ABSTRACT
The majority of the cases diagnosed as primary aldosteronism (PA) are caused by aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA). Histopathologically, both IHA and adjacent adrenal glands of APA demonstrate remodeled subcapsular zone (RSZ) but these zones in two disorders are markedly different in terms of steroidogenesis. 3ß-Hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (3ß-HSD) expression has been known to be activated synergistically by GATA6 and SF1, and repressed by DAX1 through abolishing the activation. Nerve growth factor-induced clone B (NGFIB) is also known as one of the transcription factors to bind to and activate 3ß-HSD promoter. The results of our immunohistochemical analysis demonstrated the expression levels of 3ß-HSD in RSZ of IHA were higher than in RSZ of adjacent adrenals of APA, while those in the zona glomerulosa (ZG) of normal adrenal gland (NA) were in between these two RSZs. The expression levels of GATA6, SF1 and DAX1 did not prominently differ among these three types of adrenals, especially between in RSZs of IHA and APA cases, indicating the marked difference of 3ß-HSD expression was unlikely to be explained by the levels of these three factors. However, the levels of NGFIB expression were significantly higher in RSZ of IHA than in RSZ of adjacent adrenals of APA and the ZG of NA (P<0.05), which may partly account for the expression levels of 3ß-HSD among the three groups of adrenals. These results may imply NGFIB plays important roles in the marked differences in steroidogenic functions in the two distinct types of RSZ of PA cases.
Subject(s)
DAX-1 Orphan Nuclear Receptor/metabolism , GATA6 Transcription Factor/metabolism , Hyperaldosteronism/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Steroidogenic Factor 1/metabolism , Up-Regulation , Zona Glomerulosa/metabolism , 3-Hydroxysteroid Dehydrogenases/metabolism , Adrenal Cortex Neoplasms/metabolism , Adrenal Cortex Neoplasms/pathology , Adrenal Cortex Neoplasms/physiopathology , Adrenal Cortex Neoplasms/surgery , Adrenocortical Adenoma/metabolism , Adrenocortical Adenoma/pathology , Adrenocortical Adenoma/physiopathology , Adrenocortical Adenoma/surgery , Biomarkers/metabolism , Down-Regulation , Humans , Hyperaldosteronism/etiology , Hyperaldosteronism/pathology , Hyperaldosteronism/surgery , Immunohistochemistry , Zona Glomerulosa/pathology , Zona Glomerulosa/surgeryABSTRACT
BACKGROUND: Estrogen receptor beta (ERß) has been demonstrated to be expressed in prostate carcinoma cells and estrogen signals through ERß to act as a tumor suppressor in prostate cancer patients. ERß is thought to regulate the cell cycle of prostate carcinoma cells by controlling the expression of cell cycle regulators including cyclin D1 (CCND1). This interaction is of particular interest as CCND1 has been implicated in the development of prostate cancer. METHODS: We evaluated ERß and CCND1 immunoreactivity in human prostate cancer (n = 112, surgical specimens), and correlated the findings with clinicopathological features of the patients. Subsequent in vitro experiments using PC-3 prostate carcinoma cells were also performed to examine whether estradiol (E2) could change the expression level of CCND1 mRNA. RESULTS: CCND1 immunoreactivity was detected in 78/112 cases (70%), and was significantly correlated with incidence of perineural invasion and ERß immunoreactivity (P < 0.05). Forty-eight hours incubation with E2 (10 nM) increased the expression level of CCND1 mRNA as well as c-jun (JUN) and c-fos (FOS) in PC-3 cells, and PHTPP (ERß antagonist) suppressed E2 -induced expression of those mRNAs. CONCLUSIONS: These findings suggest that CCND1 expression is possibly regulated by estrogens via ERß and that this signaling pathway may influence prostate cancer development.
Subject(s)
Carcinoma/genetics , Cyclin D1/genetics , Estrogen Receptor beta/genetics , Prostatic Neoplasms/genetics , Aged , Carcinoma/metabolism , Carcinoma/pathology , Cell Line, Tumor , Cell Nucleus/metabolism , Cyclin D1/metabolism , Estrogen Receptor beta/metabolism , Gene Expression Regulation, Neoplastic/physiology , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Staging , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Signal Transduction/physiologyABSTRACT
Androstenedione is one of several weak androgens produced in the human adrenal gland. 3ß-Hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) are both required for androstenedione production. However, previous studies demonstrated the expression of HSD3B2 within the zona glomerulosa (ZG) and fasciculata (ZF) but low levels in the zona reticularis. In contrast, CYB5A expression increases in the zona reticularis (ZR) in human adrenal glands. Although their colocalization has been reported in gonadal theca and Leydig cells this has not been studied in the human adrenal. Therefore, we immonolocalized HSD3B2 and CYB5A in normal human adrenal glands and first demonstrated their co-expression in the cortical cells located at the border between the ZF and ZR in normal human adrenal. Results of in vitro studies using the human adrenal H295R cells treated with the HSD3B2 inhibitor, trilostane, also demonstrated a markedly decreased androstenedione production. Decreasing CYB5A mRNA using its corresponding siRNA also resulted in significant inhibition of androstenedione production in the H295R cells. These findings together indicate that there are a group of cells co-expressing HSD3B2 and CYB5A with hybrid features of both ZF and ZR in human adrenal cortex, and these hybrid cortical cells may play an important role in androstenedione production in human adrenal gland.
