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.
Highlights
Pituitary neuroendocrine tumors (PitNETs) are benign intracranial endocrine tumors with potentially high prevalence in the population
This could be explained by the fact that not all patients agreed to surgical therapy immediately, and the preoperative treatment period in most cases in our cohort was longer than 3–6 months
The effects of somatostatin analogs (SSAs)/dopamine agonists (DAs) medication on the overall cellular transcriptional profile and consequent functional changes have not been elucidated. This is one of the first reports that have evaluated transcriptome profiles from PitNET tumor tissue in two groups of patients with and without medical therapy, which was applied before tumor resection
Summary
Pituitary neuroendocrine tumors (PitNETs) are benign intracranial endocrine tumors with potentially high prevalence in the population. Somatotropinoma, which develops from anterior pituitary somatotroph cells, are characterized by increased synthesis and secretion of growth hormone (GH). They constitute 10–15% of all clinically significant somatotropinomas and usually cause acromegaly in adults or gigantism in children with additional comorbidities [3]. Is a rare and chronic endocrine disorder and is characterized by abnormal growth of the extremities, cardiovascular diseases, and metabolic disorders, such as diabetes mellitus that is caused by increased levels of insulin growth factor 1 (IGF-1), activated by high GH levels [4]. If somatostatin analogs (SSAs) fail to control IGF-1 levels, dopamine agonists (DAs) that target dopamine receptor 2 (D2R) are used as complementary management options [6]. SSA and DA have demonstrated an inhibitory effect on the secretion of both hormones and cell proliferation, approximately one-third of acromegalic patients are resistant to cabergoline and octreotide treatment [6]
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