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Eldecalcitol (ED-71)-induced exosomal miR-6887-5p suppresses squamous cell carcinoma cell growth by targeting heparin-binding protein 17/fibroblast growth factor–binding protein-1 (HBp17/FGFBP-1)

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Abstract

Heparin-binding protein 17/fibroblast growth factor–binding protein-1 (HBp17/FGFBP-1) was purified from A431 cell-conditioned media based on its capacity to bind to fibroblast growth factor 1 and 2 (FGF-1 and FGF-2). HBp17/FGFBP-1 has been observed to induce the tumorigenic potential of epithelial cells and is highly expressed in oral cancer cell lines and tissues. HBp17/FGFBP-1 is also recognized as a pro-angiogenic molecule as a consequence of its interaction with FGF-2. We have previously reported that Eldecalcitol (ED-71), an analog of 1α,25(OH)2D3, downregulated the expression of HBp17/FGFBP-1 and inhibited the proliferation of squamous cell carcinoma (SCC) cells in vitro and in vivo through NF-κb inhibition. To explore the possibility of microRNA (miRNA) control of HBp17/FGFBP-1, we analyzed exosomal miRNAs from medium conditioned by A431 cells treated with ED-71. Microarray analysis revealed that 12 exosomal miRNAs were upregulated in ED-71-treated A431 cells. Among them, miR-6887-5p was identified to have a predicted mRNA target matching the 3′ untranslated region (3′-UTR) of HBp17/FGFBP-1. The 3′-UTR of HBp17/FGFBP-1 was confirmed to be a direct target of miR-6887-5p in SCC/OSCC cells, as assessed with a luciferase reporter assay. Functional assessment revealed that overexpression of miR-6887-5p in SCC/OSCC cells inhibited cell proliferation and colony formation in vitro, and inhibited tumor growth in vivo compared with control. In conclusion, our present study supports a novel anti-cancer mechanism involving the regulation of HBp17/FGFBP-1 function by exosomal miR-6887-5p in SCC/OSCC cells, which has potential utility as a miRNA-based cancer therapy.

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Acknowledgments

We would like to thank Dr. Emiko Usui for her valuable advice. We also thank Chugai Pharmaceutical Co. Ltd. for the generous gift of ED-71.

Funding

This research was supported in part by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology to T.O. (grant number: 15H05043) and T. S. (grant number: 16K11723). A part of this work was carried out at Natural Science Center for Basic Research and Development, Hiroshima University.

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  1. M. Higaki and T. Shintani contributed equally to this work.

Authors and Affiliations

  1. Oral Maxillofacial Surgery, Hiroshima University Hospital, Hiroshima, 734-8553, Japan

    M. Higaki, A. Hamada & T. Okamoto

  2. Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, 734-8553, Japan

    T. Shintani

  3. Department of Molecular Oral Medicine and Maxillofacial Surgery, Division of Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan

    S. N. Z. Rosli & T. Okamoto

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  1. M. Higaki
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  2. T. Shintani
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Correspondence to T. Shintani.

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Higaki, M., Shintani, T., Hamada, A. et al. Eldecalcitol (ED-71)-induced exosomal miR-6887-5p suppresses squamous cell carcinoma cell growth by targeting heparin-binding protein 17/fibroblast growth factor–binding protein-1 (HBp17/FGFBP-1). In Vitro Cell.Dev.Biol.-Animal 56, 222–233 (2020). https://doi.org/10.1007/s11626-020-00440-x

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