Dkk-3, a Secreted Wnt Antagonist, Suppresses Tumorigenic Potential and Pulmonary Metastasis in Osteosarcoma

Abstract EN

Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis.

Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the past 2 decades.

Dickkopf-3 protein (Dkk-3/REIC) has been known to inhibit canonical Wnt/β-catenin pathway, and its expression has been shown to be downregulated in OS cell lines.

Using in vivo and in vitro studies, we demonstrated that Dkk-3-transfected 143B cells inhibited tumorigenesis and metastasis in an orthotopic xenograft model of OS.

Inoculation of Dkk-3-transfected 143B cell lines into nude mice showed significant decreased tumor growth and less metastatic pulmonary nodules (88.7%) compared to the control vector.

In vitro experiments examining cellular motility and viability demonstrated less anchorage-independent growth and decreased cellular motility for Dkk-3-transfected 143B and SaOS2 cell lines compared to the control vector.

Downstream expressions of Met, MAPK, ALK, and S1004A were also downregulated in Dkk-3-transfected SaOS2 cells, suggesting the ability of Dkk-3 to inhibit tumorigenic potential of OS.

Together, these data suggest that Dkk-3 has a negative impact on the progression of osteosarcoma.

Reexpressing Dkk-3 in Dkk-3-deficient OS tumors may prove to be of benefit as a preventive or therapeutic strategy.