-RAMP3 promotes hepatocellular carcinoma tumor cell-mediated CCL2 degradation by supporting membrane distribution of ACKR2.

This study aimed to explore the potential bind of Receptor Activity-Modifying Protein 3 (RAMP3) with atypical chemokine receptor 2 (ACKR2), and their cooperative regulation on the degradation of the immunosuppressive chemokine CCL2 in the tumor microenvironment of HCC. Bioinformatic analysis was conducted using available bulk-tissue RNA-seq, single-cell RNA-seq, and protein-protein interaction datasets. Human HCC cell line Huh7 and HepG2 and mouse HCC cell line Hepa1-6 were utilized for experiments. Results showed that RAMP3 binds with ACKR2 in HCC tumor cells and promotes the membrane distribution of ACKR2 through RAB4-positive vesicles. RAMP3 promotes CCL2 scavenging through ACKR2 in HCC cells. Mouse RAMP3 inhibited the proliferation of mouse liver cancer cell line (Hepa1-6)-derived syngeneic tumors through ACKR2, reduced the intratumoral concentration of CCL2 in the tumor, and inhibited the phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and protein kinase B (AKT). In addition, mouse RAMP3 inhibited CD11b+/Gr-1 + myeloid cell infiltration and neovascularization in the tumors through ACKR2. In TCGA-LIHC, RAMP3 ^low /ACKR2 ^low group had the worst progression-free interval (PFI), while the RAMP3 ^high /ACKR2 ^high group had the best overall survival (OS). In summary, restoring RAMP3 expression in HCC cells may generate synergistic support for the anticancer effect of ACKR2.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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