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.