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Epigenetic silencing of the dual-role signal mediator, ANGPTL4 in tumor tissues and its overexpression in the urothelial carcinoma microenvironment

Oncogene volume 37, pages 673–686 (2018)Cite this article

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Abstract

Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 (ANGPTL4), was expressed at very low levels in all bladder cancer cell lines we examined. Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, owing to these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, using methylation-specific PCR and bisulfite pyrosequencing, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples, as compared with adjacent noncancerous bladder epithelium. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and invasion, migration, and xenograft formation in vivo. Surprisingly, circulating ANGPTL4 was significantly higher in plasma samples from UC patients than normal control, suggesting it might be secreted from other cell types. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/focal adhesion kinase axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. Finally, immunohistochemistry demonstrated that ANGPTL4 was downregulated in tumor cells but overexpressed in tumor adjacent stromal tissues of muscle-invasive UC tissue samples. In conclusion, our data support dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context.

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Acknowledgements

This study was supported by grants from the Ditmanson Medical Foundation Chiayi Christian Hospital, Taiwan (grant no. R101-9) and the Ministry of Science and Technology, Taiwan (MOST 104-2314-B-194-001-MY3). The authors would like to thank Dr Curt Balch for English editing.

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Author notes

  1. H-Y Hsieh and Y-C Jou: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Research, Ditmanson Medical Fountain Chiayi Christian Hospital, Chiayi, Taiwan,

    H-Y Hsieh & C-D Hsu

  2. Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan,

    H-Y Hsieh, Y-C Jou, C-H Shen & C-D Hsu

  3. Department of Life Science, National Chung Cheng University, Chiayi, Taiwan

    H-Y Hsieh, Y-M Chuang, S-F Wu, C Li, M W Y Chan & C-D Hsu

  4. Department of Biology, National Museum of Natural Science, Taichung, Taiwan

    H-Y Hsieh

  5. Department of Pathology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan,

    C-L Tung

  6. Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan,

    Y-S Tsai

  7. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Y-H Wang

  8. Division of General Surgery, Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan

    Y-H Wang

  9. Department of Pathology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan

    C-L Chi

  10. Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan

    R-I Lin & S-K Hung

  11. School of Medicine, Tzu Chi University, Hualien, Taiwan

    S-K Hung

  12. Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan

    Y-M Chuang, S-F Wu, C Li & M W Y Chan

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Hsieh, HY., Jou, YC., Tung, CL. et al. Epigenetic silencing of the dual-role signal mediator, ANGPTL4 in tumor tissues and its overexpression in the urothelial carcinoma microenvironment. Oncogene 37, 673–686 (2018). https://doi.org/10.1038/onc.2017.375

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