Abstract
Advances in the understanding of growth hormone-producing adenomas (GHomas) are ongoing, but current therapy is limited by moderate and variable efficacy and in need of life-long treatment. In this study, the molecular signaling pathway related to GHoma was investigated by proteomics and transcriptomics. The differentially expressed proteins and genes were significantly enriched in Extracellular Matrix-Receptor Interactions, Notch Signaling, Basal Cell Carcinoma Signaling, JAK-STAT3, Wnt Signaling, and Glioblastoma Multiforme Signaling by Ingenuity Pathway Analysis. Furthermore, the Notch2/Delta-like canonical Notch ligand (DLL) signaling pathway was identified to be associated with tumorigenesis and invasiveness of GHoma. In 76 patients, Notch2 and DLL3 were upregulated in invasive compared to those in non-invasive GHoma (p < 0.05). Disease-free survival was significantly longer in patients with low, compared with high, DLL3 expression (p = 0.027). Notch 2 knockdown inhibited cell migration in both GH3 cells and primary GHoma cells, along with downregulation of the mRNA expression of related genes. DAPT, a γ-secretase inhibitor, inhibited tumor growth and invasion in vivo and in vitro and suppressed the release of growth hormone in primary GHoma cells. The involvement of Notch2/DLL3 signaling in GHoma progression warrants additional study of Notch inhibitor, DAPT, as a potential GHoma treatment.Importance of the StudyCurrent treatments of GH adenomas (GHomas) are limited by their moderate and variable efficacy and in need of life-long treatment. We found that the Notch2/Delta-like Notch ligand 3 (DLL3) signaling pathway was active in GHoma tumorigenesis, progression, and invasion.The γ-secretase inhibitor DAPT is of potential use in GHoma treatment targeting Notch signaling.
Highlights
Growth hormone-producing adenomas (GHomas) can lead to acromegaly and the increased secretion of insulin-like growth factor 1 (IGF-1) [1]
The medical records of patients treated for pituitary adenomas at the Department of Neurosurgery, Beijing Tiantan Hospital, Abbreviations: cRNA, complementary RNA; DLL, Delta like canonical Notch ligand; DMEM, Dulbecco’s Modified Eagle’s Medium; epithelial-mesenchymal transition (EMT), epithelialmesenchymal transition; FDR, false discovery rate; GH, growth hormone; GHoma, growth hormone-producing pituitary tumor; GO, Gene Ontology; IGF-1, insulin-like growth factor 1; IHC, immunohistochemistry; Ingenuity Pathway Analysis (IPA), Ingenuity pathway analysis; LC-MS/MS, liquid chromatography tandem mass spectrometry; Magnetic Resonance Imaging (MRI), Magnetic resonance imaging; PBS, phosphate buffered saline; PVDF, polyvinylidene fluoride; quantitative realtime (qRT)–PCR, Quantitative reverse-transcription polymerase chain reaction; Transmission Electron Microscopy (TEM), Transmission electron microscopy; Tissue microarray analysis (TMA), Tissue microarray
Integrative analysis of transcriptomics and proteomics revealed several significantly altered pathways including Notch signaling in GHoma
Summary
Growth hormone-producing adenomas (GHomas) can lead to acromegaly and the increased secretion of insulin-like growth factor 1 (IGF-1) [1]. GHomas are currently treated with somatostatin receptor ligands and GH antagonists, which control growth hormone (GH) and IGF-1 levels [2]. The Notch signaling comprises a highly conserved pathway involved in determining cell activity, differentiation, and fate in both normal and tumor cells. It is initiated by the interaction of one of four Notch receptors with a number of possible ligands [10, 11]. Notch and Notch have antagonistic effects on the growth of embryonal brain tumor cell lines [12], and the anticancer activity of Notch inhibitors has been evaluated in clinical trials [13,14,15]. Notch expression is moderately elevated in non-functional pituitary adenomas (NFPAs) compared with that in functional adenomas including GHoma and prolactinsecreting adenomas (PRL) [17], but associated effects of Notch signaling have not been described
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