Transcriptome analysis of MENX-associated rat pituitary adenomas identifies novel molecular mechanisms involved in the pathogenesis of human pituitary gonadotroph adenomas.

Abstract

Gonadotroph adenomas comprise 15-40% of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we demonstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrepresentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. Bioinformatic analysis identified downstream targets of the transcription factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similarities between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95% of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonadotroph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma primary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use.

• Authors: Misu Lee, Ilaria Marinoni, Martin Irmler, Tsambika Psaras, Jürgen B Honegger, Rudi Beschorner, Natasa Anastasov, Johannes Beckers, Marily Theodoropoulou, Federico Roncaroli, Natalia S Pellegata
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 126 Issue 1 Pg. 137-50 (Jul 2013) ISSN: 1432-0533 [Electronic] Germany
• PMID: 23756599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gonadotropins, Pituitary
• Microtubule-Associated Proteins
• NUSAP1 protein, human
• Transcription Factors
• Green Fluorescent Proteins
• Cholesterol Side-Chain Cleavage Enzyme

Topics

• Adenoma (genetics, pathology)
• Animals
• Biostatistics
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics)
• Cholesterol Side-Chain Cleavage Enzyme (genetics, metabolism)
• Computational Biology
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (genetics)
• Gonadotropins, Pituitary (metabolism)
• Green Fluorescent Proteins (genetics, metabolism)
• Humans
• Microarray Analysis
• Microtubule-Associated Proteins (genetics, metabolism)
• Pituitary Neoplasms (genetics, pathology)
• RNA Interference (physiology)
• Rats
• Transcription Factors (genetics, metabolism)
• Transfection