Endocrine Abstracts

Introduction: Spindle cell oncocytomas (SCO) of the pituitary are rare tumors accounting for 0.1–0.4% of all sellar tumors. Due to its rarity, little information is available regarding its pathogonesis. The altered gene expression and the possible pathogenetic role of microRNAs (miRNAs) have been identified in many tumor types, however, until now ther is no data regarding their role in pituitary oncocytoma.

Materials and methods: Total RNA was extracted from 9 formalin-fixed paraffin embedded (FFPE) pituitary oncocytoma samples (4 primary, 3 recurrent oncocytomas and 2 normal tissues). miRNA library was performed for sequencing next-generation sequencing to identify miRNA profiling. For the comparative analysis microarray dataset of 6 samples were obtained from NBCI GEO database for gene expression reanalysis and tissue-specific target prediction. Bioinformatical analysis was applied to characterise function and biological processes of miRNAs and genes revealed to be significantly different between tumors and normal tissues.

Results: 54 differentially expressed miRNAs and 485 genes in pituitary SCO vs. normal tissue and 8 miRNAs in recurrent vs. primary SCO were detected. Transcriptome analysis revealed cell cycle alterations while miRNAs influenced mainly metabolic processes (tricarboxylic acid cycle-TCA, carbohydrate, lipid metabolism). MiRNA-mRNA interaction network analysis revealed miR-744-5p, miR-127-3p and miR-7-5p as miRNAs with the most significant effect in SCO where the overexpressed Aconitase 2 (ACO2: fold change 2.78, P<0.01) was targeted by two downregulated miRNAs (miR-744-5p: fold change 0.20; P=0.01 and miR-127-3p, fold change: 0.05; P<0.01).

Conclusion: MiRNA profile distinguishes SCO, recurrent SCO and normal pituitary suggesting that miRNAs may have a role in SCO pathogenesis by influencing cell proliferation and metabolism. Based on our results and literature data the downregulated ACO2 targeting miRNAs miR-744-5p and miR-127-3p are tumor suppressors and they can be potential candidates for miRNA-based therapy. Earlier reports showed dysregulated TCA cycle in SCO and that ACO2 inhibition led to less efficient entry to cell cycle. These are extended by our results adding the role of miR-744-5p and miR-127-3p potentially targeting ACO2 and regulating cell proliferation.

Grants and financial support: This work has been funded by National Research, Development and Innovation Office (OTKAPD116093 to Henriett Butz). Henriett Butz is a recipient of Bolyai Research Fellowship of Hungarian Academy of Sciences and ÚNKP-18-4-SE-8 New National Excellence Program of The Ministry of Human Capacities.