Neutrophil interactions with sialyl Lewis X on human nonsmall cell lung carcinoma cells regulate invasive behavior.
Neutrophil interactions with sialyl Lewis X on human nonsmall cell lung carcinoma cells regulate invasive behavior.
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DOI：
10.1002/cncr.26059
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发表时间：
2011-10-01
期刊：
影响因子：
6.2
通讯作者：
Farooqui M
中科院分区：
文献类型：
--
作者：
St Hill CA;Krieser K;Farooqui M
糖唾液酸刘易斯X（sLeX）在白细胞和癌细胞上表达，并在炎症过程和早期转移期间与选择素结合。sLeX的合成依赖于包括α（1，3/1，4）岩藻糖基转移酶（FucT-III）在内的酶的活性。肿瘤坏死因子α（TNF-α）上调FucT-III，导致呼吸系统疾病患者气道中sLeX增加，然而，在炎症肿瘤微环境中调节sLeX的机制尚未完全了解。我们用FucT-III基因稳定转染人肺癌细胞系，并将其暴露于TNF-α，通过半定量实时聚合酶链反应和流式细胞术研究其在sLeX表达和选择素结合能力调节中的作用。我们使用荧光阵列和ELISA检测转染细胞的细胞因子表达，使用Matrigel检测侵袭，以及形态学改变。分析人肺组织阵列用于sLeX和中性粒细胞的免疫组织化学检测。用重组人（rh）TNF-α刺激FucT-III转染的细胞可上调sLeX表达并增加E-选择素结合。转染细胞分泌高水平的IL-8、GRO-α和MCP-1。细胞暴露于rhTNF-α、中性粒细胞条件培养基和中性粒细胞与癌细胞5：1比例培养物中显著增加sLeX表达和侵袭力，并发生非粘附性形态学变化。在肺癌中，而不是在正常肺组织中，71%的肿瘤高度阳性sLeX表达的中性粒细胞浸润增加的地区。中性粒细胞可以被募集到肺癌中FucT-III活性和sLeX表达的区域，以增强肺癌细胞的侵袭和转移潜力。
The carbohydrate Sialyl Lewis X (sLeX) is expressed on leukocytes and carcinoma cells and binds to selectins during inflammatory processes and early metastasis. Synthesis of sLeX is dependent on activity of enzymes including α(1,3/1,4) fucosyltransferase (FucT-III). Tumor necrosis factor alpha (TNF-α) up-regulates FucT-III resulting in increased sLeX in the airways of patients with respiratory disease, however, the mechanisms that regulate sLeX in the inflammatory tumor microenvironment are not well understood. We stably transfected human lung carcinoma cell lines with the FucT-III gene and exposed them to TNF-α to investigate its role in regulation of sLeX expression and selectin binding ability by semi-quantitative real-time polymerase chain reaction and flow cytometry. We examined cytokine expression of transfected cells using chemiluminescent arrays and ELISA, invasion using Matrigel assays, and alterations in morphology. Human lung tissue arrays were analyzed for immunohistochemical detection of sLeX and neutrophils. Stimulation of FucT-III transfected cells with recombinant human (rh) TNF-α upregulated sLeX expression and increased E-selectin binding. Transfected cells secreted high levels of IL-8, GRO-α and MCP-1. Cells exposed to rhTNF-α, neutrophil conditioned media, and 5:1 ratio cultures of neutrophils to cancer cells significantly increased sLeX expression and invasiveness, and underwent non-adherent morphological changes. In lung carcinomas but not in normal lung tissues, 71% of tumors were highly positive for sLeX expression in areas of increased neutrophil infiltration. Neutrophils may be recruited to areas of FucT-III activity and sLeX expression in lung carcinomas to enhance the invasive and metastatic potential of lung cancer cells.