Abstract
Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs.
Highlights
Pituitary neuroendocrine tumors (PitNETs), formerly referred to as pituitary adenomas, are more abundant than often thought, as they represent approximately 15% of all brain tumors and have an estimated prevalence that ranges from 1 in 865–2688 people [1,2]
Results from the dynamic quantitative real-time PCR (qPCR) microfluidic custom-made array revealed a marked dysregulation of the expression levels of several components of the splicing machinery in Non-functioning pituitary tumors (NFPTs) compared to normal human pituitary gland samples (NPs), wherein nearly half of the elements examined were clearly downregulated (18 out of 42) or exhibited a trend to be downregulated in NFPTs (Figure 1A; Figure S1)
Variable Importance in Projection (VIP) score of Partial Least Squares-Discriminant Analysis (PLS-DA) analysis indicated that SRSF9, SND1, U2AF1, SRRM4, and U2AF2 were the components with a higher capacity to discriminate between both populations (Figure 1D)
Summary
Pituitary neuroendocrine tumors (PitNETs), formerly referred to as pituitary adenomas, are more abundant than often thought, as they represent approximately 15% of all brain tumors and have an estimated prevalence that ranges from 1 in 865–2688 people [1,2]. Recent studies exploring the genomic landscape of PitNETs confirmed and extended earlier studies by reporting that all major tumor subtypes studied present a relatively low number of somatic mutations per tumor and that there are scarce recurrent mutations, none of which is commonly found across PitNET subtypes [6,7] Overall, these genomic analyses, albeit highly informative and valuable, support the contention that mutations and purely genetic alterations alone would not fully explain PitNET tumorigenesis and, that alternative oncogenic events, including epigenetic alterations [8] or miRNAs [9,10], should be explored further to understand their actual contribution in this regard. The primary initiating cause of PitNETs development and the possible existence of general and distinctive signatures and molecular elements in this heterogeneous pathology is still under debate [4,5,11,12,13,14]
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