Abstract
The era of cancer genomics now provides an opportunity to discover novel determinants of osteosarcoma (OS), the most common primary bone cancer in children and adolescents known for its poor prognosis due to lung metastasis. Here, we identify CDH4 amplification in 43.6% of human osteosarcoma using array CGH and demonstrate its critical role in osteosarcoma development and progression. Gain or loss-of-function of CDH4, which encodes R-cadherin, causally impacts multiple features of human OS cells including cell migration and invasion, osteogenic differentiation, and stemness. CDH4 overexpression activates c-Jun via the JNK pathway, while CDH4 knockdown suppresses both tumor xenograft growth and lung colonization. In OS patient specimens, high CDH4 expression associates with lung metastases and poor prognosis. Collectively, our bioinformatics, functional, molecular, and clinical analyses uncover an oncogenic function of CDH4 in osteosarcoma and its relationship with patient outcome.
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Acknowledgements
This study is supported by funding from the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Society Research Institute (CCSRI) to RK, and International Science & Technology Cooperation Program of Guangzhou to JS (201704030008). Q.T. and J.L. are supported by Graduate Student Overseas Study Program of China Scholarship Council. Q.T. is also supported by National Natural Science Foundation of China (81502324), and J.L. is supported by National Postdoctoral Program for Innovative Talents (BX201600196).
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Tang, Q., Lu, J., Zou, C. et al. CDH4 is a novel determinant of osteosarcoma tumorigenesis and metastasis. Oncogene 37, 3617–3630 (2018). https://doi.org/10.1038/s41388-018-0231-2
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DOI: https://doi.org/10.1038/s41388-018-0231-2
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