AUTHOR=Lv Jinqi , Guo Tianshu , Qu Xiujuan , Che Xiaofang , Li Ce , Wang Shuo , Gong Jing , Wu Peihong , Liu Yang , Liu Yunpeng , Xu Ling 

TITLE=PD-L1 Under Regulation of miR-429 Influences the Sensitivity of Gastric Cancer Cells to TRAIL by Binding of EGFR

JOURNAL=Frontiers in Oncology

VOLUME=Volume 10 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.01067

DOI=10.3389/fonc.2020.01067

ISSN=2234-943X

ABSTRACT=TRAIL has received extensive attention as a cancer therapeutic due to its high propensity for tumor targeting with minimal toxicity to healthy tissue. Gastric cancer (GCa) cells show high levels of TRAIL resistance. EGFR antagonizes TRAIL-induced apoptosis, but the mechanisms of these effects remain unclear. Our past research confirms TRAIL resistant (BGC823 and SGC7901) and TRAIL sensitive cells (HGC27 and MKN45). MiR-429 associated with TRAIL sensitivity was screened using microRNA arrays. The transfection of mimics and inhibitors confirmed that miR-429 negatively correlated with GCa TRAIL resistance. The target gene of miR-429 was identified as PD-L1 which positively correlated with TRAIL resistance through gene silencing and recovery experiments. Using CO-Ips and proximity ligation assay, we demonstrated that the pro-survival effects of PD-L1 are mediated through the binding and activation of EGFR. Cell viability experiments demonstrated that PD-L1 is key to the maintenance of cell viability in TRAIL treated cells. This indicated that PD-L1 binds to and participates in EGFR activation through miR-429 regulation to antagonize TRAIL-induced apoptosis. This provides a new theoretical basis for the combination of the EGFR monoclonal antibodies including cetuximab, PD-L1 inhibitors and human recombinant TRAIL in gastric cancer therapy, and can filter patients who are currently sensitive to TRAIL treatment.