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MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol

Oncogene volume 32, pages 431–443 (2013)Cite this article

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Abstract

Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal–epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol—∣miRNA-520h—∣PP2A/C—∣Akt → NF-κB → FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.

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Acknowledgements

This work was partially supported by the National Science Council Grant (NSC-2632-B-001-MY3, NSC 96-2320-B-004-MY2, NSC 97-2320-B-039-039-MY3 and NSC 98-2815-C-039-082-B to J-LS); National Health Research Institutes Grant from Taiwan (NHRI-EX98-9712BC, NHRI-EX99-9712BC and NHRI-EX100-9712BC to J-LS); Department of Health, Executive Yuan Grant from Taiwan (DOH99-TD-G111-011 to J-LS); Grants from China Medical University (CMU96-220, CMU97-077 and CMU97-277 to J-LS; CMU-99-NTU-08, CMU100-TS-06 and DMR-101-014 to Y-HY).

Author contributions: J-LS, M-HC, M-CH and M-LK designed and conceived the study. P-SC and J-LS wrote the manuscript. Y-WC, Y-HC, H-AC and Y-JC performed the experiments. C-HW, M-TH, H-AC, Y-HS, W-HH, Y-MJ, C-HH, Y-HJ and MH performed and analyzed the immunohistochemistry experiments.

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Authors and Affiliations

  1. Department of Internal Medicine, Divisions of Pulmonary and Critical Care Medicine, China Medical University Hospital, Taichung, Taiwan

    Y-H Yu & W-H Hsu

  2. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

    Y-H Yu

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

    H-A Chen, C-H Wu, M-T Huang, Y-H Su & M-H Chien

  4. Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan

    H-A Chen, C-H Wu, M-T Huang & Y-H Su

  5. Institute of Toxicology, College of Medicine and Angiogenesis Research Center, National Taiwan University, Taipei, Taiwan

    P-S Chen & M-L Kuo

  6. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

    P-S Chen, M-L Kuo & J-L Su

  7. Graduate Institute of Cancer Biology, College of Medicine, China Medical University, Taichung, Taiwan

    Y-J Cheng, T-Y Chang & M-C Hung

  8. Graduate Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

    Y-W Chang

  9. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan

    Y-H Chen, Y-H Liu, M-C Hung & J-L Su

  10. The Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Y Jan & M Hsiao

  11. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Y-M Jeng

  12. Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    M-H Chien

  13. Cancer Center, China Medical University Hospital, Taichung, Taiwan

    C-Y Chen

  14. Cancer Biology and Drug Discovery Ph.D. Degree Program, China Medical University, Taichung, Taiwan

    J-L Su

  15. Department of Biotechnology, Asia University, Taichung, Taiwan

    J-L Su

  16. These authors contributed equally to this work,

    Y-H Yu & H-A Chen

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  1. Y-H Yu
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Correspondence to M-H Chien or J-L Su.

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Yu, YH., Chen, HA., Chen, PS. et al. MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol. Oncogene 32, 431–443 (2013). https://doi.org/10.1038/onc.2012.74

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