Abstract
Spindle cell oncocytomas (SCO) of the pituitary are rare tumors accounting for 0.1–0.4% of all sellar tumors. Due to their rarity, little information is available regarding their pathogenesis. Our aim was to investigate miRNA expression profile of pituitary oncocytomas. Total RNA was extracted from 9 formalin-fixed paraffin embedded pituitary samples (4 primary, 3 recurrent oncocytomas and 2 normal tissues). Next-generation sequencing was performed for miRNA profiling. Transcriptome data of additional 6 samples’ were obtained from NBCI GEO database for gene expression reanalysis and tissue-specific target prediction. Bioinformatical analysis, in vitro miRNA mimics transfection, luciferase reporter system and AlamarBlue assay were applied to characterize miRNA’s function. 54 differentially expressed miRNAs and 485 genes in pituitary SCO vs. normal tissue and 8 miRNAs in recurrent vs. primary SCO were determined. Global miRNA downregulation and decreased level of DROSHA were detected in SCO samples vs. normal tissue. Transcriptome analysis revealed cell cycle alterations while miRNAs influenced mainly metabolic processes (tricarboxylic acid cycle-TCA, carbohydrate, lipid metabolism). Through miRNA-target interaction network the overexpressed Aconitase 2 potentially targeted by two downregulated miRNAs (miR-744-5p, miR-127-3p) was revealed. ACO2 and miR-744-5p interaction was validated by luciferase assay. MiR-127-3p and miR-744-5p significantly decreased cell proliferation in vitro. Our study firstly reported miRNA profile of pituitary oncocytoma. Our results suggest that tumor suppressor miRNAs may have an essential role in the pathogenesis of pituitary oncocytoma. Earlier reports showed downregulated TCA cycle in SCO which is extended by our results adding the role of miR-744-5p targeting ACO2.
Highlights
Prevalence rate of primary tumors of the anterior pituitary varies 10–22% of all intracranial tumors, clinically relevant pituitary adenomas appear more rarely [1, 2]
More than half of the miRNAs were in low expression range between 10 and 100 reads. 23%, 17% and 19% of the miRNAs were between 100 and 1000 read and only 11%, 8% and 8% of the miRNAs appeared in the highest expression range (> 1000 reads) in the normal, oncocytoma and recurrent oncocytoma groups, respectively (Fig. 1a)
We found global miRNA downregulation in oncocytoma vs. normal and assessing the most abundant 10 miRNAs showed lower expression in the oncocytoma and recurrent oncocytoma groups compared to the normal tissue as well (Fig. 1b, c)
Summary
Prevalence rate of primary tumors of the anterior pituitary varies 10–22% of all intracranial tumors, clinically relevant pituitary adenomas appear more rarely [1, 2]. Adenomas of the anterior pituitary are the most common. Neurochemical Research (2019) 44:2360–2371 tumor type in the sellar region followed by craniopharyngioma, meningioma and posterior pituitary tumors (PPT) [3]. Based on the WHO 2017 classification, the main tumors of neurohypophysis are pituicytomas, granular cell tumors, spindle cell oncocytomas (SCO) and sellar ependymomas. According to the current hypothesis, PPTs originate from specific morphological variants of pituicytes (specialized glial cells, i.e. pituicytomas from the light/major variant, granular cell tumors from the granular variant, spindle cell oncocytomas from the oncocytic variant and sellar ependymomas from the ependymal pituicytes) [4]. Some hormonally active oncocytomas have been described [6, 7], PPTs are low-grade, non-neuroendocrine neoplasms clinically presenting with symptoms related to mass effects [4, 8, 9]
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