Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (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. Epidermal growth factor receptor (EGFR) antagonizes TRAIL-induced apoptosis, but the mechanisms of these effects remain unclear. Our past research confirmed 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-immunoprecipitation (co-IP) 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.
Highlights
Gastric cancer (GCa) remains prevalent across the globe for which current treatment strategies are lacking
MiR-429/PD-L1/Epidermal growth factor receptor (EGFR) Axis in Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) Sensitivity miR-429 Expression Correlates With the TRAIL Sensitivity of GCa Cells
GCa cells are resistant to TRAIL, it represents a promising tumor treatment due to its tumor killing selectivity and low levels of toxicity to healthy tissues
Summary
Gastric cancer (GCa) remains prevalent across the globe for which current treatment strategies are lacking. The outcomes are poor, with median survival rates of ∼1 year [1]. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily (TNFSF) that acts as an agonist for DR4 and DR5 to transfer extracellular death signals for cancer therapy [2]. In the clinic, the effectiveness of TRAIL has been suboptimal primarily due to [5] tumor resistance, the mechanisms of which are incompletely understood. The ability to overcome TRAIL resistance would represent a step change in the treatment of GCa [6, 7]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.