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Oxidative damage and response to Bacillus Calmette-Guérin in bladder cancer cells expressing sialyltransferase ST3GAL1

Authors
  • Severino, Paulo F.1, 2
  • Silva, Mariana1
  • Carrascal, Mylene1
  • Malagolini, Nadia2
  • Chiricolo, Mariella2
  • Venturi, Giulia2
  • Barbaro Forleo, Roberto2
  • Astolfi, Annalisa3
  • Catera, Mariangela2
  • Videira, Paula A.1, 4
  • Dall’Olio, Fabio2
  • 1 Universidade NOVA de Lisboa, Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Campo dos Mártires da Pátria, 130, Lisbon, 1169-056, Portugal , Lisbon (Portugal)
  • 2 Università di Bologna, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Sede di Patologia Generale, Via S. Giacomo 14, Bologna, 40126, Italy , Bologna (Italy)
  • 3 Università di Bologna, Centro Interdipartimentale Ricerche sul Cancro “Giorgio Prodi”, Bologna, Italy , Bologna (Italy)
  • 4 Universidade NOVA de Lisboa, UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Caparica, 2829-516, Portugal , Caparica (Portugal)
Type
Published Article
Journal
BMC Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Feb 17, 2018
Volume
18
Issue
1
Identifiers
DOI: 10.1186/s12885-018-4107-1
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundTreatment with Bacillus Calmette-Guérin (BCG) is the gold standard adjuvant immunotherapy of non-muscle invasive bladder cancer (NMIBC), although it fails in one third of the patients. NMIBC expresses two tumor-associated O-linked carbohydrates: the disaccharide (Galβ1,3GalNAc) Thomsen-Friedenreich (T) antigen, and its sialylated counterpart (Siaα2,3Galβ1,3GalNAc) sialyl-T (sT), synthesized by sialyltransferase ST3GAL1, whose roles in BCG response are unknown.MethodsThe human bladder cancer (BC) cell line HT1376 strongly expressing the T antigen, was retrovirally transduced with the ST3GAL1 cDNA or with an empty vector, yielding the cell lines HT1376sT and HT1376T, that express, respectively, either the sT or the T antigens. Cells were in vitro challenged with BCG. Whole gene expression was studied by microarray technology, cytokine secretion was measured by multiplex immune-beads assay. Human macrophages derived from blood monocytes were challenged with the secretome of BCG-challenged BC cells.ResultsThe secretome from BCG-challenged HT1376sT cells induced a stronger macrophage secretion of IL-6, IL-1β, TNFα and IL-10 than that of HT1376T cells. Transcriptomic analysis revealed that ST3GAL1 overexpression and T/sT replacement modulated hundreds of genes. Several genes preserving genomic stability were down-regulated in HT1376sT cells which, as a consequence, displayed increased sensitivity to oxidative damage. After BCG challenge, the transcriptome of HT1376sT cells showed higher susceptibility to BCG modulation than that of HT1376T cells.ConclusionsHigh ST3GAL1 expression and T/sT replacement in BCG challenged-BC cancer cells induce a stronger macrophage response and alter the gene expression towards genomic instability, indicating a potential impact on BC biology and patient’s response to BCG.

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