Blood Plasma Small Non-Coding RNAs as Diagnostic Molecules for the Progesterone-Receptor-Negative Phenotype of Serous Ovarian Tumors

Abstract

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 MMP7 and MUC16, along with downregulation of PGR, 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 MUC16, MMP7, and MMP9, 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.

Differential microRNA Expression Analysis in Patients with HPV-Infected Ovarian Neoplasms

“…2024, 25, 762 10 of 17 of miR-16 in serous OC tissues compared with the corresponding normal tissues was observed [85,86]. A significant increase in the expression levels of hsa-miR-16-5p was also observed in malignant ovarian tumors collected from HGSOC and LGSOC cases relative to benign serous ovarian tumors [87]. Hsa-miR-16-5p expression levels in the peripheral blood lymphocytes were found to have higher expression levels in women with OC compared to healthy controls [88].…”

KLF5 inhibits the migration and invasion in cervical cancer cell lines by regulating SNAI1

“…In addition, high expression of TWIST can also activate the Akt signaling pathway, affecting glycogen synthase kinase-3 , thereby regulating the expression of SNAI1 and inhibiting the expression of E-cadherin [ 21 ]. High expression of ZEB1, MMP7 and MMP9 can promote the EMT process of serous ovarian tumors, thereby enhancing tumor invasion and metastasis [ 21 , 47 , 48 ].…”

Analysis of miRNAs miR-125a-5p, -27a-5p, -193a-5p, -135b-5p, -451a, -495-3p and -136-5p in parental ovarian cancer cells and secreted extracellular vesicles

“…For instance, miR-205-5p and the members of the miR-200 family, which have been repeatedly shown to be upregulated in EVs from OC patients [20], as well as several other known cancer promoters. The second group included known miRNAs with tumor suppressor activity such as miR-152-3p [21], -424-5p [22,23], -199a and -199b [24,25], among others. Meanwhile, we detected molecules whose role in carcinogenesis in general and in OC progression remains unclear in the literature, as well as miRNAs that are little known in this context.…”