正常和癌性子宫内膜以及子宫内膜癌等级和分子亚型的11-氧雄激素差的受体前调节
Pre-receptor regulation of 11-oxyandrogens differs between normal and cancerous endometrium and across endometrial cancer grades and molecular subtypes
影响因子:4.60000
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
摘要
子宫内膜癌（EC）是全球普遍的妇科恶性肿瘤，发病率趋势上升。尽管经典的雄激素与EC风险有关，但其11-氧化代谢产物的作用知之甚少。在这里，我们首次研究了EC中类固醇前体的11-氧辅助形成。我们在一组不同的分化程度和分子亚型的EC细胞系上进行了体外研究，以及正常子宫内膜的对照细胞系，以评估从类固醇前体的11-氧和基因形成。我们还表征了二氢睾丸激素（DHT）和11-Keto-DHT对Ishikawa和RL95-2的转录组作用。使用公共转录组数据集在子宫内膜肿瘤中探索了11-氧和动作的关键分子参与者。我们发现，在子宫内膜肿瘤中，不经典雄激素前体的形成11-氧和生物。但是，与癌组织相比，我们观察到正常子宫内膜的受体前水平以及低度和高级肿瘤之间的不同调节机制。具体而言，与非癌性子宫内膜和高级，TP53突变的EC相比，低级EC的体外模型从11-氧和生理前体形成了较高水平的生物活性11-酮托斯托酮。此外，有效的雄激素DHT及其11-酮同源物诱导了对雄激素受体（AR）表达EC模型Ishikawa的轻度转录组作用。最后，使用公共转录组数据集，我们发现了HSD11B2和SRD5A2，编码类固醇代谢中的关键酶，与较高的疾病特异性生存有关，而较高的肿瘤内AR表达与TP53-WT失去较低的较低的肿瘤内部相关。非TP53-ALT分子亚型。我们的发现支持进一步探索循环的11-氧和糖作为EC中的预后生物标志物。
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.