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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2013-05-31 | E-GEOD-39291 | biostudies-arrayexpress
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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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>
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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.
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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).
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Project description:Adrenocortical carcinoma (ACC) is an aggressive malignancy with a low but variable overall survival rate. Even after complete tumor resection, over half of patients develop recurrent disease. Long noncoding RNAs (lncRNAs) have been found to be involved in cancer initiation/progression and as markers of cancer prognosis. The role of lncRNAs in ACC is poorly understood. Thus, in this study we performed lncRNA expression profiling in ACC, adrenocortical adenoma (ACA) and normal adrenal cortex (NAC). Total RNA was extracted from fresh frozen tissue samples (11 ACA, nine ACC and five NAC samples) with histopathological confirmed diagnosis. ArrayStar Human LncRNA/mRNA Expression Microarray V3.0 was used for transcriptome analysis. Differentially expressed lncRNAs were validated using TaqMan real-time quantitative PCR in a validation cohort including an additional 10 ACCs. The ACC dataset from the Cancer Genome Atlas (TCGA) project was used to evaluate the prognostic utility of lncRNAs found to be differentially expressed in ACC. Survival curves were plotted by Kaplan-Meier analysis, and differences in survival rates were assessed using a log-rank test. P < 0.05 was considered significant. Gene Set Enrichment Analysis (GSEA) was performed to identify lncRNA-associated biological signaling pathways. Unsupervised hierarchical and heat map clustering showed distinct clustering of ACC samples compared with NAC and ACA samples by lncRNA expression profiles. A total of 874 lncRNAs were differentially expressed between ACC and NAC, including known carcinogenesis-related lncRNAs such as HOTTIP, HOXA11-AS1, CRNDE, LINC00271 and TBXAS1. One thousand seventy-six lncRNAs were differentially expressed between ACC and ACA. LINC00271 was a prognostic marker, with patients with low LINC00271 expression surviving significantly shorter than patients with a high LINC00271 expression. Median survival time (MST) for the low-expression group was 1788 days, whereas the MST was not reached for the high-expression group (P < 0.019). Importantly, low LINC00271 expression was positively associated with WNT signaling, cell cycle, chromosome segregation and tissue morphogenesis pathways. ACC has a distinct lncRNA expression profile. LINC00271 is a prognostic marker in ACC and is involved in biological pathways commonly dysregulated in ACC.
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