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Growth hormone (GH)\u2010secreting PAs (somatotropinomas) cause acromegaly\u2010gigantism. Genetic forms of somatotropinomas due to germline <jats:italic>AIP<\/jats:italic> mutations (<jats:italic>AIP<\/jats:italic>mut+) 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 <jats:italic>AIP<\/jats:italic>mut+ vs <jats:italic>AIP<\/jats:italic>mut\u2212 PA samples by array analysis. miR\u201034a and miR\u2010145 were highly expressed in <jats:italic>AIP<\/jats:italic>mut+ vs <jats:italic>AIP<\/jats:italic>mut\u2212 somatotropinomas. Ectopic expression of <jats:italic>AIP<\/jats:italic>mut (p.R271W) in <jats:italic>Aip<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mouse embryonic fibroblasts (MEFs) upregulated miR\u201034a and miR\u2010145, establishing a causal link between <jats:italic>AIP<\/jats:italic>mut and miRNA expression. In PA cells (GH3), miR\u201034a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR\u2010145 moderately affected proliferation and apoptosis. Moreover, high miR\u201034a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR\u201034a expression significantly blunted octreotide\u2010mediated GH inhibition and antiproliferative effects. miR\u201034a directly targets <jats:italic>Gnai2<\/jats:italic> encoding G\u03b1i2, a G protein subunit inhibiting cAMP production. Accordingly, G\u03b1i2 levels were significantly lower in <jats:italic>AIP<\/jats:italic>mut+ vs <jats:italic>AIP<\/jats:italic>mut\u2212 PA. Taken together, somatotropinomas with <jats:italic>AIP<\/jats:italic> mutations overexpress miR\u201034a, which in turn downregulates G\u03b1i2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR\u201034a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR\u201034a is a novel downstream target of mutant <jats:italic>AIP<\/jats:italic> that promotes a cellular phenotype mirroring the aggressive clinical features of <jats:italic>AIP<\/jats:italic>mut+ acromegaly.<\/jats:p>","DOI":"10.1002\/ijc.33268","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T18:51:22Z","timestamp":1598640682000},"page":"3523-3538","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["<scp>miR<\/scp>\u201034a is upregulated in <i><scp>AIP<\/scp>\u2010<\/i>mutated somatotropinomas and promotes octreotide resistance"],"prefix":"10.1002","volume":"147","author":[{"given":"Eva\u2010Maria","family":"Bogner","sequence":"first","affiliation":[{"name":"Institute for Diabetes and Cancer Helmholtz Zentrum M\u00fcnchen  Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian 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