Molecular Mechanisms of Functional Adrenocortical Adenoma and Carcinoma: Genetic Characterization and Intracellular Signaling Pathway.

Hiroki Shimada,Hironobu Sasano,Akira Sugawara,Yuto Yamazaki,Yasuhiro Nakamura

doi:10.3390/biomedicines9080892

Abstract

The adrenal cortex produces steroid hormones as adrenocortical hormones in the body, secreting mineralocorticoids, glucocorticoids, and adrenal androgens, which are all considered essential for life. Adrenocortical tumors harbor divergent hormonal activity, frequently with steroid excess, and disrupt homeostasis of the body. Aldosterone-producing adenomas (APAs) cause primary aldosteronism (PA), and cortisol-producing adenomas (CPAs) are the primary cause of Cushing’s syndrome. In addition, adrenocortical carcinoma (ACC) is a highly malignant cancer harboring poor prognosis. Various genetic abnormalities have been reported, which are associated with possible pathogenesis by the alteration of intracellular signaling and activation of transcription factors. In particular, somatic mutations in APAs have been detected in genes encoding membrane proteins, especially ion channels, resulting in hypersecretion of aldosterone due to activation of intracellular calcium signaling. In addition, somatic mutations have been detected in those encoding cAMP-PKA signaling-related factors, resulting in hypersecretion of cortisol due to its driven status in CPAs. In ACC, mutations in tumor suppressor genes and Wnt-β-catenin signaling-related factors have been implicated in its pathogenesis. In this article, we review recent findings on the genetic characteristics and regulation of intracellular signaling and transcription factors in individual tumors.

Highlights

Adrenocortical tumors are broadly classified into adenomas and carcinomas based on their potential biological behavior
We will review the findings of recently reported studies on genetic alterations and their regulation of intracellular signaling in aldosterone-producing adenoma (APA) as a cause of primary aldosteronism (PA) and cortisol-producing adenoma (CPA) as a cause of Cushing’s syndrome, subclinical Cushing’s syndrome, and adrenocortical carcinoma (ACC)
It has been reported that overexpression of mutant KCNJ5 in cell line experiments increased intracellular calcium ion concentration due to depolarization, enhanced expression of NURR1, and induced expression of CYP11B2 [31]. These results suggest that the hypersecretion of aldosterone caused by the KCNJ5 mutation is mediated by the activation of NR4A family orphan receptors via calcium signaling through the increase in intracellular

Summary

Introduction

Adrenocortical tumors are broadly classified into adenomas and carcinomas based on their potential biological behavior. APA is an adenoma producing excessive aldosterone autonomously, and somatic mutations of ion channels located at the cell membrane have been frequently reported, resulting in alteration of calcium signaling and its downstream transcription factors [1,2,3,4,5]. It has been reported that overexpression of mutant KCNJ5 in cell line experiments increased intracellular calcium ion concentration due to depolarization, enhanced expression of NURR1, and induced expression of CYP11B2 [31] These results suggest that the hypersecretion of aldosterone caused by the KCNJ5 mutation is mediated by the activation of NR4A family orphan receptors via calcium signaling through the increase in intracellular. The increased intracellular calcium ion concentration induces depolarization and activation of calcium signaling, which promotes the expression of genes involved in aldosterone synthesis (Figure 2).

Mutation

Conclusions