Luming Wu1, Jing Xie2, Lei Jiang1, TingWei Su1, Lei Ye1,3, Weiwei Zhou1, Yiran Jiang1, Cui Zhang1, Guang Ning1,3, Weiqing Wang1,3. 1. Shanghai Key Laboratory for Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the Chinese Health Ministry, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China. 2. Department of Pathology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China. 3. Laboratory for Endocrine & Metabolic Diseases of Institute of Health Science, Shanghai JiaoTong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Abstract
Background: Feminizing adrenocortical carcinoma (ACC) is rare. The source of estrogen production and the underlying mechanism remain unclear. Objective: In the current study, we investigated the source and the molecular mechanism of estrogen production in feminizing ACC. Methods: A total of 46 consecutive patients with a diagnosis of ACC were recruited in our center. We described the clinical characteristics and steroid hormone profile of the peripheral and adrenal vein. In both feminizing ACC tissues and cell lines, we investigated the expression of steroidogenic biomarkers and β-catenin pathways by quantitative PCR and immunohistochemical staining. The effects of Wnt inhibitors on steroidogenesis were also analyzed in NCI-H295R cells. Results: A total of 46 consecutive patients with ACC were analyzed, and 25 had functional ACC. Four patients received a diagnosis of feminizing ACC based on feminizing manifestations, high levels of estradiol that were normalized after surgery, and histological Weiss score. Gonadal steroidogenic biomarkers including CYP19A1, HSD17B3, and LHCGR were markedly elevated in the feminizing ACC tissues. Adrenal vein sampling and liquid chromatography-tandem mass spectrometry suggested high CYP19A1 activity in the adrenal mass. β-catenin expression was also elevated. When treated with niclosamide and PNU-74654, the H295R cell line showed a decrease in β-catenin expression, cell proliferation, and steroid secretion. All steroid hormone enzymes were inhibited, whereas CYP19A1, HSD17B3, and LHCGR mRNA increased. Conclusions: Feminizing ACC can express high levels of CYP19A1, thus ectopically producing estrogens. Wnt pathway activation and dedifferentiation toward common adrenal-gonadal precursor cells may be the underlying mechanisms.
Background: Feminizing adrenocortical carcinoma (ACC) is rare. The source of estrogen production and the underlying mechanism remain unclear. Objective: In the current study, we investigated the source and the molecular mechanism of estrogen production in feminizing ACC. Methods: A total of 46 consecutive patients with a diagnosis of ACC were recruited in our center. We described the clinical characteristics and steroid hormone profile of the peripheral and adrenal vein. In both feminizing ACC tissues and cell lines, we investigated the expression of steroidogenic biomarkers and β-catenin pathways by quantitative PCR and immunohistochemical staining. The effects of Wnt inhibitors on steroidogenesis were also analyzed in NCI-H295R cells. Results: A total of 46 consecutive patients with ACC were analyzed, and 25 had functional ACC. Four patients received a diagnosis of feminizing ACC based on feminizing manifestations, high levels of estradiol that were normalized after surgery, and histological Weiss score. Gonadal steroidogenic biomarkers including CYP19A1, HSD17B3, and LHCGR were markedly elevated in the feminizing ACC tissues. Adrenal vein sampling and liquid chromatography-tandem mass spectrometry suggested high CYP19A1 activity in the adrenal mass. β-catenin expression was also elevated. When treated with niclosamide and PNU-74654, the H295R cell line showed a decrease in β-catenin expression, cell proliferation, and steroid secretion. All steroid hormone enzymes were inhibited, whereas CYP19A1, HSD17B3, and LHCGR mRNA increased. Conclusions: Feminizing ACC can express high levels of CYP19A1, thus ectopically producing estrogens. Wnt pathway activation and dedifferentiation toward common adrenal-gonadal precursor cells may be the underlying mechanisms.
Authors: L M Mermejo; F G Carvalho; C A F Molina; S Tucci; V F Muglia; J Elias; P C L Elias; M Castro; A C Moreira Journal: Endocrinol Diabetes Metab Case Rep Date: 2021-03-15