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Series GSE140604 Query DataSets for GSE140604
Status Public on Aug 18, 2020
Title miR-34a is upregulated in AIP mutated pituitary adenomas and induces octreotide-resistant cell proliferation and growth hormone secretion
Platform organism synthetic construct
Sample organism Homo sapiens
Experiment type Expression profiling by array
Summary Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and 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 investigate the role of miRNA dysregulation in AIPmut+ versus AIPmut- PA samples by array analysis. miR-34a and miR-145 were found 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+ versus 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 downstream target of mutant AIP that promotes a cellular phenotype mirroring the aggressive clinical features of AIPmut+ acromegaly.
 
Overall design We compared human somatotropinoma and prolactinoma with wild-type AIP to tumors with mutant AIP
 
Contributor(s) Bogner E, Daly AF, Karhu A, Irmler M, Beckers J, Beckers A, Pellegata NS
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Submission date Nov 18, 2019
Last update date Aug 20, 2020
Contact name Johannes Beckers
E-mail(s) johannes.beckers@helmholtz-munich.de
Organization name Helmholtz Zentrum Muenchen
Department Institute of Experimental Genetics
Street address Ingolstaedter Landstr. 1
City Neuherberg
ZIP/Postal code 85764
Country Germany
 
Platforms (1)
GPL8786 [miRNA-1] Affymetrix Multispecies miRNA-1 Array
Samples (21)
GSM4175094 P_F290F_17: prolactinoma_mutant_AIP_rep1
GSM4175095 P_R271W_14a: prolactinoma_mutant_AIP_rep3
GSM4175096 P_R271W_14b: prolactinoma_mutant_AIP_tech_rep3
Relations
BioProject PRJNA590227

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE140604_RAW.tar 3.9 Mb (http)(custom) TAR (of CEL)
GSE140604_log2_RMA_p-values.xlsx 3.4 Mb (ftp)(http) XLSX
Processed data included within Sample table
Processed data are available on Series record
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