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Insight into the molecular basis of Schistosoma haematobium-induced bladder cancer through urine proteomics

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Tumor Biology

Abstract

Infection due to Schistosoma haematobium is carcinogenic. However, the cellular and molecular mechanisms underlying urogenital schistosomiasis (UGS)-induced carcinogenesis have not been well defined. Conceptually, early molecular detection of this phenomenon, through non-invasive procedures, seems feasible and is desirable. Previous analysis of urine collected during UGS suggests that estrogen metabolites, including depurinating adducts, may be useful for this purpose. Here, a new direction was pursued: the identification of molecular pathways and potential biomarkers in S. haematobium-induced bladder cancer by analyzing the proteome profiling of urine samples from UGS patients. GeLC-MS/MS followed by protein-protein interaction analysis indicated oxidative stress and immune defense systems responsible for microbicide activity are the most representative clusters in UGS patients. Proteins involved in immunity, negative regulation of endopeptidase activity, and inflammation were more prevalent in UGS patients with bladder cancer, whereas proteins with roles in renal system process, sensory perception, and gas and oxygen transport were more abundant in subjects with urothelial carcinoma not associated with UGS. These findings highlighted a Th2-type immune response induced by S. haematobium, which seems to be further modulated by tumorigenesis, resulting in high-grade bladder cancer characterized by an inflammatory response and complement activation alternative pathway. These findings established a starting point for the development of multimarker strategies for the early detection of UGS-induced bladder cancer.

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Acknowledgments

This work was supported by the Portuguese Foundation for Science and Technology (FCT), European Union, QREN, FEDER, and COMPETE for funding the QOPNA; by iBiMED research unit (project PEst-C/QUI/UI0062/2013, UID/BIM/04501/2013, UID/IC/00051/2013, and COST action BM1305) and PhD fellowship SFRH/BD/80855/2011 (CB); and by the Portuguese Mass Spectrometry Network (RNEM). The authors also acknowledge Clínica Sagrada Esperança and Serviço de Urologia do Hospital Américo Boavida from Luanda, Angola.

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    Authors and Affiliations

    1. Experimental Pathology and Therapeutics Group - Research Center, Portuguese Oncology Institute - Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

      Carina Bernardo, Júlio Henrique Santos, Carlos Lopes & Lúcio Lara Santos

    2. Mass Spectrometry Group, QOPNA, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal

      Carina Bernardo

    3. School of Health Sciences, University of Minho, Campus Gualtar, 4710-057, Braga, Portugal

      Maria Cláudia Cunha, Francisco Amado & Rita Ferreira

    4. Center for the Study of Animal Science, CECA/ICETA, University of Porto, Rua D. Manuel II, Apt 55142, 4051-401, Porto, Portugal

      Júlio Henrique Santos & José M. Correia da Costa

    5. Center for Parasite Biology and Immunology (CIBP), National Institute of Health Dr. Ricardo Jorge (INSA), Rua Alexandro Herculano, 4000-055, Porto, Portugal

      José M. Correia da Costa

    6. Department of Microbiology, Immunology & Tropical Medicine, and Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC, 20037, USA

      Paul J. Brindley

    7. Department of Medical Sciences, Institute for Biomedicine – iBiMED, University of Aveiro, Campus Universitário de Santiago, Agra do Crasto, 3810-193, Aveiro, Portugal

      Rui Vitorino

    8. Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, 4200-072, Porto, Portugal

      Rui Vitorino

    9. Department of Surgical Oncology, Portuguese Oncology Institute - Porto (IPO-Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

      Lúcio Lara Santos

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    1. Carina Bernardo
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    2. Maria Cláudia Cunha
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    Correspondence to Lúcio Lara Santos.

    Ethics declarations

    Urine samples were obtained according to a collaborative program between Clínica da Sagrada Esperança, Américo Boavida University Hospital and IPO-Porto after obtaining informed consent from all participants. This study was approved by the local ethics committee and followed the Declaration of Helsinki.

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    Carina Bernardo and Maria Cláudia Cunha contributed equally to this work.

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    Bernardo, C., Cunha, M.C., Santos, J.H. et al. Insight into the molecular basis of Schistosoma haematobium-induced bladder cancer through urine proteomics. Tumor Biol. 37, 11279–11287 (2016). https://doi.org/10.1007/s13277-016-4997-y

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