ROR2 regulates the survival of murine osteosarcoma cells in lung capillaries

Abstract

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.

Keywords

Osteosarcoma / lung metastasis / cell survival / lung capillary / ROR2

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