Genome wide analysis of circulating miRNAs in growth hormone secreting pituitary neuroendocrine tumor patients' plasma

Helvijs Niedra; Raitis Peculis; Helena Daiga Litvina; Kaspars Megnis; Ilona Mandrika; Inga Balcere; Mihails Romanovs; Liva Steina; Janis Stukens; Austra Breiksa; Jurijs Nazarovs; Jelizaveta Sokolovska; Rasa Liutkeviciene; Alvita Vilkevicute; Ilze Konrade; Vita Rovite

doi:10.3389/fonc.2022.894317

Genome wide analysis of circulating miRNAs in growth hormone secreting pituitary neuroendocrine tumor patients' plasma

Front Oncol. 2022 Sep 9:12:894317. doi: 10.3389/fonc.2022.894317. eCollection 2022.

Authors

Helvijs Niedra¹, Raitis Peculis¹, Helena Daiga Litvina¹, Kaspars Megnis¹, Ilona Mandrika¹, Inga Balcere^{2

3}, Mihails Romanovs², Liva Steina⁴, Janis Stukens⁴, Austra Breiksa⁴, Jurijs Nazarovs⁴, Jelizaveta Sokolovska⁵, Rasa Liutkeviciene⁶, Alvita Vilkevicute⁶, Ilze Konrade^{2

3}, Vita Rovite¹

Affiliations

¹ Department of molecular and functional genomics, Latvian Biomedical Research and Study Centre, Riga, Latvia.
² Department of Endocrinology, Riga East Clinical University Hospital, Riga, Latvia.
³ Department of Internal Diseases, Riga Stradins University, Riga, Latvia.
⁴ Department of Neurosurgery, Faculty of Medicine Pauls Stradins Clinical University Hospital, Riga, Latvia.
⁵ Faculty of Medicine, University of Latvia Faculty of Medicine, Riga, Latvia.
⁶ Institute of Neuroscience, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Abstract

Background: Circulating plasma miRNAs have been increasingly studied in the field of pituitary neuroendocrine tumor (PitNET) research. Our aim was to discover circulating plasma miRNAs species associated with growth hormone (GH) secreting PitNETs versus assess how the plasma levels of discovered miRNA candidates are impacted by SSA therapy and whether there is a difference in their levels between GH secreting PitNETs versus other PitNET types and healthy individuals.

Design: We compared plasma miRNA content and levels before and after surgery focusing on GH secreting PitNET patients. Selected miRNA candidates from our data and literature were then tested in a longitudinal manner in somatostatin analogues (SSA) treatment group. Additionally, we validated selected targets in an independent GH secreting PitNET group.

Methods: miRNA candidates were discovered using the whole miRNA sequencing approach and differential expression analysis. Selected miRNAs were then analyzed using real-time polymerase chain reaction (qPCR).

Results: Whole miRNA sequencing discovered a total of 16 differentially expressed miRNAs (DEMs) in GH secreting PitNET patients' plasma 24 hours after surgery and 19 DEMs between GH secreting PitNET patients' plasma and non-functioning (NF) PitNET patients' plasma. Seven miRNAs were selected for further testing of which miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p showed a significant downregulation in plasma after 1 month of SSA treatment. mir-625-5p was found to be significantly downregulated in plasma of GH secreting PitNET patients vs. NF PitNET patients. miR-625-5p alongside miR-130b-3p were also found to be downregulated in GH PitNETs compared to healthy individuals.

Conclusions: Our study suggests that expression of plasma miRNAs miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p in GH secreting PitNETs is affected by SSA treatment. Additionally, miR-625-5p can distinguish GH secreting PitNETs from other PitNET types and healthy controls warranting further research on these miRNAs for treatment efficacy.

Keywords: acromegaly; circulating plasma micro-RNAs; growth hormone secreting pituitary neuroendocrine tumor; micro-RNA differential expression; somatostatin analogue treatment.