Abstract
Bone sarcomas such as osteosarcoma and chondrosarcoma are frequently refractory to conventional chemotherapy and radiotherapy that exhibit poor prognosis. The Wnt signaling are evolutionarily conserved and implicated in cell proliferation and sarcomagenesis. However, the potential role of the Wnt signaling in bone sarcomas is still unclear. Here we demonstrate aberrant activation of Wnt/β-catenin signaling in bone sarcoma cells, involving an autocrine Wnt signaling loop with upregulation of specific Wnt ligands and receptors. Activation of Wnt/β-catenin signaling with Wnt3a or GSK-3β inhibitor drives the proliferation of bone sarcoma cells, whereas downregulation of activated Wnt signaling with dnTCF4 or siLEF1 suppresses bone sarcoma proliferation and induces cell cycle arrest. Taken together, our findings establish the evidence that aberrant activation of Wnt/β-catenin pathway involving an autocrine Wnt singaling drives the proliferation of bone sarcoma cells, and identify the autocrine activation of the Wnt/β-catenin signaling as a potential novel therapeutic target for bone sarcomas.
Highlights
Osteosarcomas and chondrosarcomas are recognized as the most common primary bone sarcomas [1], which involve mesenchymal tissues and exhibit highly heterogeneous histologic and molecular profiles [2]
These findings indicated that bone sarcoma cell lines were equipped with the differential expression of several canonical and noncanonical Wnt signaling ligands, and Wnt ligand expression in bone sarcoma cells is dominated by canonical Wnt ligands, strongly suggesting a liganddependent activation of canonical Wnt/β-catenin signaling in human bone sarcomas
Our present findings have established that constitutive activation of the canonical Wnt/β-catenin signaling in human bone sarcoma cells, by a novel mechanism involving an autocrine Wnt signaling loop, drives the proliferation of bone sarcoma cells
Summary
Osteosarcomas and chondrosarcomas are recognized as the most common primary bone sarcomas [1], which involve mesenchymal tissues and exhibit highly heterogeneous histologic and molecular profiles [2]. DKK1, as a Wnt antagonist and a downstream target of the β-catenin/TCF in a negative feedback loop [12], disrupts Wnt-induced FzLRP6 complex formation and inhibits canonical Wnt signaling [6, 13]. Another class of Wnt antagonists, FRPs, binds to and sequesters Wnts, blocking both canonical and noncanonical Wnt signaling [14]. The Wnt signaling is involved in the maintenance of normal tissue and the developmental pathways that regulate the self-renewal and differentiation of mesenchymal stem cells (MSCs) [15, 16]. All these findings have implied that the Wnt signaling is implicated in cell fate determination, differentiation, proliferation and apoptosis during development
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