title: Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: immunohistochemical analysis and quantitative real-time polymerase chain reaction studies.
abstract: Adrenal Cushing syndrome (CS) is caused by the overproduction of cortisol in adrenocortical tumors including adrenal cortisol-producing adenoma (CPA). In CS, steroidogenic enzymes such as 17α-hydroxylase/17, 20-lase (CYP17A1), 3β-hydroxysteroid dehydrogenase (HSD3B), and 11β-hydroxylase (CYP11B1) are abundantly expressed in tumor cells. In addition, several transcriptional factors have been reported to play pivotal roles in the regulation of these enzymes in CPA, but their correlations with those enzymes above have still remained largely unknown. Therefore, in this study, we examined the status of steroidogenic enzymes and their transcriptional factors in 78 and 15 CPA cases by using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR), respectively. Immunoreactivity of HSD3B2, CYP11B1, CYP17A1, steroidogenic factor-1 (SF1[NR5A1]), GATA6, and nerve growth factor induced-B (NGFIB[NR4A1]) was detected in tumor cells. Results of qPCR analysis revealed that expression of HSD3B2 mRNA was significantly higher than that of HSD3B1, and CYP11B1 mRNA was significantly higher than CYP11B2. In addition, the expression of CYP11B1 mRNA was positively correlated with those of NR5A1, GATA6, and NR4A1. These results all indicated that HSD3B2 but not HSD3B1 was mainly involved in cortisol overproduction in CPA. In addition, NR5A1, GATA6, and NR4A1 were all considered to play important roles in cortisol overproduction through regulating CYP11B1 gene transcription.
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan; Department of Diagnostic Pathology, Tohoku Rosai Hospital, Sendai, 981-8563 Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Kubota-Nakayama
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan. Electronic address: yasu-naka@patholo2.med.tohoku.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Konosu-Fukaya
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Azmahani
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Ise
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitawaki
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan.
authors.forename: Saulo J A
authors.initials: SJ
authors.lastname: Felizola
authors.affiliation: Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Hospital, Sendai, 980-8574 Japan.
authors.forename: Yoshikiyo
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Hospital, Sendai, 980-8574 Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Omata
authors.affiliation: Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Hospital, Sendai, 980-8574 Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Morimoto
authors.affiliation: Department of Diagnostic Pathology, Tohoku Rosai Hospital, Sendai, 981-8563 Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iwama
authors.affiliation: Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Hospital, Sendai, 980-8574 Japan; Division of Clinical Hypertension, Endocrinology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan.
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Satoh
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575 Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics; D011375:Progesterone Reductase / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000235:genetics; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C539821:NR4A1 protein, human; C515057:NR5A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D013252:Steroid 11-beta-Hydroxylase; D006854:Hydrocortisone
keywords: CYP11B1; CYP11B2; Cortisol-producing adrenocortical adenoma; HSD3B1; HSD3B2