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Endocrine-related cancer. 2015 Jul 28. pii: ERC-15-0109. doi: 10.1530/ERC-15-0109
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The role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation.
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Lampichler K1, Ferrer P2, Vila G3, Lutz MI4, Wolf F5, Knosp E6, Wagner L7, Luger A8, Baumgartner-Parzer S9 |
  Author information
1Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIClinical Institute of NeurologyDepartment of Biomedical Imaging and Image-Guided TherapyDivision of NeurosurgeryDepartment of SurgeryDivision of NephrologyDepartment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
2Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIClinical Institute of NeurologyDepartment of Biomedical Imaging and Image-Guided TherapyDivision of NeurosurgeryDepartment of SurgeryDivision of NephrologyDepartment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
3Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIClinical Institute of NeurologyDepartment of Biomedical Imaging and Image-Guided TherapyDivision of NeurosurgeryDepartment of SurgeryDivision of NephrologyDepartment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
4Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIClinical Institute of NeurologyDepartment of Biomedical Imaging and Image-Guided TherapyDivision of NeurosurgeryDepartment of SurgeryDivision of NephrologyDepartment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
5Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIClinical Institute of NeurologyDepartment of Biomedical Imaging and Image-Guided TherapyDivision of NeurosurgeryDepartment of SurgeryDivision of NephrologyDepartment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
6Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIClinical Institute of NeurologyDepartment of Biomedical Imaging and Image-Guided TherapyDivision of NeurosurgeryDepartment of SurgeryDivision of NephrologyDepartment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
7Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIClinical Institute of NeurologyDepartment of Biomedical Imaging and Image-Guided TherapyDivision of NeurosurgeryDepartment of SurgeryDivision of NephrologyDepartment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
8Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIClinical Institute of NeurologyDepartment of Biomedical Imaging and Image-Guided TherapyDivision of NeurosurgeryDepartment of SurgeryDivision of NephrologyDepartment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
9Division of Endocrinology and MetabolismDepartment of Internal Medicine IIIClinical Institute of NeurologyDepartment of Biomedical Imaging and Image-Guided TherapyDivision of NeurosurgeryDepartment of SurgeryDivision of NephrologyDepartment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria sabina.baumgartner-parzer@meduniwien.ac.at.
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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.
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© 2015 Society for Endocrinology.
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KEYWORDS: GLI1, Hedgehog, pituitary adenoma, stem cells
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Publikations ID: 26219678
Quelle: öffnen
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