Oleuropin controls miR-194/XIST/PD-L1 loop in triple negative breast cancer: New role of nutri-epigenetics in immune-oncology

Abstract Oleuropein, the main secoiridoid glucoside found in Olea europaea L., has attracted scientific community as a potential anticancer agent. Immunotherapy and RNA interference revolutionized cancer treatment. Success of PD-L1/PD-1 antibodies encouraged the investigation of PD-1/PD-L1 regulation by non-coding RNAs. This study aimed to verify the cytotoxic effect of oleuropein on MDA-MB-231 cell line and to unravel novel ceRNA interaction between miR-194-5p and XIST in breast cancer and their immunomodulatory effect on PD-L1 expression to propose a promising prophylactic and preventive role of Oleuropin in diet. For the first time, miR-194/Lnc-RNA XIST/PD-L1 triad was investigated in breast cancer, where miR-194 and PD-L1 levels were significantly upregulated in 21 BC-biopsies, yet XIST was downregulated. Ectopic expression of miR-194 enhanced cell function and viability with concomitant increase in PD-L1 expression yet XIST expression decreased, in contrast to miR-194 antagomirs that yielded opposite results. XIST knock-out elevated miR194–5p and PD-L1 levels. miR-194-5p mimics and XIST siRNAs co-transfection induced PD-L1 expression, while miR-194-5p mimics and TSIX siRNAs co-transfection showed opposite effect. Oleuropein showed anti-carcinogenic impact by decreasing miR-194 and PD-L1 levels while increasing XIST level. In conclusion, our study highlighted novel ceRNA interaction controlling PD-L1 expression in BC. Oleuropein is a promising nutraceutical for cancer therapy. Therefore, oleuropin represents a new nutri-epigenetic in immune-oncology that controls miR-194/XIST/PD-L1 loop in triple negative breast cancer.