Translational Therapeutics

Hyaluronic acid family in bladder cancer: potential prognostic biomarkers and therapeutic targets

  • British Journal of Cancer volume 117, pages 15071517 (07 November 2017)
  • doi:10.1038/bjc.2017.318
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Abstract

Background:

Molecular markers of clinical outcome may aid in designing targeted treatments for bladder cancer. However, only a few bladder cancer biomarkers have been examined as therapeutic targets.

Methods:

Data from The Cancer Genome Atlas (TCGA) and bladder specimens were evaluated to determine the biomarker potential of the hyaluronic acid (HA) family of molecules – HA synthases, HA receptors and hyaluronidase. The therapeutic efficacy of 4-methylumbelliferone (4MU), a HA synthesis inhibitor, was evaluated in vitro and in xenograft models.

Results:

In clinical specimens and TCGA data sets, HA synthases and hyaluronidase-1 levels significantly predicted metastasis and poor survival. 4-Methylumbelliferone inhibited proliferation and motility/invasion and induced apoptosis in bladder cancer cells. Oral administration of 4MU both prevented and inhibited tumour growth, without dose-related toxicity. Effects of 4MU were mediated through the inhibition of CD44/RHAMM and phosphatidylinositol 3-kinase/AKT axis, and of epithelial–mesenchymal transition determinants. These were attenuated by HA, suggesting that 4MU targets oncogenic HA signalling. In tumour specimens and the TCGA data set, HA family expression correlated positively with β-catenin, Twist and Snail expression, but negatively with E-cadherin expression.

Conclusions:

This study demonstrates that the HA family can be exploited for developing a biomarker-driven, targeted treatment for bladder cancer, and 4MU, a non-toxic oral HA synthesis inhibitor, is one such candidate.

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Change history

  • Corrected online 07 November 2017

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Acknowledgements

This work was supported by R01CA72821-10 (to VBL), R21CA184018-02 (to VBL) and 5R01CA176691-02 (to VBL). MSHennig was a fellow of the Biomedical Exchange Program, International Academy of Life Sciences.

Author information

Author notes

    • Daley S Morera
    •  & Martin S Hennig

    These authors contributed equally to this work and are joint first authors.

    • Michael Garcia-Roig

    Current Address: Georgia Pediatric Urology, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA.

    • Nicolas Ortiz

    Current Address: Womack Army Medical Center, Fort Bragg, NC, USA.

    • Travis J Yates

    Present Address: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.

Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Boulevard, Room CN 1177A, Augusta, GA 30912-2100, USA

    • Daley S Morera
    • , Jiaojiao Wang
    • , Luis E Lopez
    • , Andre R Jordan
    •  & Vinata B Lokeshwar
  2. Department of Urology, University Hospital Schleswig-Holstein, Kiel, Lübeck 23538, Germany

    • Martin S Hennig
    • , Mario W Kramer
    •  & Axel S Merseburger
  3. Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA

    • Asif Talukder
  4. Honors Program in Medical Education, University of Miami-Miller School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136, USA

    • Soum D Lokeshwar
  5. Department of Urology, University of Miami-Miller School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136, USA

    • Michael Garcia-Roig
    •  & Nicolas Ortiz
  6. Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami-Miller School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136, USA

    • Travis J Yates
    •  & Andre R Jordan
  7. Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA

    • Georgios Kallifatidis
  8. Miami Cancer Institute, Baptist Health South Florida, 8900 N Kendall, Miami, FL 33176, USA

    • Murugesan Manoharan
  9. Memorial Healthcare System, 20801 Biscayne Blvd Ste 203, Aventura, FL 33180, USA

    • Mark S Soloway
  10. Department of Surgery, Division of Urology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA

    • Martha K Terris

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Vinata B Lokeshwar.

Supplementary information

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Supplementary Information accompanies this paper on British Journal of Cancer website (http://www.nature.com/bjc)

Creative Commons BY-NC-SAFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/