Article

CDH4 is a novel determinant of osteosarcoma tumorigenesis and metastasis

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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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Author notes

  1. These authors contributed equally: Qinglian Tang, Jinchang Lu.

Affiliations

  1. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, M5G 0A3, Canada

    • Qinglian Tang
    • , Jinchang Lu
    • , Yang Shao
    • , Yan Chen
    • , Swami Narala
    • , Hui Fang
    •  & Rama Khokha
  2. Department of Orthopedic Oncology, First Affiliated Hospital, Sun Yat-Sen University, 510080, Guangzhou, China

    • Qinglian Tang
    • , Jinchang Lu
    • , Changye Zou
    • , Huaiyuan Xu
    • , Jin Wang
    •  & Jingnan Shen

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Jingnan Shen or Rama Khokha.

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