title: 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.
authors.affiliation: Division 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.
authors.forename: Katharina
authors.initials: K
authors.lastname: Lampichler
authors.affiliation: Division 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.
authors.forename: Patricio
authors.initials: P
authors.lastname: Ferrer
authors.affiliation: Division 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.
authors.forename: Greisa
authors.initials: G
authors.lastname: Vila
authors.affiliation: Division 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.
authors.forename: Mirjam I
authors.initials: MI
authors.lastname: Lutz
authors.affiliation: Division 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.
authors.forename: Florian
authors.initials: F
authors.lastname: Wolf
authors.affiliation: Division 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.
authors.forename: Engelbert
authors.initials: E
authors.lastname: Knosp
authors.affiliation: Division 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.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wagner
authors.affiliation: Division 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.
authors.forename: Anton
authors.initials: A
authors.lastname: Luger
authors.affiliation: Division 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.
authors.forename: Sabina
authors.initials: S
authors.lastname: Baumgartner-Parzer
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D055815:Young Adult; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
keywords: GLI1; Hedgehog; pituitary adenoma; stem cells