Journal
ONCOTARGET
Volume 6, Issue 19, Pages 17570-17583Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4100
Keywords
bone sarcomas; Wnt/beta-catenin signaling; autocrine wnt activation; cell proliferation; therapeutic target
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Funding
- National Natural Sciences Foundation of China [81102037, 30670802]
- Ministry of Science and Technology of China (973 Program) [2009CB918903]
- Ministry of Science and Technology of China (Essential Drug Research and Development) [2014ZX09101005-004]
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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/beta-catenin signaling in bone sarcoma cells, involving an autocrine Wnt signaling loop with upregulation of specific Wnt ligands and receptors. Activation of Wnt/beta-catenin signaling with Wnt3a or GSK-3 beta 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/beta-catenin pathway involving an autocrine Wnt singaling drives the proliferation of bone sarcoma cells, and identify the autocrine activation of the Wnt/beta-catenin signaling as a potential novel therapeutic target for bone sarcomas.
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