The role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation

Abstract

The Hedgehog (Hh) pathway is an important regulator of early tissue patterning and stem cell propagation. It was found to be aberrantly activated in numerous types of human cancer and might be relevant in cancer stem cells. The identification of adult stem cells in the pituitary raised the question if tumor-initiating cells and Hh signaling are involved in pituitary adenoma formation. The present study aimed at the evaluation of Hh signaling in relation to stem cell and cell cycle markers in 30 human pituitary adenomas and in cultured murine adenoma cells. Therefore, expression levels of components of the Hh pathway, stem cell marker SOX2, cell cycle regulator tumor-protein 53 (TP53), proliferation marker Ki67 (MKI67) and superoxide dismutase 1 (SOD1) were evaluated in 30 human pituitary adenomas in comparison to control tissue. Modulation of cell function and target gene expression by the inhibition and activation of the Hh pathway were studied in murine adenoma cells. We show that transcription factor glioma-associated oncogene 1 (GLI1) is overexpressed in 87% of all pituitary adenomas. The expression of GLI1 significantly correlated with that of SOX2, TP53, MKI67 and SOD1. Inhibition of GLI1 resulted in the downregulation of the above genes and severe cell death in mouse adenoma cells. On the other hand, activation of the Hh pathway increased cell viability and target gene expression. In conclusion, our findings point toward an alternative, ligand-independent Hh pathway activation with GLI1 playing a major role in the cell survival of pituitary adenoma cells.

Pituitary stem cell regulation: who is pulling the strings?

“…As mentioned previously, transgenically induced ACP showed increased production of SHH by the β-catenin-activated SOX2 + cells, which then may contribute to ACP development and tumor cell proliferation (Andoniadou et al 2012(Andoniadou et al , 2013. Some SHH-associated genes were also found upregulated in the SP of human pituitary tumors when compared to the bulk non-SP (Mertens et al 2015) (Table 1), and GLI1 expression seems to go together with SOX2 expression as analyzed in a cohort of pituitary adenomas (Lampichler et al 2015).…”

Effect of miR-106b on Invasiveness of Pituitary Adenoma via PTEN-PI3K/AKT

“…Therefore, the understanding of pituitary adenoma occurrence/progression and the acquirement of invasiveness is of critical importance for both diagnosis and treatment. One study showed that the occurrence and progression of pituitary adenoma might be related with the absence of tumor suppressor gene or expression of oncogenes [27]. MicroRNA is a biological marker for human tumors, and has important roles in the biological process of tumors.…”

Glioma-Associated Oncogene Homolog1 (Gli1)-Aquaporin1 pathway promotes glioma cell metastasis

“…Our present data is similar to the previous studies, and showed the activation of Gli1 expression in glioma tissue as well as in two glioma cell lines (U251 and U87) by qRT-PCR and western blotting analysis. Although a comprehensive analysis of direct transcriptional targets of Gli1 at the genomic level is lacking, a number of studies have shown that Gli1 directly regulates the transcription of various genes that are known to be involved in cell proliferation, survival, and chemotolerance (16 - 18) .…”