ROR2 regulates the survival of murine osteosarcoma cells in lung capillaries

Aim:Lung metastasis is a leading cause of death in patients with osteosarcoma(OS).No effective therapy exists that improves the five-year overall survival rate of OS patients with metastasis.Therefore,finding novel therapeutic targets will help develop new treatment strategies for OS patients with lung metastasis.Methods:Based on analysis of gene expression profiles between sublines of the Dunn OS LM8 cell line with high(LM8-H)and low(LM8-L)metastatic ability,we have identified Wnt signal-related genes that play an important role in lung metastasis of OS.Function of the genes was investigated by establishing sublines of gene knockout and assessing their metastatic ability using a mouse lung metastasis model.The molecular mechanism underlying the function of the genes was further investigated by in vitro experiments.Results:We have identified that receptor tyrosine kinase-like orphan receptor 2(ROR2),a receptor of the non-canonical Wnt signaling pathway,was involved in OS cell survival in lung capillaries during metastasis.LM8-H knocked out of Ror2(H/Ror2-KO)significantly reduced lung metastasis by decreasing the viability in lung capillaries 48 h after intravenous injection.In vitro study revealed that ROR2 increased anoikis resistance through AKT activation.Reconstitution of ROR2 expression in H/Ror2-KO cells restored their metastatic ability and viability in lung capillaries.Conclusion:The results demonstrate a novel ROR2 function in OS lung metastasis and may inform new treatment strategies for OS patients.