Paclitaxel-resistant gastric cancer MGC-803 cells promote epithelial-to-mesenchymal transition and chemoresistance in paclitaxel-sensitive cells via exosomal delivery of miR-155-5p

Abstract

Paclitaxel is a first-line chemotherapeutic agent for gastric cancer; however, resistance limits its effectiveness. Investigation into the underlying mechanisms of paclitaxel resistance is urgently required. In the present study, a paclitaxel-resistantgastriccancercellline(MGC-803R)wasgenerated with a morphological phenotype of epithelial-to-mesenchymal transition (EMT) and increased expression levels of microRNA (miR)-155-5p. MGC-803R cell-derived exosomes were effectively taken up by paclitaxel-sensitive MGC-803S cells, which exhibited EMT and chemoresistance phenotypes. miR-155-5p was enriched in MGC-803R-exosomes and could be delivered into MGC-803S cells. miR-155-5p overexpression in MGC-803S cells via transfection with mimics resulted in similar phenotypic effects as treatment with MGC-803R exosome and increased miR-155-5p content in MGC-803S exosomes, which then capable of inducing the malignant phenotype in the sensitive cells. GATA binding protein 3 (GATA3) and tumor protein p53-inducible nuclear protein 1 (TP53INP1) were identified as targets of miR-155-5p. Exosomal miR-155-5p inhibited these targets by directly targeting their 3' untranslated regions. Knockdown of miR-155-5p was observed to reverse the EMT and chemoresistant phenotypes of MGC-803R cells, potentially via GATA3 and TP53INP1 upregulation, which inhibited MGC-803R-exosomes from inducing the malignant phenotype. These results demonstrated that exosomal delivery of miR-155-5p may induce EMT and chemoresistant phenotypes from paclitaxel-resistant gastric cancer cells to the sensitive cells, which may be mediated by GATA3 and TP53INP1 suppression. Targeting miR-155-5p may thus be a promising strategy to overcome paclitaxel resistance in gastric cancer.