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Inflammatory cytokines regulate the expression of glycosyltransferases involved in the biosynthesis of tumor-associated sialylated glycans in pancreatic cancer cell lines

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Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant stroma containing several pro-inflammatory cytokines, which are described to modulate the expression of important genes related to tumor promotion and progression. In the present work we have investigated the potential role of these cytokines in the biosynthesis of tumor-associated carbohydrate antigens such as sialylLewisx (SLex) through the regulation of specific glycosyltransferase genes. Methods: Two human PDAC cell lines MDAPanc-3 and MDAPanc-28 were treated with pro-inflammatory cytokines IL-1b, TNFa, IL-6 or IL-8, and the content of tumor-associated carbohydrate antigens at the cell membrane was analyzed by flow cytometry. In addition, variation in the mRNA expression of sialyltransferase (ST) and fucosyltransferase (FUT) genes, which codify for the ST and FucT enzymes involved in the carbohydrate antigens’ biosynthesis, was determined. The inflammatory microenvironment of PDAC tissues and the expression of Lewis-type antigens were analyzed by immunohistochemistry to find a possible correlation between inflammation status and the presence of tumor-associated carbohydrate antigens. Results: IL-1b stimuli increased SLex and a2,6-sialic acid levels in MDAPanc-28 cells and enhanced the mRNA levels of ST3GAL3-4 and FUT5-7, which codify for ST and FucT enzymes related to SLex biosynthesis, and of ST6GAL1. IL-6 and TNFa treatments increased the levels of SLex and Ley antigens in MDPanc-3 cells and, similarly, the mRNA expression of ST3GAL3-4, FUT1-2 and FUT6, related to these Lewis-type antigens’ biosynthesis, were increased. Most PDAC tissues stained for SLex and SLea and tended to be expressed in the tumor samples with a higher presence of inflammatory immune cells. Conclusions: The inflammatory microenvironment can modulate the glycosylation pattern of PDAC cells, increasing the expression of tumor-associated sialylated antigens such as SLex , which contributes to pancreatic tumor malignancy

This work was supported by the Spanish Ministerio de Ciencia e Innovación (Grant BIO2010-16922, awarded to RP) and by the Fundació La Marató de TV3 (Grant 050932, awarded to RP). SB acknowledges the Government of Catalonia for a pre-doctoral fellowship

Elsevier