Denticleless E3 Ubiquitin Protein Ligase Homolog as a Potential Biomarker for Adrenocortical Carcinoma Screening.

OBJECTIVE: This study aims to investigate the potential of denticleless E3 ubiquitin protein ligase homolog (DTL) as a biomarker for adrenocortical carcinoma (ACC) detection through bioinformatics analysis and experimental validation.

METHODS: Differentially expressed genes (DEGs) between ACC and adrenocortical adenoma (ACA) were identified through bioinformatics analysis. A protein-protein interaction (PPI) network was constructed using Cytoscape software, and core genes were screened with the CytoHubba MCODE plug-in. Survival analysis was performed using the University of ALabama at Birmingham CANcer (UALCAN) data analysis portal. Immunohistochemistry was employed to assess DTL expression in adjacent normal tissues, ACA, and ACC.

RESULTS: Two gene expression series (GSEs) retrieved from the Gene Expression Omnibus (GEO) database yielded 115 DEGs. Using the PPI network, three core genes were identified, among which DTL and TPX2 were highly expressed in ACC. Notably, DTL had the highest core gene score. Elevated DTL expression in individuals with ACC was significantly associated with a poor prognosis (P < 0.0001). Immunohistochemistry analysis revealed a significantly higher positive expression rate and a strong positive expression rate of DTL in ACC compared to ACA (χ2 = 11.708, P < 0.01). The positive expression rate of DTL in both ACC and ACA was significantly higher than in the adjacent normal adrenal cortex (P < 0.01). The expression of DTL followed a gradient, being highest in ACC, followed by ACA, and lowest in the normal adrenal cortex adjacent to the tumor. Additionally, DTL protein expression was significantly correlated with tumor size and infiltration metastasis (P < 0.05). Individuals with high DTL expression had significantly shorter survival times than those with low DTL expression (P < 0.05).

CONCLUSION: DTL exhibits potential as a novel biomarker for distinguishing between benign and malignant adrenocortical tumors and may serve as a prognostic indicator for ACC.

DISCUSSION: The CRL4CDT2 ubiquitin ligase complex, also known as DCX (DTL), is related to DNA synthesis. The findings suggest that DTL may serve as a key oncogene in multiple malignancies, including ACC and GC, making it a potential therapeutic target for cancer treatment. The findings collectively indicate that DTL is frequently overexpressed in various malignancies, highlighting its potential role in tumorigenesis. The findings of our study are consistent with these observations. The precise mechanisms by which Cdt2 overexpression drives tumorigenesis are not fully understood. However, one proposed mechanism involves the ability of the CRL4Cdt2 complex to promote cell cycle progression by reducing the basal steady-state levels of the cell cycle inhibitor p21, thereby impairing p53-mediated DNA damage repair mechanisms. In addition, DTL has been shown to play a key role in promoting tumor cell proliferation, migration, and invasion through both p53-dependent and p53-independent pathways.