Exosomal hsa_circ_0004658 derived from RBPJ overexpressed-macrophages inhibits hepatocellular carcinoma progression via miR-499b-5p/JAM3

Macrophage-derived exosomes (M phi-Exo) have multidimensional involvement in tumor initiation, progression, and metastasis, but their regulation in hepatocellular carcinoma (HCC) is not fully understood. RBPJ has been implicated in macrophage activation and plasticity. In this study we assess the role of exosomes derived from RBPJ-overexpressed macrophages (RBPJ(+/+) M phi-Exo) in HCC. The circular RNA (circRNA) profiles in RBPJ(+/+) M phi-Exo and THP-1-like macrophages (WT M phi)-Exo was evaluated using circRNA microarray. CCK-8, Transwell, and flow cytometry analyses were used to evaluate the function of M phi-Exo-circRNA on HCC cells. Luciferase reporter assays, RNA immunoprecipitation, and Pearson's correlation analysis were used to confirm interactions. A nude mouse xenograft model was used to further analyze the functional significance of M phi-Exo-cirRNA in vivo. Our results shown that hsa_circ_0004658 is upregulated in RBPJ(+/+) M phi-Exo compared to WT M phi-Exo. RBPJ(+/+) M phi-Exo and hsa_circ_0004658 inhibits proliferation and promotes apoptosis in HCC cells, whereas hsa_circ_0004658 knockdown stimulated cell proliferation and migration but restrained apoptosis in vitro and promotes tumor growth in vivo. The effects of RBPJ(+/+) M phi-Exo on HCC cells can be reversed by the hsa_circ_0004658 knockdown. Mechanistic investigations revealed that hsa_circ_0004658 acts as a ceRNA of miR-499b-5p, resulting in the de-repression of JAM3. These results indicate that exosome circRNAs secreted from RBPJ(+/+) M phi inhibits tumor progression through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway and hsa_circ_0004658 may be a diagnostic biomarker and potential target for HCC therapy.

Automated summary

In this study, the researchers found that exosomes derived from macrophages with overexpressed RBPJ can inhibit the progression of hepatocellular carcinoma through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway. The findings suggest that hsa_circ_0004658 could serve as a diagnostic biomarker and potential therapeutic target for HCC.