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

Daley S. Morera, Martin S. Hennig, Asif Talukder, Soum D. Lokeshwar, Jiaojiao Wang, Michael Garcia-Roig, Nicolas Ortiz, Travis J. Yates, Luis E. Lopez, Georgios Kallifatidis, Mario W. Kramer, Andre R. Jordan, Axel S. Merseburger, Murugesan Manoharan, Mark S. Soloway, Martha K. Terris, Vinata B. Lokeshwar*

*Corresponding author for this work
23 Citations (Scopus)


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.

Original languageEnglish
JournalBritish Journal of Cancer
Issue number10
Pages (from-to)1507-1517
Number of pages11
Publication statusPublished - 07.11.2017

Research Areas and Centers

  • Research Area: Luebeck Integrated Oncology Network (LION)


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