miR‐34a is upregulated in AIP‐mutated somatotropinomas and promotes octreotide resistance

Abstract

Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and have a heavy treatment burden. Growth hormone (GH)-secreting PAs (somatotropinomas) cause acromegaly-gigantism. Genetic forms of somatotropinomas due to germline AIP mutations (AIPmut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigated the role of miRNA dysregulation in AIPmut + vs AIPmut− PA samples by array analysis. miR-34a and miR-145 were highly expressed in AIPmut+ vs AIPmut− somatotropinomas. Ectopic expression of AIPmut (p.R271W) in Aip −/− mouse embryonic fibroblasts (MEFs) upregulated miR-34a and miR-145, establishing a causal link between AIPmut and miRNA expression. In PA cells (GH3), miR-34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR-145 moderately affected proliferation and apoptosis. Moreover, high miR-34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR-34a expression significantly blunted octreotide-mediated GH inhibition and antiproliferative effects. miR-34a directly targets Gnai2 encoding Gαi2, a G protein subunit inhibiting cAMP production. Accordingly, Gαi2 levels were significantly lower in AIPmut+ vs AIPmut− PA. Taken

Antagonists of Growth Hormone-Releasing Hormone Inhibit the Growth of Pituitary Adenoma Cells by Hampering Oncogenic Pathways and Promoting Apoptotic Signaling

“…In fact, MIA-602 and MIA-690 similarly and dose-dependently decreased cell viability and growth of GH3-GHRHR cells, at both 24 and 48 h. Interestingly, although they were effective also at low doses, 1 µm concentration yielded the best inhibitory effect, in line with previous findings from our and other groups in different cancer cell models [16][17][18]28]. The reduction in cell viability induced by the antagonists was similar to that of octreotide, which was previously reported to be effective in these cells [51], whereas pasireotide and lanreotide alone were inactive, likely because our experimental conditions were different from those reported in other studies [52,53]. Moreover, no additional inhibition was observed when GHRH antagonists were combined with SSAs.…”

Recent advances in understanding and managing pituitary adenomas

“…Lack of AIP or pathogenic mutations inhibits this pathway in AIP knockout mice and results in upregulation of somatotroph adenomas 76 . In somatotropinomas with AIP mutations, an overexpression of miR-34a was detected with a subsequent increase of cAMP concentration, cell growth, and reduction of response to octreotide 77 .…”

The Involvement of miRNAs in Pituitary Adenomas Pathogenesis and the Clinical Implications

“…Thus, drug resistance in PRL-PA is an urgent problem in clinical practice and attracts lots of researches. For example, upregulation of miR-34a was found to impair the hormonal and antiproliferative response of PA cells to octreotide, suggesting that miR-34a is a novel downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIPmut + acromegaly [17]. miR-1299 was found to promote the synthesis and secretion of prolactin Eur Neurol 2022;85:171-176 DOI: 10.1159/000521388 by inhibiting FOXO1 expression in drug-resistant PRL-PA [41].…”