Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans
Metastasis of cholangiocarcinoma is promoted by extended high-mannose glycans
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DOI：
10.1073/pnas.1916498117
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发表时间：
2020-04-07
影响因子：
11.1
通讯作者：
Lebrilla, Carlito B.
中科院分区：
文献类型：
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作者：
Park, Diane Dayoung;Phoomak, Chatchai;Lebrilla, Carlito B.
膜结合寡糖形成细胞与其环境之间的界面边界，介导粘附和信号传导等过程。这些结构可以根据细胞类型、外部刺激和遗传因素在组成和表达方面发生动态变化。因此，糖基化是目前无法治愈的晚期癌症的治疗干预的有希望的靶点。在这里，我们表明胆管癌转移的特征是高尔基体α-甘露糖苷酶I编码基因MAN 1A 1的下调，导致具有终止α-1，2-甘露糖残基的延伸高甘露糖聚糖的增加。随后通过抑制α-甘露糖苷酶I重塑糖组导致显著更高的迁移和侵袭能力，同时掩蔽细胞表面甘露糖基化抑制转移相关表型。差异表达的膜糖蛋白和分子建模的独家阐明表明，在转铁蛋白受体蛋白1的螺旋结构域延长高甘露糖糖基化促进构象变化，提高非共价相互作用能，并导致转移性胆管癌细胞迁移的增强。结果支持存在于癌细胞膜蛋白上的α-1，2-甘露糖基化N-聚糖可以作为预防转移的治疗靶点。
Membrane-bound oligosaccharides form the interfacial boundary between the cell and its environment, mediating processes such as adhesion and signaling. These structures can undergo dynamic changes in composition and expression based on cell type, external stimuli, and genetic factors. Glycosylation, therefore, is a promising target of therapeutic interventions for presently incurable forms of advanced cancer. Here, we show that cholangiocarcinoma metastasis is characterized by down-regulation of the Golgi a-mannosidase I coding gene MAN1A1, leading to elevation of extended high-mannose glycans with terminating alpha-1,2-mannose residues. Subsequent reshaping of the glycome by inhibiting alpha-mannosidase I resulted in significantly higher migratory and invasive capabilities while masking cell surface mannosylation suppressed metastasis-related phenotypes. Exclusive elucidation of differentially expressed membrane glycoproteins and molecular modeling suggested that extended high-mannose glycosylation at the helical domain of transferrin receptor protein 1 promotes conformational changes that improve noncovalent interaction energies and lead to enhancement of cell migration in metastatic cholangiocarcinoma. The results provide support that alpha-1,2-mannosylated N-glycans present on cancer cell membrane proteins may serve as therapeutic targets for preventing metastasis.