Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma
Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma
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DOI：
10.1016/j.jsbmb.2016.02.031
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发表时间：
2016-05-01
影响因子：
4.1
通讯作者：
Ogata, Tsutomu
中科院分区：
文献类型：
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作者：
Fujisawa, Yasuko;Sakaguchi, Kimiyoshi;Ogata, Tsutomu
虽然已知TP 53突变的儿童肾上腺皮质癌（c-ACCs）产生雄激素，但详细的类固醇生成特征尚未阐明。在这里，我们研究了类固醇代谢产物的档案和类固醇基因的表达模式的c-ACC从左肾上腺位置的2岁的巴西男孩性早熟，使用萎缩的左肾上腺肿瘤切除术作为对照。c-ACC不仅产生大量的硫酸脱氢表雄酮，而且通过Delta 5途径产生大量的睾酮，其中Delta 5-雄烯二醇而不是Delta 4-雄烯二酮作为主要中间代谢物。此外，c-ACC与CYP 11 A1、CYP 17 A1、POR、HSD 17 B3和SULT 2A 1的表达升高、CYB 5A的低但相似的表达以及AKR 1C 3（HSD 17 B5）和HSD 3B 2的表达降低相关。值得注意的是，间质细胞标记INSL 3在c-ACC中以低但可检测的水平表达。此外，分子研究揭示了母系遗传的杂合生殖系TP 53突变，和几个后合子遗传畸变的c-ACC包括缺失父系来源的17号染色体和野生型TP 53，缺失母系遗传的11号染色体，以及由此产生的父系表达生长的显著过表达促进基因IGF 2和母源性生长抑制基因CDKN 1C的显著低表达。这些结果意味着存在胎儿肾上腺和Leydig细胞的类固醇合成特性，在这个病人的c-ACC与生殖系TP 53突变和几个合子后致癌事件。(C)2016爱思唯尔有限公司版权所有
Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Delta 5 pathway with Delta 5-androstenediol rather than Delta 4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events. (C) 2016 Elsevier Ltd. All rights reserved.