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BMC Cancer. 2018 Feb 17;18(1):198. doi: 10.1186/s12885-018-4107-1.

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

Author information

1
Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisbon, Portugal.
2
Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Sede di Patologia Generale, Università di Bologna, Via S. Giacomo 14, 40126, Bologna, Italy.
3
Centro Interdipartimentale Ricerche sul Cancro "Giorgio Prodi", Università di Bologna, Bologna, Italy.
4
Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisbon, Portugal. p.videira@fct.unl.pt.
5
UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516, Caparica, Portugal. p.videira@fct.unl.pt.
6
Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Sede di Patologia Generale, Università di Bologna, Via S. Giacomo 14, 40126, Bologna, Italy. fabio.dallolio@unibo.it.

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.

KEYWORDS:

Bacillus Calmette-Guérin; Glycosylation; Sialyl T antigen; Sialyltransferase; Thomsen-Friedenreich antigen

PMID:
29454317
PMCID:
PMC5816560
DOI:
10.1186/s12885-018-4107-1
[Indexed for MEDLINE]
Free PMC Article

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