Endocrine Abstracts

The transcription factor and proto-oncogene GLI1 is the terminal mediator of the Hedgehog signalling pathway which is involved in developmental processes, stem cell maintenance and cell proliferation. Although the pathway is mainly active during embryogenesis and tissue repair, it is frequently reactivated in several cancer types.

Based on these findings we investigated the potential role of GLI1 in the pathogenesis of pituitary adenomas. GLI1 expression was studied in 30 human pituitary adenomas by qRT-PCR. Additionally, mRNA expression levels of stem cell marker SOX2, cell cycle regulator TP53, proliferation marker Ki67 and superoxide dismutase (SOD) 1 were determined. The threshold of GLI1 expression was set to be 1% of the GAPDH copy number level. Furthermore, the murine pituitary adenoma cell line AtT-20 was treated with the GLI1 antagonist GANT61 and cell viability was evaluated.

19 out of 30 human pituitary adenomas (63%) showed a GLI1 overexpression of various extent. GLI1 expression correlated with the expression of SOX2 (P<0.001, r=0.5813), TP53 (P<0.001, r=0.6111), Ki67 (P=0.0385, r=0.3798) and SOD1 (P<0.001, r=0.5889). Expression levels of all the above mentioned genes exhibited also a significant correlation among each other creating a network of cell cycle regulators and stem cell factors potentially involved in the pathogenesis of pituitary adenomas. Of note, survival rates of AtT-20 cells were highly decreased when treated with GLI1 antagonist GANT61. Cell survival was reduced by 50% (24 h) and 75% (48 h), respectively, upon incubation of cells with low concentrations (5 μM) of GANT61 and could be further decreased at a concentration of 20 μM resulting in complete cell death after 48 h.

In conclusion, our results suggest that GLI1 is potentially involved in the pathogenesis of pituitary adenomas by modulating adult stem cell fate or tumor-initiating stem cell function in the adult pituitary gland and its neoplasms.