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NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma
Open accessAbstract
Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.
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“Cultures derived from mice with spontaneous osteosarcoma 210 or from genetically engineered mouse models 100,213 are available to study disease biology or therapeutics in mice with intact immune systems.”
From Osteosarcoma (2022) · cites this paper as [213]
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Metadata
- Authors
- Zhao, S., Kurenbekova, L., Gao, Y., Roos, A., Creighton, C. J., Rao, P., Hicks, J., Man, T.-K., Lau, C., Brown, A. M. C., Jones, S. N., Lazar, A. J., Ingram, D., Lev, D., Donehower, L. A., & Yustein, J. T.
- Affiliations
- Baylor College of Medicine (US)
- Weill Cornell Medicine (US)
- University of Massachusetts Chan Medical School (US)
- The University of Texas MD Anderson Cancer Center (US)
- The Ohio State University (US)
- Corresponding author
- Yustein, J T
- ORCID
- Venue
- Oncogene
- Published
- 2015-01-12
- Volume
- 34
- Issue
- 39
- Pages
- 5069-5079
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC4802362
- OpenAlex
- W2069275038
- Cited by
- 139
- References
- 48
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 7 · 2023: 6 · 2022: 13 · 2021: 15 · 2020: 14 · 2019: 11 · 2018: 10 · 2017: 17 · 2016: 18 · 2015: 8
- FWCI
- 13.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA123238, P30CA125123)
- National Institute of General Medical Sciences (T32GM008539)
- Topics
- Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- NKD2, osteosarcoma, Wnt signaling, metastasis, tumor growth, cell migration, cell invasion, p53, genetically engineered mouse models, tumor suppressor, angiogenesis, recurrent osteosarcoma, Wnt pathway inhibitors
- MeSH terms
- Animals, Bone Neoplasms, Calcium-Binding Proteins, Carrier Proteins, Neoplasm Invasiveness, Neoplasm Metastasis, Osteosarcoma, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Wnt Signaling Pathway
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