Analysis of differential gene expression in plurihormonal pituitary adenomas using bead-based fiber-optic arrays.
ABSTRACT Plurihormonal pituitary adenomas (PHPAs) are defined as those pituitary adenomas secreting two or more hormones that differ in chemical composition, immunoreactivity, and biologic effects. Since the pathogenesis of these adenomas is not well understood, our study aimed to explore mechanisms underlying the pathogenesis of PHPAs. We used bead-based fiber-optic arrays (Illumina Human GeneChip WG-6 v3.0) to examine the gene expression profiles in seven PHPAs compared with three normal pituitary glands. Four differentially expressed genes were chosen randomly for validation by quantitative real-time reverse-transcription polymerase chain reaction. We then performed pathway analysis of all differentially expressed genes using the Kyoto Encyclopedia of Genes and Genomes. Our array analysis showed significant increases in the expression of 6 genes and decreases in 334 genes and 15 expressed sequence tags in the PHPAs. Bioinformatic analysis showed that genes HIGD1B, EPS8, ECT2, and BTG2 might play an important role in the tumorigenesis and progression of PHPAs. Pathway analysis showed that the p53 and Notch signaling pathways may play an important role in tumorigenesis and progression of PHPAs, and extracellular matrix (ECM)-receptor interactions likely play a role in the inhibition of invasion and metastasis in these tumors. Our data suggested that there are numerous aberrantly expressed genes and pathways involved in the pathogenesis of PHPAs. Bead-based fiber-optic arrays combined with pathway analysis of gene expression data appears to be a valid method for investigating the pathogenesis of tumors.
- SourceAvailable from: Nataša Anastasov[Show abstract] [Hide abstract]
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.Acta Neuropathologica 06/2013; · 9.73 Impact Factor