子宫内膜癌（EC）是全球常见的妇科恶性肿瘤，发病率呈上升趋势。虽然经典雄激素与 EC 风险有关，但其 11-氧化代谢物的作用却知之甚少。在这里，我们首次研究了 EC 中类固醇前体的 11-氧雄激素形成。我们对一组不同分化程度和分子亚型的四种 EC 细胞系以及正常子宫内膜的对照细胞系进行了体外研究，以评估 11- 氧雄激素。由类固醇前体形成氧雄激素。我们还表征了二氢睾酮 (DHT) 和 11-酮-DHT 对 Ishikawa 和 RL95-2 的转录组效应。使用公共转录组数据集探索了子宫内膜肿瘤中 11-氧雄激素代谢和作用的关键分子参与者。我们发现，在子宫内膜肿瘤中，11-氧雄激素的形成并非由经典雄激素前体发生。然而，我们观察到正常子宫内膜与癌组织以及低级别和高级别肿瘤之间在前受体水平上存在不同的调节机制。具体而言，与非癌性子宫内膜和高级别 TP53 突变 EC 模型相比，低级别 EC 的体外模型从 11-氧雄激素前体中形成了更高水平的生物活性 11-酮睾酮。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 产生轻微的转录组效应。最后，使用公共转录组数据集，我们发现编码类固醇代谢关键酶的 HSD11B2 和 SRD5A2 与更好的疾病特异性生存相关，而较高的肿瘤内 AR 表达与 TP53-wt 肿瘤的较低复发相关。 -11-氧雄激素前体的肿瘤代谢是非TP53-alt分子亚型的低级别EC的特征。我们的研究结果支持在 EC 中进一步探索循环 11-氧雄激素作为预后生物标志物。版权所有 © 2024 Gjorgoska、Šturm 和 Lanišnik Rižner。

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.Copyright © 2024 Gjorgoska, Šturm and Lanišnik Rižner.