Inflammatory cytokines regulate the expression of glycosyltransferases involved in the biosynthesis of tumor-associated sialylated glycans in pancreatic cancer cell lines
Inflammatory cytokines regulate the expression of glycosyltransferases involved in the biosynthesis of tumor-associated sialylated glycans in pancreatic cancer cell lines
复制标题
DOI：
10.1016/j.cyto.2015.04.006
复制
发表时间：
2015-09-01
期刊：
影响因子：
3.8
通讯作者：
Peracaula, Rosa
中科院分区：
文献类型：
--
作者：
Bassaganas, Sonia;Allende, Helena;Peracaula, Rosa
背景资料：胰腺导管腺癌（PDAC）的特征在于含有多种促炎细胞因子的丰富基质，这些促炎细胞因子被描述为调节与肿瘤促进和进展相关的重要基因的表达。在目前的工作中，我们已经研究了这些细胞因子在肿瘤相关的碳水化合物抗原如唾液酸路易斯（x）（SLe（x））的生物合成中通过调节特异性糖基转移酶基因的潜在作用。用促炎细胞因子IL-1 β、TNF α、IL-6或IL-8处理两种人PDAC细胞系MDAPanc-3和MDAPanc-28，流式细胞术分析细胞膜上肿瘤相关糖抗原的含量。此外，唾液酸转移酶（ST）和岩藻糖基转移酶（FLIT）基因的mRNA表达的变化，编码的ST和FucT酶参与碳水化合物抗原的生物合成，进行了测定。通过免疫组化分析PDAC组织的炎症微环境和Lewis型抗原的表达，以发现炎症状态与肿瘤相关碳水化合物抗原的存在之间的可能相关性。IL-1 β刺激增加MDAPanc-28细胞中的SLe（x）和α 2，6-唾液酸水平，并增强ST 3GAL 3 -4和FUT 5 -7的mRNA水平，其编码与Sle（x）生物合成相关的ST和FucT酶以及ST 6 GAL 1。IL-6和TNF α处理增加了MDPanc-3细胞中Sle（x）和Le（y）抗原的水平，并且类似地，与这些Lewis型抗原的生物合成相关的ST 3GAL 3 -4、FUT 1 -2和FUT 6的mRNA表达增加。结论：炎症微环境可调节PDAC细胞的糖基化模式，增加肿瘤相关唾液酸化抗原如SLex的表达，从而促进胰腺肿瘤恶性化。(C)2015爱思唯尔有限公司版权所有。
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 sialyl-Lewis(x)(SLe(x)) 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-1 beta, TNF alpha, 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 (FLIT) 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-1 beta stimuli increased SLe(x) and alpha 2,6-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 SLe(x) biosynthesis, and of ST6GAL1. IL-6 and TNF alpha treatments increased the levels of SLe(x) and Le(y) 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 SLe(x) and SLe(a) 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. (C) 2015 Elsevier Ltd. All rights reserved.