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Fibulin-3 promotes muscle-invasive bladder cancer

Oncogene volume 36, pages 5243–5251 (2017)Cite this article

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Abstract

Urothelial carcinoma is the most common type of bladder cancer and can be categorized as either non-muscle-invasive (Ta-T1) or muscle-invasive (⩾T2). The majority of bladder cancers are non-muscle-invasive at presentation; however, the recurrence rate for these tumors is high and a subset can progress to T2. In this study, we aimed to identify genes differentially expressed between T1 vs T2 bladder cancer to identify key regulators of bladder cancer progression and/or invasion. We performed RNA-Seq on T1 and T2 bladder cancer tissues and used publicly available bladder cancer profiling studies to prioritize differentially expressed genes for validation and functional assessment. This integrative approach nominated an extracellular matrix glycoprotein, fibulin-3 (FBLN3, also known as EFEMP1), as being highly expressed in T2 vs T1 bladder cancer and aggressive vs indolent disease. We confirmed the overexpression of fibulin-3 in ⩾T2 vs non-muscle-invasive bladder cancer (NMIBC) by quantitative reverse transcriptase–PCR. Consistent with these findings, fibulin-3 expression level correlated with the invasive ability of several bladder cancer cell lines and modulation of fibulin-3 expression directly affected invasion. Fibulin-3 knockdown in bladder cancer cells decreased the incidence of MIBCs in a murine orthotopic bladder cancer model and decreased the expression of insulin-like growth factor-binding protein-5 (IGFBP5). Restoring IGFBP5 in these cells rescued their invasive and migratory potential. These results indicate that fibulin-3 serves as a pro-invasive factor in bladder cancer, which may be mediated through modulation of IGFBP5 expression. This also suggests fibulin-3 and IGFBP5 may have potential as biomarkers of aggressive bladder cancer or therapeutic targets.

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Acknowledgements

We thank the University of Michigan DNA Sequencing Core for the RNA-Seq. University of Michigan Comprehensive Cancer Center Research Grant (to ETK), the Robert M and Elizabeth C Teeter Bladder Cancer Research Fund (to SAT) and the MacLeod Family (to SAT). SAT is supported by the A Alfred Taubman Emerging Scholar Award from the A Alfred Taubman Medical Institute.

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  1. L El-Sawy

    Present address: 6Current address: European Egyptian Pharmaceutical Industries, Alexandria, Egypt.,

Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    A L Han, S A Tomlins & E T Keller

  2. Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA

    B A Veeneman

  3. Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA

    L El-Sawy, K C Day, M L Day, S A Tomlins & E T Keller

  4. Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    S A Tomlins

  5. Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA

    E T Keller

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Correspondence to E T Keller.

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Competing interests

SAT has consulted for, and received honoraria from AbbVie, Astellas, Jannsen and Ventana Medical Systems. SAT has received research support from Astellas and had a sponsored research agreement with, and has received travel support from ThermoFisher Scientific/Life Technologies. SAT is a co-founder and equity holder in Strata Oncology. MLD has consulted for and received honoraria from Pharco pharmaceutical and EEPI pharmaceutical. MLD has received research support from EEPI, Genmab and Synthon. The remaining authors declare no conflict of interest.

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Han, A., Veeneman, B., El-Sawy, L. et al. Fibulin-3 promotes muscle-invasive bladder cancer. Oncogene 36, 5243–5251 (2017). https://doi.org/10.1038/onc.2017.149

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