Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: immunohistochemical analysis and quantitative real-time polymerase chain reaction studies

Kubota-Nakayama, Fumie; Nakamura, Yasuhiro; Konosu-Fukaya, Sachiko; Azmahani, Abdullah; Ise, Kazue; Yamazaki, Yuto; Kitawaki, Yuko; Felizola, Saulo J.A.; Ono, Yoshikiyo; Omata, Kei; Morimoto, Ryo; Iwama, Noriyuki; Satoh, Fumitoshi; Sasano, Hironobu

doi:10.1016/j.humpath.2016.03.016

Cited by 20 publications

(10 citation statements)

References 27 publications

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“…All resected adrenal specimens were embedded in paraffin for immunohistochemical staining of CYP11B1, CYP11B2, and C17 (17α-hydroxylase), and for immunofluorescence staining of B1+B2 cells. 16,25,26 The immunohistochemical staining and immunofluorescence staining methods are described in the online-only Data Supplement. All immunohistochemical staining sections were digitally scanned and captured by Image Scope AT2 (Leica, Wetzlar, Germany) for digital image analysis.…”

Section: Histopathologic Analysis For Expression Of Steroidogenic Enzymesmentioning

confidence: 99%

18-Oxocortisol Synthesis in Aldosterone-Producing Adrenocortical Adenoma and Significance of KCNJ5 Mutation Status

Tezuka

Yamazaki

Kitada³

et al. 2019

Hypertension

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Peripheral 18-oxocortisol (18oxoF) level could contribute to the detection of aldosteroneproducing adenoma (APA) in patients with primary aldosteronism. However, peripheral 18oxoF varies among such patients, which is a big drawback concerning its clinical application. We studied 48 cases of APA, 35 harboring KCNJ5 mutation, to clarify the significance of clinical and pathological parameters about peripheral 18oxoF. Peripheral 18oxoF concentration ranged widely from 0.50 to 183.13 ng/dL and correlated positively with intratumoral areas stained positively for steroidogenic enzymes (P<0.0001). The peripheral 18oxoF level also correlated significantly with that of circulating aldosterone (P<0.0001) but not with that of cortisol, a precursor of 18oxoF. However, a significant correlation was detected between peripheral 18oxoF and intratumoral glucocorticoids (P<0.05). In addition, peripheral 18oxoF correlated positively with the number of hybrid cells double positive for 11β-hydroxylase and aldosterone synthase (P<0.0001). Comparing between the cases with and those without KCNJ5 mutation, the KCNJ5-mutated group demonstrated a significantly higher concentration of peripheral 18oxoF (28.4±5.6 versus 3.0±0.9 ng/dL, P<0.0001) and a larger intratumoral environment including the hybrid cells (P<0.

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Section: Histopathologic Analysis For Expression Of Steroidogenic Enzymesmentioning

confidence: 99%

18-Oxocortisol Synthesis in Aldosterone-Producing Adrenocortical Adenoma and Significance of KCNJ5 Mutation Status

Tezuka

Yamazaki

Kitada³

et al. 2019

Hypertension

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“…However, the relationship between CYP11B1 overexpression and DNA methylation in hypercortisolemia has yet to be elucidated. Therefore, it is intriguing to focus on CPA that overexpresses CYP11B1 11 , 12 .…”

Section: Introductionmentioning

confidence: 99%

Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia

Kometani

Yoneda

Demura

et al. 2017

Sci Rep

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Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter.

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“…A previous study also showed that CYP11B1 transcription was not stimulated in CPAs (Sakuma et al, 2013). CYP11B1 immunoreactivity is detected in CPAs, although the expression was not compared between CPAs and NFAs (Gomez-Sanchez et al, 2014,Kubota-Nakayama et al, 2016. It has been suggested that CYP11B1 expression in PRKACA mutant adenomas is not a rate-limiting factor in the synthesis of cortisol.…”

Section: Discussionmentioning

confidence: 94%

Genotype-specific cortisol production associated with Cushing's syndrome adenoma with PRKACA mutations

Baba

Oki

Gómez-Sánchez

et al. 2021

Molecular and Cellular Endocrinology

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Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: immunohistochemical analysis and quantitative real-time polymerase chain reaction studies

Cited by 20 publications

References 27 publications

18-Oxocortisol Synthesis in Aldosterone-Producing Adrenocortical Adenoma and Significance of KCNJ5 Mutation Status

18-Oxocortisol Synthesis in Aldosterone-Producing Adrenocortical Adenoma and Significance of KCNJ5 Mutation Status

Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia

Genotype-specific cortisol production associated with Cushing's syndrome adenoma with PRKACA mutations

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