Oncotarget

Research Papers:

Expression of sialyl-Tn sugar antigen in bladder cancer cells affects response to Bacillus Calmette Guérin (BCG) and to oxidative damage

Paulo F. Severino, Mariana Silva, Mylene Carrascal, Nadia Malagolini, Mariella Chiricolo, Giulia Venturi, Annalisa Astolfi, Mariangela Catera, Paula A. Videira and Fabio Dall'Olio _

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Oncotarget. 2017; 8:54506-54517. https://doi.org/10.18632/oncotarget.17138

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Abstract

Paulo F. Severino1,3,*, Mariana Silva1,*, Mylene Carrascal1, Nadia Malagolini3, Mariella Chiricolo3, Giulia Venturi3, Annalisa Astolfi4, Mariangela Catera3, Paula A. Videira1,2 and Fabio Dall’Olio3

1Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal

2UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Lisboa, Portugal

3Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Sede di Patologia Generale, Università di Bologna, Bologna, Italy

4Centro Interdipartimentale Ricerche sul Cancro “Giorgio Prodi”, Università di Bologna, Bologna, Italy

*Co-first authors

Correspondence to:

Fabio Dall’Olio, email: [email protected]

Paula A. Videira, email: [email protected]

Keywords: Bacillus Calmette-Guérin, bladder cancer, glycosylation, sialyl-Tn antigen, ST6GALNAC1 sialyltransferase

Received: May 30, 2016    Accepted: March 30, 2017    Published: April 17, 2017

ABSTRACT

The sialyl-Tn (sTn) antigen is an O-linked carbohydrate chain aberrantly expressed in bladder cancer (BC), whose biosynthesis is mainly controlled by the sialyltransferase ST6GALNAC1. Treatment with Bacillus Calmette-Guérin (BCG) is the most effective adjuvant immunotherapy for superficial BC but one third of the patients fail to respond. A poorly understood correlation between the expression of sTn and BC patient’s response to BCG was previously observed. By analyzing tumor tissues, we showed that patients with high ST6GALNAC1 and IL-6 mRNA expression were BCG responders. To investigate the role of sTn in BC cell biology and BCG response, we established the cell lines MCRsTn and MCRNc by retroviral transduction of the BC cell line MCR with the ST6GALNAC1 cDNA or with an empty vector, respectively. Compared with MCRNc, BCG-stimulated MCRsTn secreted higher levels of IL-6 and IL-8 and their secretome induced a stronger IL-6, IL-1β, and TNFα secretion by macrophages, suggesting the induction of a stronger inflammatory response. Transcriptomic analysis of MCRNc and MCRsTn revealed that ST6GALNAC1/sTn expression modulates hundreds of genes towards a putative more malignant phenotype and down-regulates several genes maintaining genomic stability. Consistently, MCRsTn cells displayed higher H2O2 sensitivity. In MCRsTn,, BCG challenge induced an increased expression of several regulatory non coding RNA genes. These results indicate that the expression of ST6GALNAC1/sTn improves the response to BCG therapy by inducing a stronger macrophage response and alters gene expression towards malignancy and genomic instability, increasing the sensitivity of BC cells to the oxidizing agents released by BCG.


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