Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia.
Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana 1000, Slovenia.
Biomed Pharmacother. 2024 Aug;177:117069. doi: 10.1016/j.biopha.2024.117069. Epub 2024 Jul 4.
The high mortality rate due to chemoresistance in patients with high-grade ovarian cancer (HGSOC) emphasizes the urgent need to determine optimal treatment strategies for advanced and recurrent cases. Our study investigates the interplay between estrogens and chemoresistance in HGSOC and shows clear differences between platinum-sensitive and -resistant tumors. Through comprehensive transcriptome analyzes, we uncover differences in the expression of genes of estrogen biosynthesis, metabolism, transport and action underlying platinum resistance in different tissues of HGSOC subtypes and in six HGSOC cell lines. Furthermore, we identify genes involved in estrogen biosynthesis and metabolism as prognostic biomarkers for HGSOC. Additionally, our study elucidates different patterns of estrogen formation/metabolism and their effects on cell proliferation between six HGSOC cell lines with different platinum sensitivity. These results emphasize the dynamic interplay between estrogens and HGSOC chemoresistance. In particular, targeting the activity of steroid sulfatase (STS) proves to be a promising therapeutic approach with potential efficacy in limiting estrogen-driven cell proliferation. Our study reveals potential prognostic markers as well as identifies novel therapeutic targets that show promise for overcoming resistance and improving treatment outcomes in HGSOC.
由于高级别卵巢癌 (HGSOC) 患者的化疗耐药导致高死亡率，强调了迫切需要确定晚期和复发性病例的最佳治疗策略。我们的研究调查了雌激素与 HGSOC 化疗耐药之间的相互作用，并显示出铂敏感和耐药肿瘤之间的明显差异。通过全面的转录组分析，我们揭示了 HGSOC 亚型不同组织和六种 HGSOC 细胞系中与铂耐药相关的雌激素生物合成、代谢、转运和作用的基因表达差异。此外，我们还确定了参与雌激素生物合成和代谢的基因作为 HGSOC 的预后生物标志物。此外，我们的研究阐明了不同的雌激素形成/代谢模式及其对六种不同铂敏感性 HGSOC 细胞系增殖的影响。这些结果强调了雌激素与 HGSOC 化疗耐药之间的动态相互作用。特别是，靶向甾体硫酸酯酶 (STS) 的活性被证明是一种有前途的治疗方法，具有限制雌激素驱动的细胞增殖的潜在疗效。我们的研究揭示了潜在的预后标志物，并确定了新的治疗靶点，有望克服耐药性并改善 HGSOC 的治疗效果。
