These data suggest that elevated GLI1 expression has a determinant role in tumour initiation; however, additional genetic events are required for tumour progression.
We indicate that the PKN2, MKL1, MED23, CUL5 and GLI genes demonstrate a tumor suppressor profile, and that the MTR, ITGA2B, TELO2, MRPL9, MTTL1, WIPI1, KLHL20, PI4KB, FOLR1 and SHC1 genes demonstrate an oncogenic profile.
However, immunohistochemical analysis revealed that only GLI1 protein was specifically upregulated in BCC, while the other HH-related proteins did not show any significant differences between the tumors.
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.
We have previously shown that the sonic hedgehog-Gli signaling pathway is oncogenic in CCC allowing us to identify the developmental Lim1 transcription factor as a Gli target and as a new oncogene in CCC regulating cell proliferation and apoptosis, and promoting tumor growth.
The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal from the tumour suppressor Patched-1 (PTCH1) to the glioma-associated-oncogene (GLI) transcription factors, which activates the Hedgehog signalling pathway<sup>1,2</sup>.
Significant cyclopamine-induced suppression of Gli1 in 5637 and T24 mouse tumors (both p = 0.03) was seen, suggesting that muscle-invasive bladder cancer may be more dependent on Shh signaling than non-muscle-invasive bladder cancer.
Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC).
A significant correlation of SHH, DHH and GLI1 expression with advanced tumour size, stages, grades, nodal involvement and distant metastasis was observed (p < 0.05).
Moreover, GLI1 and p-S6K expression was considered to be independent prognostic factors in CRC patient and the positive co-expression of GLI1/p-S6K had greater influence than single expression positive on the prognosis of postoperative patients with tumor size≥5 cm, well differentiation, positive lymph node metastasis, venous invasion, neural invasion and TNM III-IV.
In addition, Numb has an inverse correlation with ki-67 labeling index (P < 0.05), and nuclear Gli1 was found in associated with the tumor International Mesothelioma Interest Group-stage (P < 0.05).
The expression of GLI family zinc finger 1 (Gli1) was inhibited by miR-218 overexpression, suggesting miR-218-suppression of Gli1 as a potential mechanism for the tumor-suppressive effect of miR-218.
In vertebrates, Sufu primarily functions as a tumor suppressor factor by interacting with and inhibiting glioma-associated oncogene homologues (GLIs), which are the terminal transcription factors of the Hh signalling pathway and belong to the Kruppel family of zinc finger proteins; by contrast, the regulation of Sufu itself remains relatively unclear.
Moreover, FOXS1 is both highly expressed and positively correlated with GLI1 in medulloblastoma samples of the Sonic HH subgroup, further arguing for the existence of FOXS1/GLI1 interplay in human tumors.
Taken together, our results indicate that overall glioblastoma tumor growth suppression by penfluridol was associated with Akt-mediated inhibition of GLI1.
Inhibition of GLI1 in human lung SCC cell lines suppressed tumor cell clonogenicity and proliferation in culture and <i>in vivo</i> Addition of SHH ligand, SMO antagonists, or other Hedgehog pathway agonists did not affect GLI1 expression in lung SCC cells.
We found that SHH was highly expressed in human tongue OSCC, whereas patched (PTCH1), glioma-associated oncogene 1 (GLI1) and GLI2 proteins were expressed in the microvascular cells in the tumor invasive front.
An essential downstream regulator of the pathway, encoded by the tumor suppressor gene Suppressor of fused (Sufu), plays critical roles in the production, trafficking, and function of Gli proteins, but the mechanism remains controversial.