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CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer

Oncogene volume 32, pages 2282–2291 (2013)Cite this article

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Abstract

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is expressed in the epithelial cells of a wide range of organs/tissues from which most cancers are derived. Although accumulating reports have indicated the association of cancer incidence with genetic variations in CFTR gene, the exact role of CFTR in cancer development and the possible underlying mechanism have not been elucidated. Here, we report that CFTR expression is significantly decreased in both prostate cancer cell lines and human prostate cancer tissue samples. Overexpression of CFTR in prostate cancer cell lines suppresses tumor progression (cell growth, adhesion and migration), whereas knockdown of CFTR leads to enhanced malignancies both in vitro and in vivo. In addition, we demonstrate that CFTR knockdown-enhanced cell proliferation, cell invasion and migration are significantly reversed by antibodies against either urokinase plasminogen activator (uPA) or uPA receptor (uPAR), which are known to be involved in various malignant traits of cancer development. More interestingly, overexpression of CFTR suppresses uPA by upregulating the recently described tumor suppressor microRNA-193b (miR-193b), and overexpression of pre-miR-193b significantly reverses CFTR knockdown-enhanced malignant phenotype and abrogates elevated uPA activity in prostate cancer cell line. Finally, we show that CFTR gene transfer results in significant tumor repression in prostate cancer xenografts in vivo. Taken together, the present study has demonstrated a previously undefined tumor-suppressing role of CFTR and its involvement in regulation of miR-193b in prostate cancer development.

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Acknowledgements

The work was supported by the Focused Investment Scheme of the Chinese University of Hong Kong and National 973 project (2012CB944900), GRF-CUHK466111, and the Fundamental Research Funds for the Central Universities (JiNan University). We are grateful to Professor Tzyh-Chang Hwang at Department of Biological Engineering, University of Missouri-Columbia, USA for providing CFTR-peGFP-C3 and control plasmids. The authors thank Mrs Huang Xiao ru and Mr Qin Wei from Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, for their helpful technical assistance.

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Author notes

  1. C Xie and X H Jiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong

    C Xie, X H Jiang, J T Zhang, T T Sun, J D Dong, R Y Diao, Y Wang, K L Fok, L L Tsang, M K Yu, X H Zhang, Y W Chung, M Y Zhao, J H Guo, Z J Xiao & H C Chan

  2. Key Laboratory for Regenerative Medicine (Jinan University-the Chinese University of Hong Kong), Ministry of Education of The People’s Republic of China, Guangzhou, The People’s Republic of China

    X H Jiang & H C Chan

  3. Department of Surgery, Metastasis and Angiogenesis Research Group, Cardiff University School of Medicine, Cardiff, UK

    A J Sanders, L Ye & W G Jiang

  4. Shenzhen Key Laboratory of Male Reproduction Medicine and Genetics, Peking University Shenzhen Hospital, Shenzhen, China

    R Y Diao & Z M Cai

  5. Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong

    H Y Lan

  6. Department of Surgery, Division of Urology, The Chinese University of Hong Kong, Shatin, Hong Kong

    C F Ng

  7. Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong

    K M Lau

  8. Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, China

    H C Chan

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  1. C Xie
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Correspondence to W G Jiang or H C Chan.

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Xie, C., Jiang, X., Zhang, J. et al. CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer. Oncogene 32, 2282–2291 (2013). https://doi.org/10.1038/onc.2012.251

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