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Transcriptome analysis of MENX-associated rat pituitary adenomas identifies novel molecular mechanisms involved in the pathogenesis of human pituitary gonadotroph adenomas
- Source :
- Acta Neuropathologica, Acta Neuropathol. 126, 137-150 (2013)
- Publication Year :
- 2013
- Publisher :
- Springer-Verlag, 2013.
-
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. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1132-7) contains supplementary material, which is available to authorized users.
- Subjects :
- Adenoma
endocrine system
Pituitary gonadotroph adenoma
Cellular differentiation
Green Fluorescent Proteins
Clinical Neurology
Biology
Biostatistics
medicine.disease_cause
Bioinformatics
Transfection
Pathology and Forensic Medicine
Transcriptome
CYP11A1
Cellular and Molecular Neuroscience
Cell Line, Tumor
medicine
Animals
Humans
Pituitary Neoplasms
Cholesterol Side-Chain Cleavage Enzyme
Pituitary Gonadotroph Adenoma
Transcriptome Analysis
Menx Model
Cyp11a1
Nusap1
Original Paper
Microarray analysis techniques
Gene Expression Profiling
Pituitary tumors
MENX model
Computational Biology
medicine.disease
Microarray Analysis
Rats
Gene expression profiling
Gene Expression Regulation, Neoplastic
Cell Transformation, Neoplastic
Gonadotropins, Pituitary
Immunohistochemistry
RNA Interference
Neurology (clinical)
NUSAP1
Transcriptome analysis
Carcinogenesis
Microtubule-Associated Proteins
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 14320533 and 00016322
- Volume :
- 126
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica
- Accession number :
- edsair.doi.dedup.....462d07ee42847f8f094fe4847f056133