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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.
Highlights
Intravesical inoculation with Bacillus CalmetteGuérin (BCG) is an effective adjuvant therapy for treating non-muscle invasive bladder cancer (BC)
We analyzed the expression of ST6GALNAC1 mRNA in matched tissues of normal urothelium and bladder cancer from 43 BC patients before Bacillus Calmette-Guérin (BCG) therapy
In this study we have shown that BC patients responding to BCG-therapy express higher levels of IL-6 mRNAs and that a positive correlation exists between IL-6 and ST6GALNAC1 mRNA, but only among BCG responders
Summary
Intravesical inoculation with Bacillus CalmetteGuérin (BCG) is an effective adjuvant therapy for treating non-muscle invasive bladder cancer (BC). The precise mechanisms of its action remains uncertain, it is clear that BCG is internalized by cancer cells and induces www.impactjournals.com/oncotarget a local inflammatory response, which is responsible for the anti-tumor effect [1,2,3]. The tumor-associated-antigen sialyl-Tn (sTn) is a disaccharide O-glycosidically linked to serine or threonine, whose biosynthesis is mainly controlled by its cognate sialyltransferase ST6GALNAC1 (Figure 1) [9, 11, 12]. BC patients expressing the sTn and/or the related antigen sialyl-6-T (Figure 1) show a better response to BCG immunotherapy. STn expression induces a more aggressive phenotype but a better clinical response to BCG, the mechanisms underlying these biological effects remain to be elucidated
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