Tumor exosomal circPTBP3 drives gastric cancer peritoneal metastasis via mesothelial-mesenchymal transition

The peritoneum is the most common site of metastasis in advanced gastric cancer (GC), and the mechanisms underlying this process of gastric cancer peritoneal metastasis (GCPM) remain largely elusive. Mesothelial-mesenchymal transition (MMT) plays a crucial role in the progression of GCPM. In our current study, the data confirmed that GC-derived exosomes could significantly promote peritoneal metastasis through an MMT-dependent manner in vivo and in vitro. Using RNA-seq, we successfully identified a key circular RNA (circPTBP3). The expression of exosomal circPTBP3 in the plasma of GCPM patients was significantly upregulated and closely correlated with tumor differentiation, depth of invasion, lymphatic invasion, peritoneal metastasis, and TNM stage. Exosomal circPTBP3 thus serves as a reliable diagnostic and prognostic indicator in GCPM patients. Mechanistically, exosomal circPTBP3 could effectively promote the MMT phenotype of mesothelial cells in vitro. Located in the nucleus, circPTPB3 was found to recruit transcription factor AP-2-beta (TFAP2B) to the serum- and glucocorticoid-inducible kinase 1 (SGK1) promoter sites, thereby initiating its transcription in mesothelial cells. These findings suggest that exosomal circPTPB3 functions as a pivotal mediator in facilitating the interplay between GC cells and mesothelial cells, and it provides a promising diagnostic indicator and therapeutic target for GCPM patients.