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 (<i>ESM1</i>) is closely related to tumorigenesis of multitudinous tumors. However, the prognosis value and biological function of <i>ESM1</i> 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 <i>ESM1</i> was evidently correlated with dismal overall survival (OS) in ACC patients. Then, the gene-set enrichment analysis (GSEA) was applied to unravel that <i>ESM1</i> was mostly involved in cell cycle and Notch4 signaling pathway. Furthermore, <i>in vitro</i> experiment, RNA interference of <i>ESM1</i> was carried out to state that ESM1 augments CDK1 and p21-mediated G2/M-phase transition of mitosis, cell proliferation <i>via</i> 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 <i>ESM1</i> 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 <i>ESM1</i> and related regulators might act as underlying prognostic biomarkers or novel therapeutic targets for ACC.