Medication for Acromegaly Reduces Expression of MUC16, MACC1 and GRHL2 in Pituitary Neuroendocrine Tumour Tissue

Rihards Saksis; Ivars Silamikelis; Pola Laksa; Kaspars Megnis; Raitis Peculis; Ilona Mandrika; Olesja Rogoza; Ramona Petrovska; Inga Balcere; Ilze Konrade; Liva Steina; Janis Stukens; Austra Breiksa; Jurijs Nazarovs; Jelizaveta Sokolovska; Valdis Pirags; Janis Klovins; Vita Rovite

doi:10.3389/fonc.2020.593760

Medication for Acromegaly Reduces Expression of MUC16, MACC1 and GRHL2 in Pituitary Neuroendocrine Tumour Tissue

Front Oncol. 2021 Feb 15:10:593760. doi: 10.3389/fonc.2020.593760. eCollection 2020.

Authors

Rihards Saksis¹, Ivars Silamikelis¹, Pola Laksa¹, Kaspars Megnis¹, Raitis Peculis¹, Ilona Mandrika¹, Olesja Rogoza¹, Ramona Petrovska¹, Inga Balcere^{2

3}, Ilze Konrade^{2

3}, Liva Steina⁴, Janis Stukens⁴, Austra Breiksa⁴, Jurijs Nazarovs⁴, Jelizaveta Sokolovska⁵, Valdis Pirags^{4

5}, Janis Klovins¹, Vita Rovite¹

Affiliations

¹ Latvian Biomedical Research and Study Centre, Riga, Latvia.
² Riga East Clinical University Hospital, Riga, Latvia.
³ Riga Stradins University, Riga, Latvia.
⁴ Pauls Stradins Clinical University Hospital, Riga, Latvia.
⁵ University of Latvia Faculty of Medicine, Riga, Latvia.

Abstract

Acromegaly is a disease mainly caused by pituitary neuroendocrine tumor (PitNET) overproducing growth hormone. First-line medication for this condition is the use of somatostatin analogs (SSAs), that decrease tumor mass and induce antiproliferative effects on PitNET cells. Dopamine agonists (DAs) can also be used if SSA treatment is not effective. This study aimed to determine differences in transcriptome signatures induced by SSA/DA therapy in PitNET tissue. We selected tumor tissue from twelve patients with somatotropinomas, with half of the patients receiving SSA/DA treatment before surgery and the other half treatment naive. Transcriptome sequencing was then carried out to identify differentially expressed genes (DEGs) and their protein-protein interactions, using pathway analyses. We found 34 upregulated and six downregulated DEGs in patients with SSA/DA treatment. Three tumor development promoting factors MUC16, MACC1, and GRHL2, were significantly downregulated in therapy administered PitNET tissue; this finding was supported by functional studies in GH3 cells. Protein-protein interactions and pathway analyses revealed extracellular matrix involvement in the antiproliferative effects of this type of the drug treatment, with pronounced alterations in collagen regulation. Here, we have demonstrated that somatotropinomas can be distinguished based on their transcriptional profiles following SSA/DA therapy, and SSA/DA treatment does indeed cause changes in gene expression. Treatment with SSA/DA significantly downregulated several factors involved in tumorigenesis, including MUC16, MACC1, and GRHL2. Genes that were upregulated, however, did not have a direct influence on antiproliferative function in the PitNET cells. These findings suggested that SSA/DA treatment acted in a tumor suppressive manner and furthermore, collagen related interactions and pathways were enriched, implicating extracellular matrix involvement in this anti-tumor effect of drug treatment.

Keywords: acromegaly; next generation sequencing (NGS); somatostatin/dopamine (SSA/DA) therapy; somatotropinoma; transcriptome.