CXCR7 promoted proliferation, migration and invasion in HCC Cells by inactivating Hippo-YAP signaling.

BACKGROUND: CXCR7 (ACKR3) has been well-supported as a promoter of growth and metastasis in hepatocellular carcinoma (HCC). Both CXCR7 and Hippo signaling play roles in organ development. We aimed to verify the involvement of Hippo-YAP signaling in CXCR7-regulated HCC proliferation, migration, and invasion. METHODS: HCCLM3 cells were transfected with si-CXCR7, pcDNA-CXCR7, or related control RNA/empty vector. Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8), and mRNA and protein levels were measured via quantitative real-time PCR (qPCR) and Western blotting. Colony formation assays were conducted to evaluate proliferation capacity, and Transwell assays were used to assess invasion and migration. Transcriptome data from the TCGA-LIHC dataset were analyzed to investigate the potential effects of CXCR7 in HCC. RESULTS: si-CXCR7 inhibited cell proliferation in HCCLM3 cells, while pcDNA-CXCR7 promoted it. Migration and invasion were suppressed by si-CXCR7 but enhanced by pcDNA-CXCR7. Patients with higher CXCR7 expression in the TCGA-LIHC dataset had lower overall survival rates and increased gene transcription. The CXCR7-high expressing samples were characterized by the activation of several pathways, including PI3K-AKT signaling, calcium signaling, and the Hippo signaling pathway. si-CXCR7 reduced the relative protein levels of Gαq/11 and GαS while increasing phosphorylated LATS and phosphorylated YAP. Opposite trends in these proteins were observed with pcDNA-CXCR7. Finally, the inhibitory effects of si-CXCR7 on cell proliferation, migration, and invasion were reversed by the YAP inhibitor verteporfin. CONCLUSION: We suggest that CXCR7 promotes the growth and metastasis of HCC cells, at least in part, by inactivating the Hippo-YAP signaling pathway.