Aberrant DNA methylation of synaptophysin is involved in adrenal cortisol-producing adenoma.

Jia-Yu Zhong,Xiao Lin,Feng Xu,Ting Zhu,Ling-Qing Yuan,Feng Wu,Lu Yi,En Zhou,Rong-Rong Cui,Fuxingzi Li

doi:10.18632/aging.102119

Abstract

Cortisol-producing adenoma (CPA) is the main cause of Adrenal Cushing syndrome. However, its molecular mechanism is not fully understood. Previous study revealed Synaptophysin (SYP) is ubiquitously expressed in adrenocortical tumors, but its function in CPA still need to be discovered. In the present study we determine the molecular mechanism involved in SYP dysregulation in CPA and how SYP affects the secretion of cortisol in CPA. Our results showed that aberrant DNA methylation of SYP is involved in CPA progress. Using a miRNA microarray and qRT-PCR, we found decreased expression of miR-27a-5p in CPA compared with normal adrenal tissue. Moreover, the expression of TET3, the target gene of miR-27a-5p, increased in CPA compared with normal adrenal tissue. Knock-down of TET3 resulted in hypermethylation of SYP which reducing the expression level of SYP in H295R cells. The miR-27a-5p-TET3-SYP signalling pathway may regulate proliferation and cortisol secretion in H295R cells and, thus, play a key role in CPA development.

Highlights

Adrenal Cushing syndrome (CS), consists of a set of systemic manifestations similar to those found in aging, is caused by glucocorticoid excess due to a cortisolproducing adenoma (CPA) or adrenocortical carcinoma [1]
We analysed the mechanism of the miR-27a-5p-TET3-SYP signal pathway in adrenocortical adenomas causing CPA dysregulation (Figure 5)
We used immunohistochemistry, western blotting and qRT-PCR to identify SYP expression signatures in CPA tissues and normal adrenal cortex tissues and found that SYP is significantly upregulated in the CPA tissues compared to the control group

Summary

Introduction

Adrenal Cushing syndrome (CS), consists of a set of systemic manifestations similar to those found in aging, is caused by glucocorticoid excess due to a cortisolproducing adenoma (CPA) or adrenocortical carcinoma [1]. It is associated with hypertension, physical and cognitive degeneration in aging and accelerated atherogenesis, obesity, and osteoporosis [2,3,4]. The mechanism involved in this hyperfunction of the adrenal cortex in CPA remains unknown. The adrenal cortex is not an intrinsic part of the diffuse neuroendocrine www.aging-us.com system, but neuroendocrine differentiation appears in some adrenocortical tumours [11]. The effect of SYP and the mechanisms of the SYP genomic or genetic alterations in CPA still need to be validated

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