MicroRNA in Acromegaly: Involvement in the Pathogenesis and in the Response to First-Generation Somatostatin Receptor Ligands

Abstract

Acromegaly is a chronic and systemic disease due to excessive growth hormone and insulin-like growth factor type I caused, in the vast majority of cases, by a GH-secreting pituitary adenoma. About 40% of these tumors have somatic mutations in the stimulatory G protein alpha-subunit 1 gene. The pathogenesis of the remaining tumors, however, is still not fully comprehended. Surgery is the first-line therapy for these tumors, and first-generation somatostatin receptor ligands (fg-SRL) are the most prescribed medications in patients who are not cured by surgery. MicroRNAs are small, non-coding RNAs that control the translation of many mRNAs, and are involved in the post-transcriptional regulation of gene expression. Differentially expressed miRNAs can explain differences in the pathogenesis of acromegaly and tumor resistance. In this review, we focus on the most validated miRNAs, which are mainly involved in acromegaly’s tumorigenesis and fg-SRL resistance, as well as in circulating miRNAs in acromegaly.

Keywords: acromegaly; miRNA; somatostatin receptor ligands; tumorigenesis.

Figure 1

Classical pathway: miRNA synthesis. (1) miRNA is mostly transcribed by RNA polymerase II through genomic regions. (2) pri-miRNA, a hairpin sequence, is then processed by DROSHA and DGCR8 proteins, which results in pre-miRNA. (3) pre-miRNA is transported to the cytoplasm through Exportin 5. (4) In the cytoplasm, pre-miRNA is processed by Dicer, which removes the terminal loop generating a 19-25nt miRNA. (5) miRNA is incorporated into the RNA-inducing silencing complex (RISC) with Argonaute (AGO) protein that retains one of the strands, the mature miRNA, while the other strand is degraded. (6) Mature miRNA associated with AGO and RISC binds its seed sequence in the target miRNA response element (MRE) in the mRNA. After binding, mRNA translation might be inhibited by two main mechanisms. (7) RISC represses translation or (8) RISC leads to mRNA degradation.

Figure 2

Circulating miRNAs. Circulating miRNAs arise in different ways: (1) Pre-miRNAs leave the nucleus and enter the classical processing pathway, where they might be secreted in their free form, by an unknown route, and circulate associated with high-density lipoprotein (HDL) and Argonaute proteins (AGO, as demonstrated in number (4). Alternatively, they might be incorporated into multivesicular bodies (MVB) and secreted into exosomes; (2) pre-miRNAs are integrated into MVBs and released through exosomes, finishing their processing in target cells; (3) both pre-miRNA and mature miRNA can be integrated into microvesicles that sprout from the cell surface and reach the bloodstream.

Figure 3

miRNAs involved in SST2 signaling. SST2 acts to inhibit adenylyl cyclase (AC) through inhibitory G protein. AIP also stimulates this inhibition. AC turns ATP into cyclic AMP (cAMP), which activates protein kinase A (PKA) that, through its pathway, leads to cell proliferation, growth, and hormone secretion. miR-34a targets AIP and G inhibitory $$a$$ subunit and it is also inhibited by AIP by unknown mechanisms. miR-185 directly targets SST2 mRNA and might play a role in decreasing SST2 levels. Figure adapted from “Activation of Protein Kinase A (PKA)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.