前受体调节对11-氧类雄激素在正常与癌变子宫内膜及不同癌症分级和分子亚型中的差异

Pre-receptor regulation of 11-oxyandrogens differs between normal and cancerous endometrium and across endometrial cancer grades and molecular subtypes

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Frontiers in Endocrinology

影响因子:4.6

分区:医学3区 / 内分泌学与代谢3区

发表日期:2024

作者: Marija Gjorgoska, Lea Šturm, Tea Lanišnik Rižner

DOI: 10.3389/fendo.2024.1404804

摘要

子宫内膜癌（EC）是全球常见的妇科恶性肿瘤，发病率逐年上升。经典雄激素与EC风险有关，但其11-氧化代谢物的作用尚不清楚。本文首次研究了EC中11-氧类雄激素的形成机制。我们在不同分化程度和分子亚型的四个EC细胞系及正常子宫内膜对照细胞系中，体外检测了类固醇前体向11-氧类雄激素的转化能力。还分析了二氢睾酮（DHT）和11-酮-DHT对Ishikawa和RL95-2细胞的转录组影响。利用公共转录组数据库，探索了子宫内膜肿瘤中与11-氧类雄激素代谢和作用相关的关键分子。研究发现，子宫内膜肿瘤中，11-氧类雄激素的形成并不来自经典雄激素前体。然而，在正常子宫内膜与癌变组织、低级别与高级别肿瘤之间，存在不同的调控机制。具体而言，低级别EC模型中，从11-氧类雄激素前体形成的生物活性11-酮睾酮水平高于非癌变子宫内膜和高级别、TP53突变的EC模型。此外，强效雄激素DHT及其11-酮同系物对表达雄激素受体（AR）的EC模型Ishikawa具有轻微的转录组影响。在公共数据库分析中，HSD11B2和SRD5A2（编码关键固醇代谢酶）与更好的疾病特异性存活相关，而肿瘤内AR表达越高，TP53野生型（TP53-wt）肿瘤的复发率越低。研究表明，低级别非TP53突变型EC中，肿瘤内11-氧类雄激素前体的代谢具有特异性。这些发现支持进一步探索循环中11-氧类雄激素作为EC预后生物标志物的潜力。

Abstract

Endometrial cancer (EC) is a prevalent gynecological malignancy globally, with a rising incidence trend. While classic androgens have been implicated with EC risk, the role of their 11-oxygenated metabolites is poorly understood. Here, we studied 11-oxyandrogen formation from steroid precursors in EC for the first time.We performed in vitro studies on a panel of four EC cell lines of varying differentiation degree and molecular subtype and a control cell line of normal endometrium to assess 11-oxyandrogen formation from steroid precursors. We also characterized the transcriptomic effects of dihydrotestosterone (DHT) and 11-keto-DHT on Ishikawa and RL95-2. Key molecular players in 11-oxyandrogen metabolism and action were explored in endometrial tumors using public transcriptomic datasets.We discovered that within endometrial tumors, the formation of 11-oxyandrogens does not occur from classic androgen precursors. However, we observed distinct regulatory mechanisms at a pre-receptor level in normal endometrium compared to cancerous tissue, and between low- and high-grade tumors. Specifically, in vitro models of low-grade EC formed higher levels of bioactive 11-keto-testosterone from 11-oxyandrogen precursors compared to models of noncancerous endometrium and high-grade, TP53-mutated EC. Moreover, the potent androgen, DHT and its 11-keto homologue induced mild transcriptomic effects on androgen receptor (AR)-expressing EC model, Ishikawa. Finally, using public transcriptomic datasets, we found HSD11B2 and SRD5A2, coding for key enzymes in steroid metabolism, to be associated with better disease-specific survival, whereas higher intra-tumoral AR expression correlated with lower recurrence in TP53-wt tumors.The intra-tumoral metabolism of 11-oxyandrogen precursors is characteristic for low-grade EC of non-TP53-alt molecular subtypes. Our findings support further exploration of circulating 11-oxyandrogens as prognostic biomarkers in EC.