Medication for acromegaly reduces expression of MUC16, MACC1 and GRHL2 in pituitary neuroendocrine tumour tissue
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA672302 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12905700.fastq.gz | Fastqsanger.gz | |||
| SRR12905701.fastq.gz | Fastqsanger.gz | |||
| SRR12905702.fastq.gz | Fastqsanger.gz | |||
| SRR12905703.fastq.gz | Fastqsanger.gz | |||
| SRR12905692.fastq.gz | Fastqsanger.gz |
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Project description:Acromegaly is a disease mainly caused by pituitary neuroendocrine tumours (PitNETs) overproducing growth hormone. First-line medication for this condition is the use of somatostatin analogues (SSAs), that decrease tumour mass and induce antiproliferative effects on PitNET cells. Dopamine agonists (DAs) can also be used, if SSA treatment is not effective. This study aimed to determine differences in transcriptome signatures induced by SSA/DA therapy in PitNET tissue. We selected tumour tissue from twelve patients with somatotrophinomas, with half of the patients receiving SSA/DA treatment before surgery, and the other half treatment naive. Transcriptome sequencing was then carried out to identify differentially expressed genes (DEGs) and their protein-protein interactions, using pathway analyses. We found 34 upregulated and six downregulated DEGs in patients with SSA/DA treatment. Three tumour development promoting factors MUC16, MACC1 and GRHL2, were significantly downregulated in therapy administered PitNET tissue. Protein-protein interactions and pathway analyses revealed extracellular matrix involvement in the antiproliferative effects of this type of the drug treatment, with pronounced alterations in collagen regulation. Here, we have demonstrated that somatotrophinomas can be distinguished based on their transcriptional profiles following SSA/DA therapy, and SSA/DA treatment does indeed cause changes in gene expression. Treatment with SSA/DA, significantly downregulated several factors involved in tumourigenesis, including MUC16, MACC1 and GRHL2. Genes that were upregulated, however, did not have a direct influence on antiproliferative function in the PitNET cells. These findings suggested that SSA/DA treatment acted in a tumour suppressive manner and furthermore, collagen related interactions and pathways were enriched, implicating extracellular matrix involvement in this anti-tumour effect of drug treatment.
2020-10-28 | GSE160195 | GEO
Project description:The clinical characteristics of growth hormone (GH)-producing pituitary adenomas vary across patients. In this study, we aimed to integrate the genetic alterations, protein expression profiles, transcriptomes, and clinical characteristics of GH-producing pituitary adenomas to detect molecules associated with acromegaly characteristics. Targeted capture sequencing and copy number analysis of 36 genes and non-targeted proteomics analysis were performed on fresh-frozen samples from 121 sporadic GH-producing pituitary adenomas. Targeted capture sequencing revealed GNAS as the only driver gene, as previously reported. Classification by consensus clustering using both RNA sequencing and proteomics revealed many similarities between the proteome and the transcriptome. Gene ontology analysis was performed for differentially expressed proteins between wild-type and mutant GNAS samples identified by non-targeted proteomics analysis and involved in G protein–coupled receptor (GPCR) pathways. The results suggested that GNAS mutations impact endocrinological features in acromegaly through GPCR pathway induction. ATP2A2 and ARID5B correlated with the GH change rate in the octreotide loading test, and WWC3, SERINC1, and ZFAND3 correlated with the tumor volume change rate after somatostatin analog treatment. These results identified a biological connection between GNAS mutations and the clinical and biochemical characteristics of acromegaly, revealing novel molecules associated with acromegaly that may affect medical treatment efficacy.
2022-11-25 | GSE213527 | GEO
Project description:Acromegaly is a severe and life-threatening disease caused by persistent excess of growth hormone (GH) which stimulates the synthesis and secretion of insulin-like growth factor-1 (IGF-1). In the majority (95%) of patients acromegaly is caused by sporadic GH-secreting neuroendocrine pituitary tumor (PitNET). Acromegaly-causing tumors are histologically diverse. The aim was to determine transcriptomic profiles in different histological subtypes and evaluate clinical implication of differential gene expression.
2022-12-01 | E-MTAB-11889 | biostudies-arrayexpress
Project description:Acromegaly is a disease mainly caused by pituitary neuroendocrine tumor (PitNET) overproducing growth hormone. First-line medication for this condition is the use of somatostatin analogs (SSAs), that decrease tumor mass and induce antiproliferative effects on PitNET cells. Dopamine agonists (DAs) can also be used if SSA treatment is not effective. This study aimed to determine differences in transcriptome signatures induced by SSA/DA therapy in PitNET tissue. We selected tumor tissue from twelve patients with somatotropinomas, with half of the patients receiving SSA/DA treatment before surgery and the other half treatment naive. Transcriptome sequencing was then carried out to identify differentially expressed genes (DEGs) and their protein-protein interactions, using pathway analyses. We found 34 upregulated and six downregulated DEGs in patients with SSA/DA treatment. Three tumor development promoting factors MUC16, MACC1, and GRHL2, were significantly downregulated in therapy administered PitNET tissue; this finding was supported by functional studies in GH3 cells. Protein-protein interactions and pathway analyses revealed extracellular matrix involvement in the antiproliferative effects of this type of the drug treatment, with pronounced alterations in collagen regulation. Here, we have demonstrated that somatotropinomas can be distinguished based on their transcriptional profiles following SSA/DA therapy, and SSA/DA treatment does indeed cause changes in gene expression. Treatment with SSA/DA significantly downregulated several factors involved in tumorigenesis, including MUC16, MACC1, and GRHL2. Genes that were upregulated, however, did not have a direct influence on antiproliferative function in the PitNET cells. These findings suggested that SSA/DA treatment acted in a tumor suppressive manner and furthermore, collagen related interactions and pathways were enriched, implicating extracellular matrix involvement in this anti-tumor effect of drug treatment.
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Project description:Pituitary neuroendocrine tumours (PitNET) are rare neoplasms of the pituitary gland that can overproduce pituitary hormones or cause headaches and visual impairment due to mass effect. Growth hormone overproducing somatotroph PitNETs cause acromegaly leading to wide range of connective tissue, metabolic and oncologic disorders. The medical treamment of acromegaly is somatostin analogues (SSA) in specific cases combined with dopamine agnoists (DA), but almost half of patients excert SSA resistence and potential causes of this is unknown. The aim of this study was to characterize transcriptomic patterns of somatotroph PitNETs specifically assessing impact of SSA treatment effects. We investigated gene expession on several levels and functional models of GH PitNETs - tumour tissue of patients with and without SSA preoperative treamtment, tumour derived pituisphere model and classically used GH3 cell line treated with SSA.
2022-04-08 | GSE200175 | GEO
Project description:CDI HuProt™ (Human Proteome Microarray), was used to study Pituitary Adenomas PAs (Acromegaly, Cushing's and NFPA) using serum samples, from around 14 individuals (4 Healthy control, 4 Acromegaly, 3 Cushing’s and 3 NFPAs patient samples) were used study their autoantibody profiles. Patient serum samples in dilution 1:500 ratio were used for primary incubation. Secondary incubation was performed with anti-human IgG conjugated with Cy5 (Jackson Immuno Research, catalogue number 109-175-064) in 1:5000 dilutions was used. This CDI HuProt™ array was scanned with GenePix 4000B Microarray Scanner (Molecular Devices), with a PMT gain of 500, Scan Power 100 and Laser power of 1.31.
2022-09-30 | E-MTAB-11947 | biostudies-arrayexpress
Project description:This study investigated differential gene expression between granulation patterns in growth hormone (GH)-secreting pituitary tumors, aiming to elucidate novel transcriptomes that explain clinical variances in patients with acromegaly. Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enrichment of neuronal development and acute inflammatory response pathways, along with a significant enhancement of JAK–STAT, phosphatidylinositol 3-kinase, and MAPK signaling. The results suggest that granulation-specific gene expression may underpin diverse clinical presentations in acromegaly, highlighting the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK–STAT signaling in SGST.
2024-04-28 | GSE264621 | GEO
Project description:Gene alteration analysis on 121 GH-producing pituitary adenomas and non-target proteomics analysis with RNA sequencing analysis on 45 non-functioning pituitary adenomas (NFPAs) and 60 growth hormone (GH)-producing pituitary adenomas were performed, and integrated these results with the clinical characteristics of acromegaly. We attempted to identify key players involved in shaping the clinical features of acromegaly, especially those related to treatment efficacy. This project revealed the importance of GNAS mutations in terms of clinical and biochemical characteristics and identified novel molecules that may be involved in the responsiveness to medical treatment.
2022-11-24 | PXD036604 | JPOST Repository
Project description:The Grainyhead family of transcription factors controls morphogenesis and differentiation of epithelial cell layers in multicellular organisms by regulating cell junction- and proliferation-related genes. Grainyhead-like 2 (Grhl2) is expressed in developing mouse lung epithelium and is required for normal lung organogenesis. The specific epithelial cells expressing Grhl2 and the genes regulated by Grhl2 in normal lungs are mostly unknown. In these studies, we identified the NK2 homeobox 1 transcription factor (Nkx2-1) as a direct transcriptional target of Grhl2. By binding and transcriptional assays, and by confocal microscopy we showed that these two transcription factors form a positive feed-back loop in vivo and in cell lines, and are co-expressed in lung bronchiolar and alveolar type II cells. The morphological changes observed in flattening lung alveolar type II cells in culture are associated with down-regulation of Grhl2 and Nkx2-1. Reduction of Grhl2 in lung epithelial cell lines results in lower expression levels of Nkx2-1 and of known Grhl2 target genes. By microarray analysis we identified that in addition to Cadherin1 and Claudin4, Grhl2 regulates other cell interaction genes such as semaphorins and their receptors, which also play a functional role in developing lung epithelium. Impaired collective cell migration observed in Grhl2 knockdown cell monolayers is associated with reduced expression of these genes and may contribute to the altered epithelial phenotype reported in Grhl2 mutant mice. Thus, Grhl2 functions at the nexus of a novel regulatory network, connecting lung epithelial cell identity, migration and cell-cell interactions. To identify genes regulated by GRHL2 in lung epithelial cells, we performed cDNA microarray analyses in MLE15 cells transduced with Grhl2-shRNA and compared to a non-silencing control. Independent transductions of MLE15 cells using Grhl2-shRNA (n=3) and a non-silencing control (n=2) were analyzed.
2012-09-10 | E-GEOD-40729 | biostudies-arrayexpress
Project description:Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in preeclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branchingmorphogenesis.Selective Grhl2 inactivation only in epiblastderived cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIPseq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2−/− placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction. In vivo genome-wide examination of binding sites of the transcription factor GRHL2 by ChIP-seq using wild-type murine E17.5 placenta tissue. Two samples in total: one GRHL2 ChIP sample and one IgG ChIP sample using wild-type placentas tissue as antibody control.
2015-03-10 | E-GEOD-65962 | biostudies-arrayexpress