MiR-34a is upregulated in AIP mutated pituitary adenomas and induces octreotide-resistant cell proliferation and growth hormone secretion
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PROVIDER: PRJNA590227 | ENA |
REPOSITORIES: ENA
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Project description: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.
2020-08-18 | GSE140604 | GEO
Project description:The aim of this study was to perform comparative gene expression analysis of AIP mutation-positive, AIP mutation-negative familial and sporadic somatotroph tumours to discover the genes/pathways responsible for the aggressive phenotype. Gene expression analysis was performed on 25 pituitary samples (five normal pituitary, six AIPpos GH, three AIPneg GH, four sporadic GH, two AIPneg familial NFPA and five sporadic NFPA adenomas) using the Affymetrix human Gene Chip HG-U133 Plus 2.0 array.
2018-04-13 | GSE63357 | GEO
Project description:Gene-level expression profiles of 7 Aip knock-out (triplicates from each) and 9 Aip wild-type mouse embryonic fibroblast cell lines were studied using Affymetrix GeneChip Mouse Exon 1.0 ST Arrays
2014-03-05 | GSE37927 | GEO
Project description:BackgroundPituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy.AimsWe performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center.MethodsPituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response.ResultsFifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen.ConclusionsGermline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients.
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Project description:miR-34a and miR-34b/c genes are frequently epigenetically silenced in primary CRCs. However, the in vivo relevance of miR-34a/b/c for suppression of intestinal tumor formation has not been analyzed by genetic approaches. ApcMin/+ mice with deletion of the miR-34a and miR-34b/c genes were generated and analyzed. The mRNA expression profiles of intestinal adenomas with and without functional miR-34a/b/c genes were compared.
2017-05-28 | GSE84138 | GEO
Project description:Gonadotroph adenomas comprise 15–40 % of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we dem¬onstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrep¬resentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. Bioinfor¬matic analysis identified downstream targets of the transcrip¬tion factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similari¬ties between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95 % of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonado¬troph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma pri¬mary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use.
2013-07-10 | GSE23207 | GEO
Project description:The reasons why some pituitary adenomas are fucntioning(secreting hormones) or not is not well understood. This analysis dig into the transcriptomes of secreting and non-secreting corticotropic adenomas as well as non-fucntioning gonadotropic adenomas.
2022-04-28 | GSE201439 | GEO
Project description:To address the in vivo relevance of CSF1R regulation by miR-34a during intestinal tumor formation, we generated ApcMin/+ mice with intestinal-epithelial cell (IEC)-specific deletions of the Mir34a and/or Csf1r genes. The mRNA expression profiles of intestinal adenomas with and without functional miR-34a and/or Csf1r were compared.
2022-10-04 | GSE167448 | GEO
Project description:To address the in vivo relevance of CSF1R regulation by miR-34a during intestinal tumor formation, we generated ApcMin/+ mice with intestinal-epithelial cell (IEC)-specific deletions of the Mir34a and/or Csf1r genes. The mRNA expression profiles of tumor organoids derived ffrom intestinal adenomas with and without functional miR-34a and/or Csf1r were compared.
2022-10-04 | GSE167449 | GEO
Project description:Aryl hydrocarbon receptor-interacting protein (AIP) gene mutations (AIPmut) are the most frequent germline mutations found in apparently sporadic pituitary adenomas (SPA). Our aim was to evaluate the frequency of AIPmut among young Brazilian patients with SPA. We performed an observational cohort study between 2013 and 2016 in a single referral center. AIPmut screening was carried out in 132 SPA patients with macroadenomas diagnosed up to 40 years or in adenomas of any size diagnosed until 18 years of age. Twelve tumor samples were also analyzed. Leukocyte DNA and tumor tissue DNA were sequenced for the entire AIP-coding region for evaluation of mutations. Eleven (8.3%) of the 132 patients had AIPmut, comprising 9/74 (12%) somatotropinomas, 1/38 (2.6%) prolactinoma, 1/10 (10%) corticotropinoma and no non-functioning adenomas. In pediatric patients (≤18 years), AIPmut frequency was 13.3% (2/15). Out of the 5 patients with gigantism, two had AIPmut, both truncating mutations. The Y268* mutation was described in Brazilian patients and the K273Rfs*30 mutation is a novel mutation in our patient. No somatic AIP mutations were found in the 12 tumor samples. A tumor sample from an acromegaly patient harboring the A299V AIPmut showed loss of heterozygosity. In conclusion, AIPmut frequency in SPA Brazilian patients is similar to other populations. Our study identified two mutations exclusively found in Brazilians and also shows, for the first time, loss of heterozygosity in tumor DNA from an acromegaly patient harboring the A299V AIPmut Our findings corroborate previous observations that AIPmut screening should be performed in young patients with SPA.
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