induced EMT in neuroblastoma cells.
Taken together, our results indicate that overall glioblastoma tumor growth suppression by penfluridol was associated with Akt-mediated inhibition of GLI1.
O<sup>6</sup>-Methylguanine DNA methyltransferase-positive GBM tissues had a significantly higher rate of Gli1 nuclear staining than MGMT-negative ones (67.7% vs. 32.3%, p = 0.0159).
We conclude from our study that this single continuous distribution pattern of GLI1 mRNA expression technically puts almost all GBM patients in a single group rather than discrete high- or low-clusters in terms of Hh-pathway activity.
Cyclopamine treatment effectively increased apoptosis and inhibited cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT) by downregulating the Hh final arbiter glioblastoma 1 (Gli1), which regulates the transcription of target genes in the nucleus.
Recently it was discovered that the transcription factor Gli1, which is activated by hedgehog signaling, is a highly predictive marker in GBM, as determined by immunohistochemistry.