National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov Ministry of Healthcare of the Russian Federation, Ac. Oparina 4, 117997 Moscow, Russia.
Center for Proteomics and Metabolomics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands.
Int J Mol Sci. 2023 Jul 30;24(15):12214. doi: 10.3390/ijms241512214.
The expression level of the progesterone receptor (PGR) plays a crucial role in determining the biological characteristics of serous ovarian carcinoma. Low PGR expression is associated with chemoresistance and a poorer outcome. In this study, our objective was to explore the relationship between tumor progesterone receptor levels and RNA profiles (miRNAs, piwiRNAs, and mRNAs) to understand their biological characteristics and behavior. To achieve this, we employed next-generation sequencing of small non-coding RNAs, quantitative RT-PCR, and immunohistochemistry to analyze both FFPE and frozen tumor samples, as well as blood plasma from patients with benign cystadenoma (BSC), serous borderline tumor (SBT), low-grade serous ovarian carcinoma (LGSOC), and high-grade serous ovarian carcinoma (HGSOC). Our findings revealed significant upregulation of and , along with downregulation of , in LGSOC and HGSOC compared to BSC. We observed significant correlations of PGR expression levels in tumor tissue with the contents of miR-199a-5p, miR-214-3p, miR-424-3p, miR-424-5p, and miR-125b-5p, which potentially target , and , as well as with the tissue content of miR-16-5p, miR-17-5p, miR-20a-5p, and miR-93-5p, which are associated with the epithelial-mesenchymal transition (EMT) of cells. The levels of EMT-associated miRNAs were significantly correlated with the content of hsa_piR_022437, hsa_piR_009295, hsa_piR_020813, hsa_piR_004307, and hsa_piR_019914 in tumor tissues. We developed two optimal logistic regression models using the quantitation of hsa_piR_020813, miR-16-5p, and hsa_piR_022437 or hsa_piR_004307, hsa_piR_019914, and miR-93-5p in the tumor tissue, which exhibited a significant ability to diagnose the PGR-negative tumor phenotype with 93% sensitivity. Of particular interest, the blood plasma levels of miR-16-5p and hsa_piR_022437 could be used to diagnose the PGR-negative tumor phenotype with 86% sensitivity even before surgery and chemotherapy. This knowledge can help in choosing the most effective treatment strategy for this aggressive type of ovarian cancer, such as neoadjuvant chemotherapy followed by cytoreduction in combination with hyperthermic intraperitoneal chemotherapy and targeted therapy, thus enhancing the treatment's effectiveness and the patient's longevity.
孕激素受体（PGR）的表达水平在决定浆液性卵巢癌的生物学特征方面起着至关重要的作用。低 PGR 表达与化疗耐药和预后不良有关。在这项研究中，我们的目的是探讨肿瘤孕激素受体水平与 RNA 谱（miRNAs、piwiRNAs 和 mRNAs）之间的关系，以了解其生物学特征和行为。为了实现这一目标，我们采用了下一代小非编码 RNA 测序、定量 RT-PCR 和免疫组织化学分析，对福尔马林固定石蜡包埋（FFPE）和冷冻肿瘤样本以及来自良性囊腺瘤（BSC）、浆液性交界性肿瘤（SBT）、低级别浆液性卵巢癌（LGSOC）和高级别浆液性卵巢癌（HGSOC）患者的血浆进行了分析。我们的研究结果显示，与 BSC 相比，LGSOC 和 HGSOC 中 和 显著上调，而 下调。我们观察到肿瘤组织中 PGR 表达水平与 miR-199a-5p、miR-214-3p、miR-424-3p、miR-424-5p 和 miR-125b-5p 的含量之间存在显著相关性，这些 miRNA 可能靶向 和 ，以及与 miR-16-5p、miR-17-5p、miR-20a-5p 和 miR-93-5p 的组织含量相关，这些 miRNA 与细胞的上皮-间充质转化（EMT）有关。与 EMT 相关的 miRNA 水平与肿瘤组织中 hsa_piR_022437、hsa_piR_009295、hsa_piR_020813、hsa_piR_004307 和 hsa_piR_019914 的含量显著相关。我们使用肿瘤组织中 hsa_piR_020813、miR-16-5p 和 hsa_piR_022437 或 hsa_piR_004307、hsa_piR_019914 和 miR-93-5p 的定量，开发了两个最佳的逻辑回归模型，这些模型显示出了诊断 PGR 阴性肿瘤表型的显著能力，敏感性为 93%。值得注意的是，miR-16-5p 和 hsa_piR_022437 的血浆水平甚至在手术和化疗之前就可以用于诊断 PGR 阴性肿瘤表型，敏感性为 86%。这些知识可以帮助选择这种侵袭性卵巢癌最有效的治疗策略，例如新辅助化疗后联合减瘤术和腹腔热灌注化疗以及靶向治疗，从而提高治疗的有效性和患者的生存率。
