BMC Cancer (Feb 2018)

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

  • Paulo F. Severino,
  • Mariana Silva,
  • Mylene Carrascal,
  • Nadia Malagolini,
  • Mariella Chiricolo,
  • Giulia Venturi,
  • Roberto Barbaro Forleo,
  • Annalisa Astolfi,
  • Mariangela Catera,
  • Paula A. Videira,
  • Fabio Dall’Olio

DOI
https://doi.org/10.1186/s12885-018-4107-1
Journal volume & issue
Vol. 18, no. 1
pp. 1 – 9

Abstract

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Abstract Background Treatment 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. Methods The 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. Results The 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. Conclusions High 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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