High Wnt signaling represses the proapoptotic proteoglycan syndecan-2 in osteosarcoma cells.

Abstract

Osteosarcoma is characterized by frequent relapse and metastatic disease associated with resistance to chemotherapy. We previously showed that syndecan-2 is a mediator of the antioncogenic effect of chemotherapeutic drugs. The purpose of this work was to elucidate molecular mechanisms responsible for the low expression of syndecan-2 in osteosarcoma. We compared the regulatory activity of cis-acting DNA sequences of the syndecan-2 gene in osteosarcoma and osteoblastic cell lines. We identified a DNA region that negatively regulates syndecan-2 transcription in the osteosarcoma cells. T-cell factors (TCF) bind to this sequence in vivo. Wnt3a stimulation, beta-catenin activation, and TCF overexpression resulted in syndecan-2 repression, whereas Wnt inhibition using sFRP-1 increased syndecan-2 expression in U2OS cells. RhoA activation blunted the stimulatory effect of sFRP-1 on syndecan-2 transcription, whereas RhoA inhibition enhanced syndecan-2 expression. These results indicate that Wnt/beta-catenin and Wnt/RhoA signaling contribute to syndecan-2 repression. The alteration of syndecan-2 expression in osteosarcoma cell lines also seemed to be related to a higher shedding, controlled by Wnt/RhoA. Conversely, syndecan-2 was found to activate its own expression in U2OS cells through RhoA inhibition. These data identify a molecular network that may contribute to the low expression of the proapoptotic proteoglycan syndecan-2 in osteosarcoma cells. The high activity of the canonical Wnt pathway in the different osteosarcoma cells induces a constitutive repression of syndecan-2 transcription, whereas Wnt/RhoA signaling blocks the amplification loop of syndecan-2 expression. Our results identify syndecan-2 as a Wnt target and bring new insights into a possible pathologic role of Wnt signaling in osteosarcoma.

• Authors: François-Xavier Dieudonné, Allison Marion, Eric Haÿ, Pierre Jacques Marie, Dominique Modrowski
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 13 Pg. 5399-408 (Jul 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20530678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 AACR.

Chemical References

• LEF1 protein, human
• Lymphoid Enhancer-Binding Factor 1
• Wnt Proteins
• RHOA protein, human
• Syndecan-2
• rhoA GTP-Binding Protein

Topics

• Bone Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphoid Enhancer-Binding Factor 1 (genetics, metabolism)
• Osteosarcoma (genetics, metabolism)
• Signal Transduction
• Syndecan-2 (biosynthesis, genetics)
• Transcription, Genetic
• Wnt Proteins (genetics, metabolism)
• rhoA GTP-Binding Protein (antagonists & inhibitors, metabolism)