Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.
Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal.
Int J Mol Sci. 2017 Oct 28;18(11):2262. doi: 10.3390/ijms18112262.
Aberrant expression and hyperactivation of the human epidermal growth factor receptor 2 (ErbB2) constitute crucial molecular events underpinning gastric neoplastic transformation. Despite ErbB2 extracellular domain being a well-known target for glycosylation, its glycosylation profile and the molecular mechanisms through which it actively tunes tumorigenesis in gastric cancer (GC) cells remain elusive. We aimed at disclosing relevant ErbB2 glycan signatures and their functional impact on receptor's biology in GC cells. The transcriptomic profile of cancer-relevant glycosylation enzymes, and the expression and activation of the ErbB receptors were characterized in four GC cell lines. Cellular- and receptor-specific glycan profiling of ErbB2-overexpressing NCI-N87 cells unveiled a heterogeneous glycosylation pattern harboring the tumor-associated sialyl Lewis a (SLe) antigen. The expression of SLe and key enzymes integrating its biosynthetic pathway were strongly upregulated in this GC cell line. An association between the expression of and , a central gene in SLe biosynthesis, was disclosed in GC patients, further highlighting the crosstalk between ErbB2 and SLe expression. Moreover, cellular deglycosylation and CA 19.9 antibody-mediated blocking of SLe drastically altered ErbB2 expression and activation in NCI-N87 cells. Altogether, NCI-N87 cell line constitutes an appealing in vitro model to address glycan-mediated regulation of ErbB2 in GC.
人类表皮生长因子受体 2（ErbB2）的异常表达和过度激活构成了胃肿瘤转化的关键分子事件。尽管 ErbB2 细胞外结构域是众所周知的糖基化靶点，但它的糖基化谱及其主动调节胃癌（GC）细胞发生癌变的分子机制仍不清楚。我们旨在揭示相关的 ErbB2 聚糖特征及其对 GC 细胞中受体生物学的功能影响。在四种 GC 细胞系中，我们对与癌症相关的糖基化酶的转录组谱以及 ErbB 受体的表达和激活进行了表征。在过表达 ErbB2 的 NCI-N87 细胞中，对细胞和受体特异性的 ErbB2 聚糖进行了分析，揭示了一种具有肿瘤相关唾液酸 Lewis a（SLe）抗原的异质糖基化模式。在这种 GC 细胞系中，SLe 的表达及其生物合成途径中的关键酶强烈上调。在 GC 患者中发现了 和 ，SLe 生物合成的核心基因的表达之间存在关联，这进一步强调了 ErbB2 和 SLe 表达之间的串扰。此外，细胞去糖基化和 CA 19.9 抗体介导的 SLe 阻断显著改变了 NCI-N87 细胞中 ErbB2 的表达和激活。总之，NCI-N87 细胞系构成了一种有吸引力的体外模型，可用于研究聚糖对 GC 中 ErbB2 的调节作用。
