Abstract

Pseudomyxoma peritonei (PMP) is a highly mucinous adenocarcinoma growing in the peritoneal cavity and most commonly originating from the appendix. Glycans play an important role in carcinogenesis, and glycosylation is altered in malignant diseases, including PMP. We have previously demonstrated that fucosylation of N-glycans is increased in PMP, but we did not observe modulation of overall sialylation. As sialic acids can be attached to the rest of the glycan via α2,3- or α2,6-linkage, we have now analyzed the linkage patterns of sialic acids in tissue specimens of normal appendices, low-grade appendiceal mucinous neoplasms (LAMN), low-grade (LG) PMP and high-grade (HG) PMP. For the linkage analysis, the enzymatically released acidic N-glycans were first treated with ethyl esterification or α2,3-sialidase digestion followed by MALDI-TOF mass spectrometry. Significant increase in the relative abundance of α2,6-sialylated and decrease in α2,3-sialylated N-glycans was observed in PMP tumors as compared to the normal appendices (P < 0.025). More specifically, increased α2,6-sialylation (P < 0.05) and decreased α2,3-sialylation (P < 0.01) were detected in afucosylated and monofucosylated N-glycans of PMPs, whereas the less abundant multifucosylated glycans, containing terminal fucose, demonstrated increased α2,3-sialylation (P < 0.01). Importantly, the increase in α2,6-sialylation was also detected between PMP and the appendiceal precursor lesion LAMN (P < 0.01). The identified glycosylation alterations produce ligands for sialic acid-binding immunoglobulin-like lectins (Siglecs) and sialofucosylated glycans binding selectins, which play a role in the peritoneal dissemination and progression of the disease.

中文翻译：

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腹膜假粘液瘤中 N-聚糖唾液酸的连接模式改变

摘要

腹膜假粘液瘤 (PMP) 是一种生长在腹膜腔的高度粘液性腺癌，最常见于阑尾。聚糖在致癌作用中起重要作用，并且糖基化在包括 PMP 在内的恶性疾病中发生改变。我们之前已经证明 PMP 中 N-聚糖的岩藻糖基化增加，但我们没有观察到整体唾液酸化的调节。由于唾液酸可以通过 α2,3- 或 α2,6- 键连接到聚糖的其余部分，我们现在分析了正常阑尾、低级别阑尾粘液性肿瘤 (LAMN) 组织标本中唾液酸的连接模式、低档（LG）PMP和高档（HG）PMP。对于连接分析，酶促释放的酸性 N-聚糖首先用乙酯化或 α2 处理，3-唾液酸酶消化，然后进行 MALDI-TOF 质谱分析。与正常阑尾相比，在 PMP 肿瘤中观察到 α2,6-唾液酸化的相对丰度显着增加，α2,3-唾液酸化 N-聚糖减少。P  < 0.025)。更具体地说， 在 PMP 的非岩藻糖基化和单岩藻糖基化 N-聚糖中检测到增加的 α2,6-唾液酸化 ( P  < 0.05) 和减少的 α2,3-唾液酸化 ( P < 0.01)，而含有末端岩藻糖的较少丰富的多岩藻糖基化聚糖证明增加 α2,3-唾液酸化 ( P  < 0.01)。重要的是，在 PMP 和阑尾前体病变 LAMN 之间也检测到 α2,6-唾液酸化的增加（P  < 0.01）。已鉴定的糖基化改变产生唾液酸结合免疫球蛋白样凝集素 (Siglecs) 和唾液酸化聚糖结合选择素的配体，它们在疾病的腹膜传播和进展中发挥作用。