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Altered Proteome of Extracellular Vesicles Derived from Bladder Cancer Patients Urine

  • Lee, Jingyun (Proteomics Laboratory for Clinical and Translational Research, Carolinas HealthCare System) ;
  • McKinney, Kimberly Q. (Proteomics Laboratory for Clinical and Translational Research, Carolinas HealthCare System) ;
  • Pavlopoulos, Antonis J. (Proteomics Laboratory for Clinical and Translational Research, Carolinas HealthCare System) ;
  • Niu, Meng (Proteomics Laboratory for Clinical and Translational Research, Carolinas HealthCare System) ;
  • Kang, Jung Won (Omics Core Laboratory, Research Institute, National Cancer Center) ;
  • Oh, Jae Won (Department of Applied Chemistry, The Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University) ;
  • Kim, Kwang Pyo (Department of Applied Chemistry, The Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University) ;
  • Hwang, Sunil (Proteomics Laboratory for Clinical and Translational Research, Carolinas HealthCare System)
  • Received : 2017.06.30
  • Accepted : 2017.12.20
  • Published : 2018.03.31

Abstract

Proteomic analysis of extracellular vesicles (EVs) from biological fluid is a powerful approach to discover potential biomarkers for human diseases including cancers, as EV secreted to biological fluids are originated from the affected tissue. In order to investigate significant molecules related to the pathogenesis of bladder cancer, EVs were isolated from patient urine which was analyzed by mass spectrometry based proteomics. Comparison of the EV proteome to the whole urine proteome demonstrated an increased number of protein identification in EV. Comparative MS analyses of urinary EV from control subjects and bladder cancer patients identified a total of 1,222 proteins. Statistical analyses provided 56 proteins significantly increased in bladder cancer urine, including proteins for which expression levels varied by cancer stage (P-value < 0.05). While urine represents a valuable, non-invasive specimen for biomarker discovery in urologic cancers, there is a high degree of intra- and inter-individual variability in urine samples. The enrichment of urinary EV demonstrated its capability and applicability of providing a focused identification of biologically relevant proteins in urological diseases.

Acknowledgement

Supported by : GRRC

References

  1. Adada, M.M., Canals, D., Jeong, N., Kelkar, A.D., Hernandez-Corbacho, M., Pulkoski-Gross, M.J., Donaldson, J.C., Hannun, Y.A., and Obeid, L.M. (2015). Intracellular sphingosine kinase 2-derived sphingosine-1-phosphate mediates epidermal growth factor-induced ezrin-radixin-moesin phosphorylation and cancer cell invasion. FASEB J. 29, 4654-4669. https://doi.org/10.1096/fj.15-274340
  2. Beckham, C.J., Olsen, J., Yin, P.N., Wu, C.H., Ting, H.J., Hagen, F.K., Scosyrev, E., Messing, E.M., and Lee, Y.F. (2014). Bladder cancer exosomes contain EDIL-3/Del1 and facilitate cancer progression. J. Urol. 192, 583-592. https://doi.org/10.1016/j.juro.2014.02.035
  3. Bramswig, K.H., Poettler, M., Unseld, M., Wrba, F., Uhrin, P., Zimmermann, W., Zielinski, C.C., and Prager, G.W. (2013). Soluble carcinoembryonic antigen activates endothelial cells and tumor angiogenesis. Cancer Res. 73, 6584-6596. https://doi.org/10.1158/0008-5472.CAN-13-0123
  4. Colas, E., Perez, C., Cabrera, S., Pedrola, N., Monge, M., Castellvi, J., Eyzaguirre, F., Gregorio, J., Ruiz, A., Llaurado, M., et al. (2011). Molecular markers of endometrial carcinoma detected in uterine aspirates. Int. J. Cancer 129, 2435-2444. https://doi.org/10.1002/ijc.25901
  5. Frantzi, M., Latosinska, A., Fluhe, L., Hupe, M.C., Critselis, E., Kramer, M.W., Merseburger, A.S., Mischak, H., and Vlahou, A. (2015). Developing proteomic biomarkers for bladder cancer: towards clinical application. Nat. Rev. Urol. 12, 317-330. https://doi.org/10.1038/nrurol.2015.100
  6. Franzen, C.A., Blackwell, R.H., Todorovic, V., Greco, K.A., Foreman, K.E., Flanigan, R.C., Kuo, P.C., and Gupta, G.N. (2015). Urothelial cells undergo epithelial-to-mesenchymal transition after exposure to muscle invasive bladder cancer exosomes. Oncogenesis 4, e163. https://doi.org/10.1038/oncsis.2015.21
  7. Jiang, L., Phang, J.M., Yu, J., Harrop, S.J., Sokolova, A.V., Duff, A.P., Wilk, K.E., Alkhamici, H., Breit, S.N., Valenzuela, S.M., et al. (2014). CLIC proteins, ezrin, radixin, moesin and the coupling of membranes to the actin cytoskeleton: a smoking gun? Biochim. Biophys. Acta 1838, 643-657. https://doi.org/10.1016/j.bbamem.2013.05.025
  8. King, H. W., Michael, M. Z., and Gleadle, J. M. (2012). Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 12, 421. https://doi.org/10.1186/1471-2407-12-421
  9. Kalluri, R. (2016). The biology and function of exosomes in cancer. J. Clin. Invest. 126, 1208-1215. https://doi.org/10.1172/JCI81135
  10. Larion, S., Caballes, F.R., Hwang, S.I., Lee, J.G., Rossman, W.E., Parsons, J., Steuerwald, N., Li, T., Maddukuri, V., Groseclose, G., et al. (2013). Circadian rhythms in acute intermittent porphyria--a pilot study. Eur. J. Clin. Invest. 43, 727-739. https://doi.org/10.1111/eci.12102
  11. Lee, J., McKinney, K.Q., Pavlopoulos, A.J., Han, M.H., Kim, S.H., Kim, H.J., and Hwang, S. (2016). Exosomal proteome analysis of cerebrospinal fluid detects biosignatures of neuromyelitis optica and multiple sclerosis. Clin. Chim Acta 462, 118-126. https://doi.org/10.1016/j.cca.2016.09.001
  12. Mathivanan, S., and Simpson, R.J. (2009). ExoCarta: A compendium of exosomal proteins and RNA. Proteomics 9, 4997-5000. https://doi.org/10.1002/pmic.200900351
  13. Nielsen, T.O., Borre, M., Nexo, E., and Sorensen, B.S. (2015). Coexpression of HER3 and MUC1 is associated with a favourable prognosis in patients with bladder cancer. BJU Int. 115, 163-165. https://doi.org/10.1111/bju.12658
  14. Pavelka, N., Pelizzola, M., Vizzardelli, C., Capozzoli, M., Splendiani, A., Granucci, F., and Ricciardi-Castagnoli, P. (2004). A power law global error model for the identification of differentially expressed genes in microarray data. BMC Bioinformatics 5, 203. https://doi.org/10.1186/1471-2105-5-203
  15. Piao, J., Liu, S., Xu, Y., Wang, C., Lin, Z., Qin, Y., and Liu, S. (2015). Ezrin protein overexpression predicts the poor prognosis of pancreatic ductal adenocarcinomas. Exp. Mol. Pathol. 98, 1-6. https://doi.org/10.1016/j.yexmp.2014.11.003
  16. Stern, N., Markel, G., Arnon, T.I., Gruda, R., Wong, H., Gray-Owen, S.D., and Mandelboim, O. (2005). Carcinoembryonic antigen (CEA) inhibits NK killing via interaction with CEA-related cell adhesion molecule 1. J. Immunol. 174, 6692-6701. https://doi.org/10.4049/jimmunol.174.11.6692
  17. Suzuki, Y., Sutoh, M., Hatakeyama, S., Mori, K., Yamamoto, H., Koie, T., Saitoh, H., Yamaya, K., Funyu, T., Habuchi, T., et al. (2012). MUC1 carrying core 2 O-glycans functions as a molecular shield against NK cell attack, promoting bladder tumor metastasis. Int. J. Oncol. 40, 1831-1838.
  18. Wang, Y., Yago, T., Zhang, N., Abdisalaam, S., Alexandrakis, G., Rodgers, W., and McEver, R.P. (2014). Cytoskeletal regulation of CD44 membrane organization and interactions with E-selectin. J. Biol. Chem. 289, 35159-35171. https://doi.org/10.1074/jbc.M114.600767
  19. Watts, J.A., Lee, Y.Y., Gellar, M.A., Fulkerson, M.B., Hwang, S.I., and Kline, J.A. (2012). Proteomics of microparticles after experimental pulmonary embolism. Thrombosis Res. 130, 122-128. https://doi.org/10.1016/j.thromres.2011.09.016
  20. Wood, S.L., Knowles, M.A., Thompson, D., Selby, P.J., and Banks, R.E. (2013). Proteomic studies of urinary biomarkers for prostate, bladder and kidney cancers. Nat. Rev. Urol. 10, 206-218. https://doi.org/10.1038/nrurol.2013.24
  21. Yang, L., Wu, X.H., Wang, D., Luo, C.L., and Chen, L.X. (2013). Bladder cancer cell-derived exosomes inhibit tumor cell apoptosis and induce cell proliferation in vitro. Mol. Med. Rep. 8, 1272-1278. https://doi.org/10.3892/mmr.2013.1634

Cited by

  1. Urinary Markers in Bladder Cancer: An Update vol.8, pp.2234-943X, 2018, https://doi.org/10.3389/fonc.2018.00362
  2. Extracellular Vesicles in Bladder Cancer: Biomarkers and Beyond vol.19, pp.9, 2018, https://doi.org/10.3390/ijms19092822