NR2F2-AS1 Suppressed Trastuzumab Effects on Esophageal Cancer By Inhibiting miR-4429 and miR-425-5p Expression Through Targeting IGF1R

Aim: In this manuscript, we aimed to investigate the involvement of non-coding RNAs in mediating trastuzumab effects in EAC. Background: Scarce evidences supported that targeted drugs, like Trastuzumab, can be applied to esophageal adenocarcinoma patients (EAC). Objective: Evaluating the role and mechanism of NR2F2-AS1 in regulating Trastuzumab effects in EAC patients. Method: RNA sequencing to screen IGF1R related lncRNAs. qRT-PCR and western blot were used to evaluate the expression level of genes. CCK-8 was used to test the cell proliferation ability. Dual luciferase reporter gene assay and RNA pull-down were used for crosstalk evaluation. Results: : NR2F2-AS1 was identified to be associated with HER2 expression by RNA sequencing and its expression related to worse prognosis and advanced T and N stage.NR2F2-AS1 expression induced by Trastuzumab through mediating H3K27ac. Furtherly, miR-4429 and miR-425-5p, which were predicted and proved to interact with NR2F2-AS1 and IGF1R, expressed lowly in esophageal cancer both in vivo and in vitro and suppressed cell viability. Most importantly, miR-4429 and miR-425-5p overexpression could increase trastuzumab’s inhibitory effect on cell viability. Conclusion: Trastuzumab has the potential to suppress EAC progression mainly in the presence of miR-4429 and miR-425-5p overexpression targeting HER2. However, Trastuzumab induces exosomal NR2F2-AS1 expression, which binds to miR-4429 and miR-425-5p to suppress their expression, resulting in the failure of trastuzumab treatment. Therefore, targeting exosomes might be a novel way to develop auxiliary drugs for trastuzumab in EAC.