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

[en] 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 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 anti-proliferative 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 together, somatotropinomas with AIP mutations overexpress miR-34a, which in turn downregulates Gαi2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR-34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR-34a is a novel downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIPmut + acromegaly. This article is protected by copyright. All rights reserved.

Disciplines :

Endocrinology, metabolism & nutrition
Endocrinology, metabolism & nutrition
Endocrinology, metabolism & nutrition

Author, co-author :

Bogner, Eva-Maria

Daly, Adrian ; Université de Liège - ULiège > Département des sciences cliniques > Endocrinologie

Gulde, Sebastian

Karhu, Auli

Irmler, Martin

Beckers, Johannes

Mohr, Hermine

Beckers, Albert ; Université de Liège - ULiège > Département des sciences cliniques > Endocrinologie

Pellegata, Natalia S.

Language :

English

Title :

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

Publication date :

September 2020

Journal title :

International Journal of Cancer

ISSN :

0020-7136

eISSN :

1097-0215

Publisher :

John Wiley & Sons, Hoboken, United States - New York

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 30 August 2020

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