A Novel Gene Expression Profile and Combined Effects in the Pathogenesis of Adrenocorticotropic Hormone-Secreting Pituitary Neuroendocrine Tumors

Abstract

Aims

Cushing’s disease is a rare endocrine disorder characterized by excessive endogenous glucocorticoid production, primarily resulting from adrenocorticotropic hormone-secreting pituitary neuroendocrine tumors (ACTH-PitNETs). This study investigated the expression of several genes implicated in the development of ACTH-PitNETs, including EGFR, USP8, CABLES1, USP2, STAM2, VPS28, HDAC2, IL-6, SMARCA4, WEE1, CDKN2A, CCND1, NR4A1, NEUROD1, and RIPK1. The methylation levels of the USP8 and CDKN2A genes were also assessed for insights into their regulatory mechanisms.

Methods

Formalin-fixed paraffin-embedded pituitary tumor tissue samples from 32 patients diagnosed with ACTH-PitNET and 15 anterior pituitary tissue samples were analyzed. Gene expression was analyzed through quantitative reverse transcription polymerase chain reaction, while methylation was examined through methylation-specific polymerase chain reaction. All data were analyzed with IBM SPSS Statistics 21. The relationships among gene expressions were assessed using principal component analysis.

Results

The expression of CABLES1, NR4A1, CCND1, NEUROD1, USP2, and WEE1 differed significantly between the patient and control groups. Additionally, significant correlations were observed between the levels of RIPK1, SMARCA4, and USP2 and pre-operative cortisol levels; WEE1 expression and pre-operative ACTH levels; CDKN2A expression and urinary cortisol levels; CABLES1, NEUROD1, SMARCA4, and STAM2 expression and post-operative cortisol levels at 48 h. CCND1 expression was correlated with adenoma size, while WEE1 expression was linked to remission status. Notably, the CDKN2A gene displayed partial methylation, whereas the USP8 gene was fully unmethylated.

Conclusions

The altered expression levels of the USP2, CABLES1, CDKN2A, and WEE1 may be closely associated with the development of ACTH-PitNETs. Notably, WEE1 emerged as a target gene for predicting clinical remission in patients with Cushing’s disease.

Keywords

Cushing’s disease - methylation - USP2 - CABLES1 - CDKN2A - WEE1

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