Timofeeva, A.V.; Fedorov, I.S.; Asaturova, A.V.; Sannikova, M.V.; Tregubova, A.V.; Mayboroda, O.A.; Khabas, G.N.; Frankevich, V.E.; Sukhikh, G.T. Blood Plasma Small Non-Coding RNAs as Diagnostic Molecules for the Progesterone-Receptor-Negative Phenotype of Serous Ovarian Tumors. Int. J. Mol. Sci.2023, 24, 12214.
Timofeeva, A.V.; Fedorov, I.S.; Asaturova, A.V.; Sannikova, M.V.; Tregubova, A.V.; Mayboroda, O.A.; Khabas, G.N.; Frankevich, V.E.; Sukhikh, G.T. Blood Plasma Small Non-Coding RNAs as Diagnostic Molecules for the Progesterone-Receptor-Negative Phenotype of Serous Ovarian Tumors. Int. J. Mol. Sci. 2023, 24, 12214.
Timofeeva, A.V.; Fedorov, I.S.; Asaturova, A.V.; Sannikova, M.V.; Tregubova, A.V.; Mayboroda, O.A.; Khabas, G.N.; Frankevich, V.E.; Sukhikh, G.T. Blood Plasma Small Non-Coding RNAs as Diagnostic Molecules for the Progesterone-Receptor-Negative Phenotype of Serous Ovarian Tumors. Int. J. Mol. Sci.2023, 24, 12214.
Timofeeva, A.V.; Fedorov, I.S.; Asaturova, A.V.; Sannikova, M.V.; Tregubova, A.V.; Mayboroda, O.A.; Khabas, G.N.; Frankevich, V.E.; Sukhikh, G.T. Blood Plasma Small Non-Coding RNAs as Diagnostic Molecules for the Progesterone-Receptor-Negative Phenotype of Serous Ovarian Tumors. Int. J. Mol. Sci. 2023, 24, 12214.
Abstract
Progesterone receptor (PGR) expression level determines biological characteristics of the serous ovarian carcinoma, and low PGR expression appears to be associated with chemoresistance and worse outcome. In this study, we aimed to find relationships between tumor progesterone receptor level and RNA-profile (miRNAs, piwiRNAs, and mRNAs), determining its biological characteristics and behavior. For this purpose, we applied next generation sequencing of small noncoding RNAs, quantitative RT-PCR, and immunohistochemistry to analyze FFPE and frozen tumor samples as well as blood plasma from patients with benign cystadenoma (BSC), serous borderline tumour (SBT), low-grade and high-grade serous ovarian carcinoma (LGSOC and HGSOC, respectively). We found significant upregulation of MMP7 and MUC16 and downregulation of PGR in LGSOC and HGSOC in comparison with BSC. The tissue content of miR-199a-5p, miR-214-3p, miR-424-3p, miR-424-5p, miR-125b-5p significantly inversely correlated with the expression level of MUC16 and blood serum CA125 concentration, and significantly directly correlated with the PGR expression level in tumor tissue. On the contrary, the tissue content of miR-16-5p, miR-17-5p, miR-20a-5p, miR-93-5p, responsible for epithelial-mesenchymal transition (EMT) of the cell, significantly directly correlated with the blood serum CA125 concentration and significantly inversely correlated with the PGR expression level in the tumor tissue. Levels of the EMT-associated miRNAs significantly directly correlated with the content of hsa_piR_022437, hsa_piR_009295, hsa_piR_020813, hsa_piR_004307, hsa_piR_019914 in tumor tissues. Among them, expression level of hsa_piR_004307 significantly inversly correlated with the PGR expression level in the tumor. Two optimal logistic regression models were developed based on the quantitation of hsa_piR_020813, miR-16-5p, hsa_piR_022437 or hsa_piR_004307, hsa_piR_019914, miR-93-5p in the tumor tissue, both of which significantly diagnose PGR-negative tumor phenotype with 93% sensitivity. According to FunRich3.1.3 functional enrichment analysis tool, 72 gene-targets of miRNA and piRNA identified here as markers of PGR-negative ovarian tumor phenotype were proven to be mutated in different cancers such as ovarian, breast, colorectal, liver, stomach, lung, endometrial, thyroid cancer. Among them, the blood plasma levels of miR-16-5p and hsa_piR_022437 can be used to diagnose PGR-negative tumor phenotype with 86% sensitivity before surgery and chemotherapy to choose the treatment strategy for this most aggressive type of ovarian cancer (for instance, neoadjuvant chemotherapy followed by cytoreduction in combination with hyperthermic intraperitoneal chemotherapy) to increase the effectiveness of treatment and longevity of the patient.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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