Introduction/Background Endometrial cancer (EC) is the most prevalent gyneacological cancer. It presents two subtypes, (Type-1 and Type-2), being the lately associated to worse prognosis and increased epithelial-to-mesenchymal transition (EMT). A growing evidence supports that uPA and PAI-1 play a role in solid tumour progression, though the exact role of PAI-1 and its epigenetic regulation in EC has not been completely established yet.
Methodology 67 patients with EC and 36 control women were included. 5 miRNAs targeting PAI-1 mRNA (namely miR-99a-5p, miR-143-3p, miR-145-5p, miR-196b-5p y miR-301a-3p) were selected from miRNA expression profiles (Affymetrix, GeneChipmiRNA 2.0) and validated by RT-qPCR. mRNA levels of E-cadherin, Vimentin, Fibronectin, Snail1 and Twist were assessed by RT-qPCR; PAI-1 tissue and plasma levels by ELISA (DuoSet).
Results At the tissue level, PAI-1 is over-expressed in EC in comparison to control endometria (CE) (88.67±12.65 vs. 65.89±9.39 pg/mg), and is significantly increased in Type-2 vs. Type-1 EC (124.43±18.31 vs. 65.90±13.57 pg/mg; p=0.02). At the plasma level, PAI-1 increases in EC vs. control plasma (3.06±0.34 vs. 0.99±0.19 ng/mL, p<0.001), but is reduced in Type-2 vs. Type-1 EC (1.75±0.38 vs. 3.49±0.46 ng/mL; p=0.01). The levels of miR-196b-5p were significantly reduced in EC vs. CE (0.42±0.12 vs.1.00±0.27; p<0.05), inversely correlating with PAI-1 levels, especially in Type-2 EC. Nevertheless, miR-301a-3p is significantly increased in EC vs. CE (1.90±0.30 vs. 1.00±0.16; p<0.05), which could act via targeting PTEN. Finally, we observed decreased levels of E-Cadherin (1.00±0.12 vs. 0.57±0.20; p<0.01) and increased levels of Snail1 and Twist1 in Type-2 vs. Type-1 EC (1.00±0.17 vs. 3.49±0.90; p<0.01; 1.00±0.16 vs. 3.56±1.18; p<0.01; respectively).
Conclusion PAI-1 plasma and tissue levels are over-expressed in EC vs. CE, but only in tissues it is over-expressed in the worst-prognose subtype, which is associated with increased EMT markers. This local action of PAI-1 might be mediated by down-regulation of miR-196b-5p.
Disclosure All authors have declared no conflicts of interest. This work has been supported by grants from ISCIII (PI17/01945). J. M-A. is supported by a FETH 2016-2018 award and a post-doctoral grant (APOSTD/2019/087).
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