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.
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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: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.
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