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

Abstract

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.

Mesenchymal Tumors Can Derive from Ng2/Cspg4-Expressing Pericytes with β-Catenin Modulating the Neoplastic Phenotype

“…4C and D). While both activation or inactivation of β-catenin transcription in sarcomas have been reported (Dieudonne et al, 2010; Hoang et al, 2004; Iwao et al, 1999; Iwaya et al, 2003; Lin et al, 2013; Matushansky et al, 2007; Sakamoto et al, 2002; Wan et al, 2014), our data showed that β-catenin mediated transcription was inactivated in both the bone and soft tissue sarcomas compared to the Ng2/Cspg4 expressing cells.…”

Oridonin inhibits the proliferation of human osteosarcoma cells by suppressing Wnt/β-catenin signaling

“…In addition to GSK-3β, other natural Wnt antagonists have been identified, including the Dickkopf (Dkk) family consisting of four secretory proteins (Dkk-1, Dkk-2, Dkk-3, and Dkk-4) (47,48). Dkk-3 has been shown to have a negative impact on the progression of OS (49,50). To further explore the mechanism underlying the regulatory role of ORI in Wnt/β-catenin signaling, we examined whether Dkks could be influenced by ORI.…”

Enrichment of human osteosarcoma stem cells based on hTERT transcriptional activity

“…These findings provide evidence that a telomerase inhibitor can be preferentially effective in CSCs. It is reported that TERT promotes epithelial proliferation through Myc- and Wnt-related pathways [45], and the Wnt pathway has also been shown to be involved in osteosarcoma pathogenesis [46, 47]. Due to the facts that (i): The MST312 dose used in this study was nontoxic [44]; and (ii): the short duration of treatment, we believe that the effects observed here are mostly due to inhibition of proliferation and self-renewal, and independent of telomere-maintenance.…”