Downregulation of Cytochrome P450 4B1 is Associated with Large, Hormone-Inactive Adrenocortical Adenomas
*Thomas R Schneider1,2, *Norman G Nicolson2,3, *Reju Korah2,3, Tobias Carling2,3
1Frank H. Netter MD School of Medicine, North Haven, CT;2Yale Endocrine Neoplasia Laboratory, New Haven, CT;3Yale School of Medicine, Department of Surgery, New Haven, CT
Objective: Cytochrome P450 4B1 (CYP4B1) is an extrahepatic member of the cytochrome P450 superfamily. CYP4B1 is known to be involved in cholesterol metabolism, and previous studies suggest that its silencing may play an important role in the development of adrenocortical tumors. In order to better understand its role in adrenocortical tumorigenesis, we sought to characterize the expression and function of CYP4B1 in adrenocortical adenomas (ACAs).
Design: Expression levels of CYP4B1 were determined by RT-qPCR. CYP4B1 protein expression relative to normal adrenal cortex was determined by immunohistochemistry, and colocalization of CYP4B1 with known mediators of lipid peroxidation and autophagy was investigated with tricolor immunohistochemistry. Clinical correlations were explored to define potential associations with CYP4B1 gene expression.
Setting: Academic medical center.
Patients: Tumor samples were obtained from patients who underwent an adrenalectomy for adrenocortical adenoma, and tumors were categorized according to their hormone secretion phenotype: aldosterone (n=10), cortisol (n=10), or non-secreting (n=10). Control samples (n=11) were collected from histologically normal, adenoma-adjacent tissue.
Main Outcome Measures: Association of CYP4B1 expression with tumor characteristics including hormone secretion phenotype, tumor size, and molecular features.
Results: CYP4B1 expression was significantly suppressed in endocrine-inactive adenomas compared to control tissue (p<0.01) and aldosterone-producing adenomas (p<0.01) but not compared to cortisol-producing adenomas (p=0.61). Immunohistochemistry confirmed markedly reduced expression of CYP4B1 in endocrine-inactive tumors. Furthermore, CYP4B1 expression was negatively correlated with ACA tumor size (p<0.01). Immunohistochemical analysis suggested potential roles for CYP4B1 in regulating lipid peroxidation and autophagy signaling in the adrenal cortex.
Conclusions: Silencing of CYP4B1 may interfere with cholesterol metabolism and autophagy response in endocrine-inactive adrenal tumors, thereby facilitating larger growth compared with their aldosterone-secreting counterparts.
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