Transcription profiling of Mitotane induced expression changes in adrenocortical carcinoma cell-line NCI-H295
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ABSTRACT:
INSTRUMENT(S): in a humid atmosphere at 37M-eM-!C and 5% CO2
ORGANISM(S): Homo sapiens
SUBMITTER: Silviu Sbiera
PROVIDER: E-MTAB-3241 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Adrenocortical carcinoma (ACC) is characterized by disruption of tissue development and homeostatic pathways. Here, using genetic fate mapping and murine ACC models, we have identified a population of adrenocortical stem cells that express Delta-like non-canonical Notch ligand 1 (DLK1). These cells are active during development, near dormant postnatally but are re-expressed in ACC. DLK1 expression is widespread in human ACC samples and independently influences recurrence-free survival. Spatial transcriptomic analysis has identified DLK1 positive ACC cells to have increased steroidogenic potential, a finding also observed in both human and murine ACC cell lines. Additionally, the cleavable DLK1 ectodomain is detectable in patients’ serum and effectively distinguishes ACC from other adrenal pathologies, offering potential diagnostic and follow-up utility for ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, elucidate its hierarchical expression in homeostasis and cancer and suggest its utility as a biomarker in this malignancy.
2024-10-21 | GSE277486 | GEO
Project description:Adrenocortical carcinoma (ACC) is characterized by disruption of tissue development and homeostatic pathways. Here, using genetic fate mapping and murine ACC models, we have identified a population of adrenocortical stem cells that express Delta-like non-canonical Notch ligand 1 (DLK1). These cells are active during development, near dormant postnatally but are re-expressed in ACC. DLK1 expression is widespread in human ACC samples and independently influences recurrence-free survival. Spatial transcriptomic analysis has identified DLK1 positive ACC cells to have increased steroidogenic potential, a finding also observed in both human and murine ACC cell lines. Additionally, the cleavable DLK1 ectodomain is detectable in patients’ serum and effectively distinguishes ACC from other adrenal pathologies, offering potential diagnostic and follow-up utility for ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, elucidate its hierarchical expression in homeostasis and cancer and suggest its utility as a biomarker in this malignancy.
2025-03-01 | GSE286393 | GEO
Project description:Background: Adrenal myelolipoma (AML) is a relatively common and invariably benign tumor composed of adipose tissue and hematopoietic elements. Due to the variable proportion of fat and hematopoietic elements, it is sometimes challenging to differentiate AML from adrenocortical carcinoma (ACC). MicroRNAs have been identified as promising biomarkers in many tumors, including adrenocortical neoplasms, but the microRNA expression of adrenal myelolipoma has not been investigated, yet. Aims: To perform a large scale microRNA expression profiling in adrenal myelolipoma, benign and malignant adrenocortical tumors to identify potential microRNA biomarkers. Methods: Next-generation sequencing (NGS) on 30 formalin-fixed paraffin-embedded archived tissue samples (discovery cohort: 10 adrenocortical adenoma (ACA), 10 ACC and 10 myelolipoma) was performed by Illumina MiSeq. Significantly differentially expressed microRNAs were validated by real-time RT-qPCR in an independent validation cohort comprised of 10 ACA, 10 myelolipoma and 9 ACC samples. Results: We have found relative overexpression of miR- 451a, miR-486-5p, miR-363-3p and miR-150-5p in myelolipoma compared to the other two tumor groups by NGS. For ACC, we have found up-regulation of miR-184, miR-483-5p, miR-431-5p and miR-183-5p compared to myelolipoma and ACA. Validation by RT-qPCR, confirmed significant overexpression of miR-451a, miR-486-5p and miR-150-5p in myelolipomas relative to ACA and ACC, whereas significant overexpression of miR-184 and miR-183-5p was confirmed in ACC relative to the other 2 groups. The overexpression of miR-483-5p has not turned out to be significant in ACC relative to myelolipomas in the validation cohort. Conclusions: Overexpressed miR-451a, miR-486-5p and miR-150-5p might be potential tissue markers of adrenal myelolipoma. The lack of significance in the expression of miR-483-5p between ACC and myelolipoma is remarkable, as miR-483-5p has been considered to be the best marker of adrenal malignancy to date.
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2013-12-01 | E-GEOD-44317 | biostudies-arrayexpress
Project description:<p>Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high risk of relapse and metastatisation. The actin-bundling protein fascin (FSCN1) is overexpressed in aggressive ACC and represents a reliable prognostic indicator. FSCN1 has been shown to synergize with the Rho/Rac GEF VAV2 in enhancing the invasion properties of ACC cancer cells. Based on those results, we investigated the effects of FSCN1 inactivation by CRISPR/Cas9 or pharmacological blockade on the invasive properties of ACC cells, both <em>in vitro</em> and in an <em>in vivo</em> metastatic ACC zebrafish model. Here we showed that FSCN1 is a transcriptional target for Beta-catenin in H295R ACC cells and that its inactivation resulted in defects in cell attachment and proliferation. Additionally, FSCN1 knock-out modulated the expression of genes involved in cytoskeleton dynamics and cell adhesion. When SF-1 dosage was upregulated in H95R cells, activating their invasive capacities, FSCN1 knock-out reduced the number of filopodia, lamellipodia/ruffles and focal adhesions, while decreasing cell invasion in Matrigel. Similar effects were produced by the FSCN1 inhibitor G2-044, which also diminished the invasion of ACC cell lines (CU-ACC2, JIL-2266, MUC-1) expressing lower levels of FSCN1 than H295R. In the zebrafish model, metastases formation was significantly reduced in FSCN1 knock-out cells and G2-044 significantly reduced the number of metastases formed by ACC cells. Our results indicate that FSCN1 represents a new druggable target for ACC and provide the rationale for future clinical trials with FSCN1 inhibitors in patients with ACC, possibly in combination with immunotherapy.</p>
2023-03-20 | MTBLS6402 | MetaboLights
Project description:Background: Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data prognostic biomarkers and novel therapeutic targets. Methods: 44 ACC and 4 normal adrenal glands were profiled on Affymetrix U133 Plus 2 expression microarrays and pathway and transcriptional enrichment analysis performed. Protein levels were determined by western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed as validation data sets. Results: Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Over-expression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average beta-actin <-3.04 ) was 1.8 years compared to 9.0 years if tumors expressed lower levels of PTTG1 (P<0.0001). These findings were confirmed by our analysis of previously published datasets. Treatment of ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (IC50s of 1.69 uM and 0.891 uM, for SW-13 and H295R, respectively). Conclusion: Over-expression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.
2013-11-21 | GSE19750 | GEO
Project description:Context: Adrenocortical carcinomas (ACC) are a rare tumor type with a poor five-year survival rate and limited treatment options. Objective: Understanding of the molecular pathogenesis of this disease has been aided by genomic analyses highlighting alterations in TP53, WNT, and IGF signaling pathways. Further elucidation is needed to reveal therapeutically actionable targets in ACC. Design: In this study, global DNA methylation levels were assessed by the Infinium HumanMethylation450 BeadChip Array on 18 ACC tumors and 6 normal adrenal tissues. A new, non-linear correlation approach, the discretization method, assessed the relationship between DNA methylation/gene expression across ACC tumors. Results: This correlation analysis revealed epigenetic regulation of genes known to modulate TP53, WNT, and IGF signaling, as well as tumor suppressor silencing previously unreported in ACC. Conclusions: DNA methylation may regulate genes known to play a role in ACC pathogenesis as well as known tumor suppressors.
2016-03-07 | GSE77871 | GEO
Project description:The actual drug treatment options for adrenocortical carcinoma (ACC) are rather narrow and intensive efforts are going on to find novel effective agents. In our previous functional genomics study, retinoid signaling via the retinoid X receptor (RXR) was detected as a major pathogenic pathway in ACC and we have demonstrated the in vitro activity of 9-cis retinoic acid (9-cisRA) acting via the RXR on NCI-H295R cells and also found that 9-cisRA has antitumoral effects in a small pilot xenograft study. In the present study our aim was to confirm the antitumoral effect of 9-cisRA on adrenocortical cancer in a large xenograft study involving both mitotane and 9-cisRA and their combination. 43 male SCID mice inoculated with NCI-H295R cells were treated in four groups (i. control – corn oil vehicle, ii. 5 mg/kg 9-cisRA, iii. 200 mg/kg mitotane, iv. 5 mg/kg 9-cisRA + 200 mg/kg mitotane) for 28 days. Regular tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray have been performed. Quantitative real-time-PCR was used for the validation of the microarray results and to detect circulating and tissue microRNAs. To examine the proteome proteomics and Western-blot analysis were executed. We have found that both 9-cisRA and mitotane reduced tumor growth relative to control, but only the combination of the two agents resulted in significant tumor size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Gene expression analysis revealed 483 genes with significant differences in expression, but only without Benjamini-Hochberg correction (APOA4 and PDE4A were validated).
2016-06-07 | GSE73417 | GEO
Project description:Adrenocortical carcinoma (ACC) is an aggressive endocrine tumor with a poor 5 year survival rate of 10-20%. We used expression profiling to assess the transcriptional changes associated with ACC as compared to normal adrenal glands with the goal of identifying new targets for treatment. Fourteen ACC tumors were profiled on both Affymetrix U133 Plus 2 or Agilent 22K Human Genome arrays; an additional six tumors were profiled on one or the other array. The data demonstrate a marked dysregulation of the cell cycle control, focused on sister chromatid adhesion and cytokinesis in the G2/M transistion. Genes associated with this pattern, and identified because of coordinate expression with CDC2, were capable of clustering ACC into two clusters that almost completely recapitulated histological grade. Exploration of the data sets by both Gene Set Enrichment Analysis and GeneGo Interactome analysis identified additional dysregulation of the IGF2-IGF1R axis, aside from IGF2 over-expression, as an early event present in low grade tumors. Additionally, p53 and MDM2 were consistently identified as drivers in leading edge analyses of the tumors, implicating the p53 pathway in ACC pathogenesis. Finally, over-expression of PTTG1, which encodes securin, and is involved in sister chromatid adhesion as well as negative regulation of p53, was associated with poor prognosis in our samples. Taken together, these data point toward a tumor type driven in part by dysregulated IGF2 signaling in the context of a lack of a functional p53 response, with potential vulnerabilities in the G2/M transition that may make viable therapeutic targets.
2013-11-21 | GSE19775 | GEO