TY - JOUR
T1 - Oxidative damage and response to Bacillus Calmette-Guérin in bladder cancer cells expressing sialyltransferase ST3GAL1
AU - Severino, Paulo F
AU - Silva, Mariana
AU - Carrascal, Mylene
AU - Malagolini, Nadia
AU - Chiricolo, Mariella
AU - Venturi, Giulia
AU - Barbaro Forleo, Roberto
AU - Astolfi, Annalisa
AU - Catera, Mariangela
AU - Videira, Paula A
AU - Dall'Olio, Fabio
N1 - info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F81860%2F2011/PT#
info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F45120%2F2008/PT#
This work was supported by: Portuguese Foundation for Science and Technology (FCT) PhD grants SFRH/BD/45120/2008 (Paulo F. Severino), SFRH/BD/81860/2011 (Mariana Silva) and SFRH/BD/100970/2014 (Mylene Carrascal), Liga Portuguesa Contra o Cancro 2011 (Mylene A. Carrascal); Premio Bluepharma Inovacao Universidade de Coimbra and the Santander Totta/Universidade NOVA de Lisboa prizes (Paula Videira). Grants from the University of Bologna (Fabio Dall'Olio). Mariangela Catera and Giulia Venturi are PhD students supported by grants from the University of Bologna.
PY - 2018/2/17
Y1 - 2018/2/17
N2 - 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 HT1376sTand 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 HT1376sTcells induced a stronger macrophage secretion of IL-6, IL-1β, TNFα and IL-10 than that of HT1376Tcells. Transcriptomic analysis revealed that ST3GAL1 overexpression and T/sT replacement modulated hundreds of genes. Several genes preserving genomic stability were down-regulated in HT1376sTcells which, as a consequence, displayed increased sensitivity to oxidative damage. After BCG challenge, the transcriptome of HT1376sTcells showed higher susceptibility to BCG modulation than that of HT1376Tcells.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.
AB - 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 HT1376sTand 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 HT1376sTcells induced a stronger macrophage secretion of IL-6, IL-1β, TNFα and IL-10 than that of HT1376Tcells. Transcriptomic analysis revealed that ST3GAL1 overexpression and T/sT replacement modulated hundreds of genes. Several genes preserving genomic stability were down-regulated in HT1376sTcells which, as a consequence, displayed increased sensitivity to oxidative damage. After BCG challenge, the transcriptome of HT1376sTcells showed higher susceptibility to BCG modulation than that of HT1376Tcells.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.
KW - Bacillus Calmette-Guérin
KW - Glycosylation
KW - Sialyl T antigen
KW - Sialyltransferas
KW - Thomsen-Friedenreich antige
U2 - 10.1186/s12885-018-4107-1
DO - 10.1186/s12885-018-4107-1
M3 - Article
C2 - 29454317
SN - 1471-2407
VL - 18
JO - BMC Cancer
JF - BMC Cancer
IS - 1
M1 - 198
ER -
