Difference in miRNA Expression in Functioning and Silent Corticotroph Pituitary Adenomas Indicates the Role of miRNA in the Regulation of Corticosteroid Receptors.

Beata J Mossakowska,Jacek Kunicki,Grzegorz Zieliński,Tomasz Mandat,Mateusz Bujko,Maria Maksymowicz,Natalia Rusetska,Andrzej Styk,Paulina Kober,Monika Pękul,Joanna Boresowicz

doi:10.3390/ijms23052867

Abstract

Corticotroph pituitary adenomas commonly cause Cushing’s disease (CD), but some of them are clinically silent. The reason why they do not cause endocrinological symptoms remains unclear. We used data from small RNA sequencing in adenomas causing CD (n = 28) and silent ones (n = 20) to explore the role of miRNA in hormone secretion and clinical status of the tumors. By comparing miRNA profiles, we identified 19 miRNAs differentially expressed in clinically functioning and silent corticotroph adenomas. The analysis of their putative target genes indicates a role of miRNAs in regulation of the corticosteroid receptors expression. Adenomas causing CD have higher expression of hsa-miR-124-3p and hsa-miR-135-5p and lower expression of their target genes NR3C1 and NR3C2. The role of hsa-miR-124-3p in the regulation of NR3C1 was further validated in vitro using AtT-20/D16v-F2 cells. The cells transfected with miR-124-3p mimics showed lower levels of glucocorticoid receptor expression than control cells while the interaction between miR-124-3p and NR3C1 3′ UTR was confirmed using luciferase reporter assay. The results indicate a relatively small difference in miRNA expression between clinically functioning and silent corticotroph pituitary adenomas. High expression of hsa-miR-124-3p in adenomas causing CD plays a role in the regulation of glucocorticoid receptor level and probably in reducing the effect of negative feedback mediated by corticosteroids.

Highlights

Pituitary adenomas represent about 10–20% of intracranial neoplasms in adults
Cushing’s disease (CD)-causing ACTH tumors are commonly small microadenomas with approximately 50% being smaller than 5 mm, which is challenging for MRI diagnostics [2]
All patients with CD had clear clinical signs and symptoms of hypercortisolism verified according to biochemical criteria including elevated midnight cortisol levels and 24 h urinary free cortisol (UFC)

Summary

Introduction

Pituitary adenomas ( referred to as pituitary neuroendocrine tumors, PitNETs) represent about 10–20% of intracranial neoplasms in adults. SCAs are commonly diagnosed due to neurological symptoms related to tumor mass at the stage of large macroadenomas They show invasive growth and increased proliferation index [1]. SCAs are referred to as “high-risk” pituitary adenomas which refers to their fast and invasive growth, high risk of recurrence and resistance to medical therapy [3,4]. They are recognized to be more aggressive than other clinically nonfunctioning pituitary tumors such as those of gonadotroph origin or null-cell adenomas [5]

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