Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

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.

Proteomic and Transcriptomic Analysis Identify Spliceosome as a Significant Component of the Molecular Machinery in the Pituitary Tumors Derived from POU1F1- and NR5A1-Cell Lineages

“…These tumor-specific spliceosome components and mRNA isoforms generated could support the notion that the pituitary tumors arise from divergent cell lineage origins or that they develop from partially committed pituitary stem cells, previously proposed by our group [10,11]. Similar results where the upregulation of several splicing factors in tumor-specific manner being observed in PA [12]. It is now established that alternative splicing contributes to cell differentiation and lineage determination, tissue identity acquisition and maintenance, and organ development [5].…”

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

“…Integration of microarray datasets has also been used to identify immune-related genes and further explore this possibility ( 318 ). Recently, evaluation of splicing machinery components in GH-PTs, ACTH-PTs, and PRL-PTs showed severe dysregulation in all subtypes compared to normal pituitary ( 319 ).…”

Dietary Intervention Modulates the Expression of Splicing Machinery in Cardiovascular Patients at High Risk of Type 2 Diabetes Development: From the CORDIOPREV Study

“…The activity of the spliceosome is precisely modulated by more than 300 auxiliary proteins, the so-called splicing factors, that recognize specific sequences in exons and introns [ 13 , 14 ]. An emerging body of evidence indicates that, under adverse health conditions, there is a profound dysregulation of certain spliceosomal components and splicing factors that results in altered and even aberrant splicing processes which, in turn, substantially contribute to the development of severe pathologies, including cancer, neurodegeneration, liver disease and diabetes [ 13 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Indeed, the correct function of the splicing machinery is essential to maintain cell homeostasis [ 17 , 18 , 22 , 23 ].…”