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1073 High-throughput epigenomic analysis point to MIR-145–3P as a potential therapeutic target in advanced high-grade serous ovarian cancer
  1. Eva González-Cantó1,
  2. Sarai Tomás-Pérez1,
  3. Bárbara Andrea Mc Cormack1,2,
  4. Mariana Monteiro1,
  5. Cristina Aghababyan1,3,
  6. Javier García-Oms1,3,
  7. Ruth Millán-Bover3,
  8. Lourdes Carbó-Julve3,
  9. Vicente Pérez García4,
  10. Josep Marí-Alexandre1,5 and
  11. Juan Gilabert-Estellés1,3,6
  1. 1Research Laboratory in Biomarkers in Reproduction, Obstetrics and Gynecology, Research Foundation of the General University Hospital of Valencia, Valencia, Spain
  2. 2Hemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe, Valencia, Spain
  3. 3Department of Obstetrics and Gynecology, General University Hospital of Valencia Consortium, Valencia, Spain
  4. 4Research Laboratory of Placental Invasion, Centro de Investigación Príncipe Felipe, Valencia, Spain
  5. 5Department of Pathology, General University Hospital of Valencia Consortium, Valencia, Spain
  6. 6Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain


Introduction/Background High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic cancer for which no curative treatment exists. miRNAs are small non-coding RNAs (18–21 nucleotides) that act as regulators of gene expression, reducing the expression of their target mRNAs. Accumulating evidence has shown that epigenetic mechanisms, as miRNAs and DNA methylation, are involved in the pathogenesis of human cancers, including HGSOC. We aimed to gain insight in the epigenetic mechanisms involved in HGSOC pathogenesis to identify therapeutic targets.

Methodology Fresh paired tissue samples (tumoral and control non-tumoral ovarian tissue (PCOT)) from n=20 advanced-HGSOC patients were analyzed. miRNA library preparation and miRNA-Sequencing were performed. miRNA-Sequencing results were validated by RT-qPCR. DNA methylation levels were measured using the Infinium Human MethylationEPIC 850K BeadChip platform (Illumina). miR-145–3p was transfected and wound healing assay was performed in SK-OV-3 and Caov-3 ovarian cancer (OC) cell lines. R (v.3.6.2) was used for statistical analyses.

Results miRNA-Sequencing results reported 20 differentially expressed miRNAs (DEmiRNAs), 8 down- and 12 up-regulated. Differences were validated by RT-qPCR in 11 selected DEmiRNAs in HGSOC patients’ samples (figure 1A) and OC cell lines. Of them, we focused on miR-145–3p since 1) its expression was not recovered after neoadjuvant treatment (NT) (figure 1B), 2) it distinguished tumoral tissues from PCOT with an area under the curve of 0.81 (p<0.001) (figure 1C) and 3) presented a putative regulation by DNA methylation at its proximal promoter (figure 1D). Remarkably, miR-145–3p transfection reduced cell migration in SK-OV-3 (figure 1E) and Caov-3 (figure 1F) cell lines with statistically significant differences in wound confluence at different time points.

Conclusion miRNA-Sequencing analysis revealed DEmiRNAs in HGSOC patients, including the down-regulated miR-145–3p. Functional analyses revealed that decreased miR-145–3p levels increased cell mobility in HGSOC, suggesting a role in the regulation of genes involved in the metastatic process of HGSOC.

Disclosures This research was funded by the ’Instituto de Salud Carlos III Fondo Europeo de Desarrollo Regional’ (PI17/01945 and PI22/01872) and Amunt Contra el Càncer (patients’ non-profit association; Denia, Spain). E. G.-C. is supported by a pre-doctoral grant from the ’Generalitat Valenciana’ (ACIF/2020/216); S. T.-P. is supported by a pre-doctoral grant from the ’Junta Asociada Provincial de Valencia de la Asociación Española Contra el Cáncer (AECC)’; B. A. M.-C. is supported by a post-doctoral grant from the ’Sociedad Española de Trombosis y Hemostasia (Prize SETH); V. P.-G. is supported by a Ramón y Cajal contract from the Spanish Government.

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