Feminizing Adrenocortical Carcinoma: The Source of Estrogen Production and the Role of Adrenal-Gonadal Dedifferentiation
Feminizing Adrenocortical Carcinoma: The Source of Estrogen Production and the Role of Adrenal-Gonadal Dedifferentiation
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女性化肾上腺皮质癌：雌激素产生的来源和肾上腺-性腺去分化的作用
DOI：
10.1210/jc.2018-00689
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发表时间：
2018-10-01
影响因子：
5.8
通讯作者：
Wang, Weiqing
中科院分区：
文献类型：
--
作者：
Wu, Luming;Xie, Jing;Wang, Weiqing
背景：女性化肾上腺皮质癌（ACC）很少见。雌激素产生的来源及其潜在机制仍不清楚。目的：在本研究中，我们探讨了女性化ACC中雌激素产生的来源和分子机制。方法：我们中心连续招募了46例诊断为ACC的患者。我们描述了外周静脉和肾上腺静脉的临床特征和类固醇激素谱。在女性化的 ACC 组织和细胞系中，我们通过定量 PCR 和免疫组织化学染色研究了类固醇生成生物标志物和 β-连环蛋白途径的表达。还在 NCI-H295R 细胞中分析了 Wnt 抑制剂对类固醇生成的影响。结果：总共分析了 46 名连续的 ACC 患者，其中 25 名具有功能性 ACC。根据女性化表现、手术后恢复正常的高雌二醇水平以及组织学 Weiss 评分，4 名患者被诊断为女性化 ACC。性腺类固醇生成生物标志物（包括 CYP19A1、HSD17B3 和 LHCGR）在女性化 ACC 组织中显着升高。肾上腺静脉取样和液相色谱-串联质谱分析表明肾上腺肿块中存在高 CYP19A1 活性。 β-连环蛋白表达也升高。当用氯硝柳胺和 PNU-74654 处理时，H295R 细胞系表现出 β-连环蛋白表达、细胞增殖和类固醇分泌减少。所有类固醇激素酶均受到抑制，而CYP19A1、HSD17B3和LHCGR mRNA增加。结论：女性化ACC可以表达高水平的CYP19A1，从而异位产生雌激素。 Wnt 通路激活和向常见肾上腺-性腺前体细胞的去分化可能是潜在的机制。
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 beta-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. beta-catenin expression was also elevated. When treated with niclosamide and PNU-74654, the H295R cell line showed a decrease in beta-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.