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Research of the mechanism on miRNA193 in exosomes promotes cisplatin resistance in esophageal cancer cells.

ABSTRACT: PURPOSE:Chemotherapy resistance of esophageal cancer is a key factor affecting the postoperative treatment of esophageal cancer. Among the media that transmit signals between cells, the exosomes secreted by tumor cells mediate information transmission between tumor cells, which can make sensitive cells obtain resistance. Although some cellular exosomes play an important role in tumor's acquired drug resistance, the related action mechanism is still not explored specifically. METHODS:To elucidate this process, we constructed a cisplatin-resistant esophageal cancer cell line, and proved that exosomes conferring cellular resistance in esophageal cancer can promote cisplatin resistance in sensitive cells. Through high-throughput sequencing analysis of the exosome and of cells after stimulation by exosomes, we determined that the miRNA193 in exosomes conferring cellular resistance played a key role in sensitive cells acquiring resistance to cisplatin. In vitro experiments showed that miRNA193 can regulate the cell cycle of esophageal cancer cells and inhibit apoptosis, so that sensitive cells can acquire resistance to cisplatin. An in vivo experiment proved that miRNA193 can promote tumor proliferation through the exosomes, and provide sensitive cells with slight resistance to cisplatin. RESULTS:Small RNA sequencing of exosomes showed that exosomes in drug-resistant cells have 189 up-regulated and 304 down-regulated miRNAs; transcriptome results showed that drug-sensitive cells treated with drug-resistant cellular exosomes have 3446 high-expression and 1709 low-expression genes; correlation analysis showed that drug-resistant cellular exosomes mainly affect the drug resistance of sensitive cells through paths such as cytokine-cytokine receptor interaction, and the VEGF and Jak-STAT signaling pathways; miRNA193, one of the high-expression miRNAs in drug-resistant cellular exosomes, can promote drug resistance by removing cisplatin's inhibition of the cell cycle of sensitive cells. CONCLUSION:Sensitive cells can become resistant to cisplatin through acquired drug-resistant cellular exosomes, and miRNA193 can make tumor cells acquire cisplatin resistance by regulating the cell cycle.

SUBMITTER: Shi S

PROVIDER: S-EPMC7199973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundsCancer cell resistance to chemotherapy drugs such as Gemcitabine, Oxaliplatin, Cisplatin, Doxorubicin, and 5-fluorouracil account for the main reason of chemotherapy failure for HCC patients, especially for those with advanced HCC or metastasis patients. This emerging resistance limits the effectiveness and clinical application of these chemotherapy drugs. Previous studies reported that drug-resistant tumor cell-derived exosomes could transfer their resistance property to tumor sensitive cells in some cancer, including lung and gastric cancer. This study sought to explore whether HepG2/DDP cell-derived exosomes transmit cisplatin (DDP) resistance to HepG2 and other HCC sensitive cells, and provide considerable guidance for HCC nursing with Cisplatin DDP clinically.MethodsThe HepG2 DDP-resistant cell line (HepG2/DDP) was established, and the exosomes from both HepG2/DDP and HepG2 cells were isolated and named ES-2, ES-1, respectively. HepG2 or SMMC-7721 or Huh7 cells were treated with DDP or DDP + ES-2, and HepG2/DDP cells were treated with ES-1. Then, the activation of drug resistance via HepG2/DDP exosomes transfer to HepG2, SMMC-7721 and Huh7 cells were assessed by cell viability assay and ROS formation. Moreover, the relative expression of P-glycoprotein (P-gp) was measured by western blot analysis.ResultsHepG2/DDP cell-derived exosomes were successfully isolated from cisplatin-resistant HepG2 cells, and named ES-2. Cell viability of HepG2 or SMMC-7721 or Huh7 cells treated with DDP + ES-2 was enhanced compared with that of DDP treatment group. Also, the concentration of ROS generated in cells under DDP or DDP + ES-2 treatment was strongly increased compared with that of control, although the concentration of ROS was clearly smaller in DDP + ES-2 treatment group compared with DDP treatment. At the same time, the expression of P-gp was upregulated on the ES-2 surface.ConclusionThe results mentioned above clarified that HepG2/DDP cell-derived exosomes conferred cisplatin resistance to HepG2 and other HCC cell lines, and provided a new significance for improving the effectiveness of DDP in treating HCC.

Project description:Platinum?containing doublet chemotherapy is the cornerstone of lung cancer treatment; however, cisplatin resistance is a major obstacle in the treatment of lung cancer. However, the mechanism underlying this resistance has not been fully elucidated. Previous studies have shown that serum apurinic/apyrimidinic endonuclease 1 (APE1) levels in patients with NSCLC are inversely associated with progression?free survival after platinum?containing doublet chemotherapy, and can serve as a biomarker for predicting disease prognosis and treatment efficacy. The present study was designed to investigate the role played by APE1 in the resistance of lung cancer to cisplatin. The levels of mitochondrial apurinic endonuclease 1 (m?APE1) and total APE1 (t?APE1) protein in a cisplatin?resistant A549 cell line (A549/DDP) and cisplatin?sensitive A549 cells were analyzed by western blotting. Mitochondrial membrane potential was detected by using the JC?1 staining method. The cisplatin?resistance of APE1?overexpressing A549 cells and APE1?silenced A549/DDP cells was assessed by cell apoptosis and colony formation assays. The results revealed that cisplatin?resistant A549 cells contained high levels of APE1, and exhibited elevated levels of autophagy. The levels of m?APE1 and t?APE1 protein were increased in the A549/DDP cells when compared with these levels in the A549 cells. Overexpression of APE1 and Mia40 enhanced the cisplatin resistance and autophagy of the A549 cells. APE1 knockdown restored the cisplatin sensitivity and reduced the levels of LC3II and Parkin in the A549/DDP cells, but promoted the release of cytochrome c. Furthermore, Parkin silencing or treatment with 3?methyladenine (3?MA, an autophagy inhibitor) promoted the apoptosis of APE1?overexpressing A549 cells, indicating that Parkin?mediated mitophagy plays an important role in the APE1?induced cisplatin resistance of A549 cells. In conclusion, APE1 promotes the cisplatin resistance of lung cancer cells by inducing Parkin?mediated mitophagy.

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Research of the mechanism on miRNA193 in exosomes promotes cisplatin resistance in esophageal cancer cells.

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