Exosomal CircPRRX1 Enhances Doxorubicin Resistance in Gastric Cancer by Regulating MiR-3064-5p/PTPN14 Signaling

Abstract

Purpose Gastric cancer (GC) is a malignant tumor with a high mortality rate. Drug resistance is a major obstacle to GC therapy. This study aimed to investigate the role and mechanism of exosomal circPRRX1 in doxorubicin resistance in GC. Materials and Methods HGC-27 and AGS cells were exposed to different doses of doxorubicin to construct doxorubicin-resistant cell lines. Levels of circPRRX1, miR-3064-5p, and nonreceptor tyrosine phosphatase 14 (PTPN14) were detected by quantitative real-time PCR or Western blot assay. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, transwell, and Western blot assays were used to explore the function of circPRRX1 in GC cells. Interactions among circPRRX1, miR-3064-5p, and PTPN14 were confirmed by dual-luciferase reporter assay. The in vivo function of circPRRX1 was analyzed in a xenograft tumor model. Results CircPRRX1 was highly expressed in doxorubicin-resistant GC cell lines. Knockdown of circPRRX1 reversed doxorubicin resistance in doxorubicin-resistant GC cells. Additionally, extracellular circPRRX1 was carried by exosomes to spread doxorubicin resistance. CircPRRX1 silencing reduced doxorubicin resistance by targeting miR-3064-5p or regulating PTPN14. In GC patients, high levels of circPRRX1 in serum exosomes were associated with poor responses to doxorubicin treatment. Moreover, depletion of circPRRX1 reduced doxorubicin resistance in vivo. Conclusion CircPRRX1 strengthened doxorubicin resistance by modulating miR-3064-5p/PTPN14 signaling and might be a therapeutic target for GC patients.

Exosome-derived noncoding RNAs in gastric cancer: functions and clinical applications

“…In addition, exosome-derived miR-155-5p is efficiently taken up by MGC-803 cells, which were sensitive to paclitaxel, subsequently inducing paclitaxel-resistance in an autocrine manner [84]. A high level of circPRRX1 expression was observed in HGC-27 and AGS doxorubicin-resistant GC cell lines, and further research showed that circPRRX1 spread doxorubicin resistance via exosomes [85]. In addition, mechanistic assays found that circPRRX enhanced doxorubicin resistance by sponging miR-3064-5p or regulating expression levels of PTPN14.…”

MiR-3064 in Epicardial Adipose-Derived Exosomes Targets Neuronatin to Regulate Adipogenic Differentiation of Epicardial Adipose Stem Cells

“…At present, there are relatively few research reports on miR-3064-5p, and the studies mainly focus on tumor-related fields. In our study, we noticed that miR-3064-5p was significantly up-regulated in EAT-derived exosomes from CAHD patients, and its inhibitor could obviously improve the inhibitory effect of CAHD-derived exosomes on the adipogenic differentiation of EASCs ( 13 , 14 ). Further analysis showed that Nnat is the target gene of miR-3064-5p in EASCs.…”

The Sensitivity Prediction of Neoadjuvant Chemotherapy for Gastric Cancer

“…Furthermore, it was reported that exosome miR-155-5p directly inhibits GATA3 (GATA binding protein 3) and TP53INP1 (tumor protein p53-induced nuclear protein 1) to induce paclitaxel resistant GC cells to sensitive ones (67). And Wang SM (68) found that exosomal circPRRX1 (circular paired-related homeobox 1) strengthened doxorubicin resistance of GC cells by modulating miR-3064-5p/PTPN14 (non-receptor tyrosine phosphatase 14) signaling pathway.…”