Exosome‐transmitted miR‐769‐5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53

Abstract

Background Cisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism underlying cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participate in tumor metastasis and drug resistance. Methods Exosomes isolated from BGC823 and BGC823/DDP culture medium were characterized by transmission electron microscopy and differential ultracentrifugation, and miRNA expression profiles of BGC823 and BGC823/DDP cells derived exosomes were analyzed using miRNA microarray. In vivo and in vitro assays were used to identify roles of exosomal miR‐769‐5p and clarify the mechanism of exosomal miR‐769‐5p regulated the crosstalk between sensitive and resistant GC cells. Results In this study, we found that cisplatin‐resistant GC cells communicated with the tumor microenvironment by secreting microvesicles. MiR‐769‐5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin‐resistant patients. The biologically active miR‐769‐5p could be integrated into exosomes and delivered to sensitive cells, spreading cisplatin resistance. Underlying cellular and molecular mechanism was miR‐769‐5p targeting CASP9, thus inhibiting the downstream caspase pathway and promoting the degradation of the apoptosis‐related protein p53 through the ubiquitin‐proteasome pathway. Targeting miR‐769‐5p with its antagonist to treat cisplatin‐resistant GC cells can restore the cisplatin response, confirming that exosomal miR‐769‐5p can act as a key regulator of cisplatin resistance in GC. Conclusions These findings indicate that exosome‐transmitted miR‐769‐5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53. These findings reveal exosomal miR‐769‐5p derived from drug‐resistant cells can be used as a potential therapeutic predictor of anti‐tumor chemotherapy to enhance the effect of anti‐cancer chemotherapy, which provides a new treatment option for GC.

Study of Drug Resistance in Chemotherapy Induced by Extracellular Vesicles on a Microchip

“…Over the past decades, considerable attention has been paid to the effect of EV-mediated drug resistance. , However, the drug resistance caused by cell-to-cell transmission through EVs still needed to be further explored. Through the above off-chip experiments, we verified that EVs are the main factor inducing drug resistance in susceptible cells.…”

Comprehensive analysis illustrating the role of PANoptosis-related genes in lung cancer based on bioinformatic algorithms and experiments

“…Wang et al revealed that the TNFRSF1A might exert as a prognosis and immune infiltration biomarker for the glioblastoma multiforme ( Wang et al, 2022b ). Using a cellular mechanism that involves targeting CASP9 and enhancing the ubiquitination degradation of p53, Jing et al observed the exosome-transmitted miR-769-5p imparts cisplatin resistance and gastric cancer progression ( Jing et al, 2022 ). Li et al revealed that LINC00607 could facilitate thyroid cancer progression by regulating the CASP9 promoter methylation ( Li et al, 2021 ).…”

Extracellular Vesicles in Cancer Drug Resistance: Roles, Mechanisms, and Implications

“…[ 112 ] Jing et al suggest that miR‐769‐5p is highly expressed in serum exosomes of cisplatin‐resistant patients and exosomal miR‐769‐5p targets CASP9 to suppress caspase pathway activation and p53 stability. [ 113 ] Exosomal miR‐501 confers resistance to DOX in sensitive gastric cancer cells via inhibition of apoptosis and exosomal miR‐155‐5p from PTX‐resistant gastric cancer cells induce chemoresistance in the sensitive cells by targeting GATA3 and TP53INP1. [ 114 ] The levels of exosomal miR‐1238 are higher in TMZ‐resistant GBM cells than sensitive cells and exosomal miR‐1238 induces TMZ resistance by targeting caveolin‐1.…”