Lingyu Qian1,2, Fangcen Liu3, Yanhong Chu1, Qingqing Zhai1, Xiao Wei3, Jie Shao1, Rutian Li1, Qiuping Xu1, Lixia Yu1, Baorui Liu1, Qin Liu1. 1. The Comprehensive Cancer Centre of Drum Tower Hospital, Nanjing University Medical School & Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China. 2. Department of Oncology, Rudong Peoples' Hospital of Jiangsu Province, Nantong, People's Republic of China. 3. Department of Pathology, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, People's Republic of China.
Abstract
INTRODUCTION: Immuno-checkpoint inhibitors (ICIs) in advanced gastric cancer either as monotherapy or in combining strategies are rapidly evolving but still in early phase. Various efforts have been made to provide insights into regulating immune checkpoint molecule programmed cell death ligand-1 (PD-L1) expression to improve ICIs efficacy. The aim of this study was to investigate the effect and potential mechanism of miR-200c nanoparticles combined with radiotherapy in gastric cancer cells. METHODS: We prepared miR-200c-loaded nanoparticles (miR-200c NPs) to achieve targeted delivery of miR-200c to AGS cells. The roles of miR-200c NPs and radiotherapy in regulating the viability of AGS cells were assessed by CCK-8 toxicity test and Annexin V-FITC/PI apoptosis kit. Flow cytometry was used to analyze expression of PD-L1 and CD44 on the surface of AGS cells treated by miR-200c NPs and/or ionizing radiation. Enzyme-linked immunosorbent assay (ELISA) was used to test the level of transforming growth factor-beta 1 (TGF-β1) secreted by AGS cells. The cooperation mechanism between miR-200c NPs and radiotherapy was also explored in vitro. RESULTS: Compared with naked miR-200c mimics, miR-200c NPs significantly downregulated PD-L1 expression of gastric cancer cells. The combination of miR-200c NPs and radiotherapy showed significantly synergistic inhibitory effect on gastric cancer cells by inhibiting immune escape mediated by PD-L1, reversing EMT phenotype as well as abrogating cancer stem cells (CSCs)-associated properties of tumor cells. CONCLUSION: MiR-200c NPs sensitized gastric cancer cells to radiotherapy by regulating PD-L1 expression and EMT.
INTRODUCTION: Immuno-checkpoint inhibitors (ICIs) in advanced gastric cancer either as monotherapy or in combining strategies are rapidly evolving but still in early phase. Various efforts have been made to provide insights into regulating immune checkpoint molecule programmed cell death ligand-1 (PD-L1) expression to improve ICIs efficacy. The aim of this study was to investigate the effect and potential mechanism of miR-200c nanoparticles combined with radiotherapy in gastric cancer cells. METHODS: We prepared miR-200c-loaded nanoparticles (miR-200c NPs) to achieve targeted delivery of miR-200c to AGS cells. The roles of miR-200c NPs and radiotherapy in regulating the viability of AGS cells were assessed by CCK-8 toxicity test and Annexin V-FITC/PI apoptosis kit. Flow cytometry was used to analyze expression of PD-L1 and CD44 on the surface of AGS cells treated by miR-200c NPs and/or ionizing radiation. Enzyme-linked immunosorbent assay (ELISA) was used to test the level of transforming growth factor-beta 1 (TGF-β1) secreted by AGS cells. The cooperation mechanism between miR-200c NPs and radiotherapy was also explored in vitro. RESULTS: Compared with naked miR-200c mimics, miR-200c NPs significantly downregulated PD-L1 expression of gastric cancer cells. The combination of miR-200c NPs and radiotherapy showed significantly synergistic inhibitory effect on gastric cancer cells by inhibiting immune escape mediated by PD-L1, reversing EMT phenotype as well as abrogating cancer stem cells (CSCs)-associated properties of tumor cells. CONCLUSION: MiR-200c NPs sensitized gastric cancer cells to radiotherapy by regulating PD-L1 expression and EMT.
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