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EMS1/DLL4-Notch Signaling Axis Augments Cell Cycle-Mediated Tumorigenesis and Progress in Human Adrenocortical Carcinoma.

ABSTRACT: Adrenocortical carcinoma (ACC) is a rare malignant neoplasm that is prone to local invasion and metastasis. Meanwhile, overexpressed endothelial cell-specific molecule 1 (ESM1) is closely related to tumorigenesis of multitudinous tumors. However, the prognosis value and biological function of ESM1 in ACC remains undefined. In the current essay, the assessment in human ACC samples and multiple public cancer databases suggested that ESM1 was significantly overexpressed in ACC patients. The abnormal expression of ESM1 was evidently correlated with dismal overall survival (OS) in ACC patients. Then, the gene-set enrichment analysis (GSEA) was applied to unravel that ESM1 was mostly involved in cell cycle and Notch4 signaling pathway. Furthermore, in vitro experiment, RNA interference of ESM1 was carried out to state that ESM1 augments CDK1 and p21-mediated G2/M-phase transition of mitosis, cell proliferation via DLL4-Notch signaling pathway in human ACC cell line, SW13 cells. Additionally, two possible or available therapeutic strategies, including immunotherapy and chemotherapy, have been further explored. Immune infiltration analysis highlighted that no significant difference was found in ACC patients between EMS1^high and EMS1^low group for immune checkpoint-related genes. In addition, the overexpression of ESM1 might trigger the accumulation of tumor mutation burden (TMB) during the cell cycle of DNA replication in ACC. The gene-drug interaction network then indicated that ESM1 inhibitors, such as cisplatin, might serve as potential drugs for the therapy of ACC. Collectively, the results asserted that ESM1 and related regulators might act as underlying prognostic biomarkers or novel therapeutic targets for ACC.

SUBMITTER: Huang YG

PROVIDER: S-EPMC8631517 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Adrenocortical carcinoma (ACC) is a limited endocrine fatality with a minor diagnosis and rare remedial options. The progressive and predictive meaning of message RNA (mRNA) expression oddity in ACC has been studied extensively in recent years. However, differences in measurement platforms and lab protocols as well as small sample sizes can render gene expression levels incomparable. METHODS:An extensive study of GEO datasets was conducted to define potential mRNA biomarkers for ACC. The study compared the mRNA expression profiles of ACC tissues and neighboring noncancerous adrenal tissues in the pair. The study covered a sum of 165 tumors and 36 benign control samples. Hub genes were identified through a protein-protein interaction (PPI) network and Robust Rank Aggregation method. Then the Cancer Genome Atlas (TCGA) and Oncomine database were used to perform the validation of hub genes. 4 ACC tissues and 4 normal tissues were collected and then Polymerase Chain Reaction (PCR), Western-blot and immunofluorescence were conducted to validate the expression of five hub genes. RESULTS:We identified five statistically significant genes (TOP2A, NDC80, CEP55, CDKN3, CDK1) corrected with clinical features. The expression of five hub genes in TCGA and Oncomine database were significantly overexpressed in ACC compared with normal ones. Among all the TCGA ACC cases, the strong expression of TOP2A (logrank p=1.4e-04, HR=4.7), NDC80 (logrank p=8.8e-05, HR=4.9), CEP55 (logrank p=5.2e-07, HR=8.6), CDKN3 (log rank p=2.3e-06, HR=7.6) and CDK1 (logrank p=7e-08, HR=11) were correlated with low comprehensive survival, disease free survival (logrank p < 0.001), pathology stage and pathology T stage (FDR < 0.001). PCR results showed that the transcriptional levels of these five genes were significantly higher in ACC tissues than in normal tissues. The western blotting results also showed that the translational level of TOP2A was significantly higher in tumor tissues than in normal tissues. The results of immunofluorescence showed that TOP2A was abundantly observed in the adrenal cortical cell membrane and nucleus and its expression in ACC tissues was significantly higher than that in normal tissues. CONCLUSIONS:The distinguished five genes may be utilized to form a board of progressive and predictive biomarkers for ACC for clinical purpose.

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EMS1/DLL4-Notch Signaling Axis Augments Cell Cycle-Mediated Tumorigenesis and Progress in Human Adrenocortical Carcinoma.

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