缺失α-1,2-甘露糖苷酶 MAN1C1 通过增强 CD133-FIP200 相互作用促进肝内胆管癌的发生。

Loss of α-1,2-mannosidase MAN1C1 promotes tumorigenesis of intrahepatic cholangiocarcinoma through enhancing CD133-FIP200 interaction.

机构信息

NHC Key Laboratory of Glycoconjuates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China.

出版信息

Cell Rep. 2023 Dec 26;42(12):113588. doi: 10.1016/j.celrep.2023.113588. Epub 2023 Dec 19.

DOI:10.1016/j.celrep.2023.113588

PMID:38117655

Abstract

CD133 is widely used as a marker to isolate tumor-initiating cells in many types of cancers. The structure of N-glycan on CD133 is altered during the differentiation of tumor-initiating cells. However, the relationship between CD133 N-glycosylation and stem cell characteristics remains elusive. Here, we found that the level of α-1,2-mannosylated CD133 was associated with the level of stemness genes in intrahepatic cholangiocarcinoma (iCCA) tissues. α-1,2-mannosylated CD133 cells possessed the characteristics of tumor-initiating cells. The loss of the Golgi α-mannosidase I coding gene MAN1C1 resulted in the formation of α-1,2-mannosylated CD133 in iCCA-initiating cells. Mechanistically, α-1,2-mannosylation promoted the cytoplasmic distribution of CD133 and enhanced the interaction between CD133 and the autophagy gene FIP200, subsequently promoting the tumorigenesis of α-1,2-mannosylated CD133 cells. Analysis of iCCA samples showed that the level of cytoplasmic CD133 was associated with poor iCCA prognosis. Collectively, α-1,2-mannosylated CD133 is a functional marker of iCCA-initiating cells.

摘要

CD133 被广泛用作许多类型癌症中肿瘤起始细胞的分离标志物。在肿瘤起始细胞的分化过程中，CD133 的 N-糖链结构发生改变。然而，CD133 N-糖基化与干细胞特性之间的关系仍不清楚。在这里，我们发现在肝内胆管癌（iCCA）组织中，α-1,2-甘露糖化 CD133 的水平与干性基因的水平相关。α-1,2-甘露糖化 CD133 细胞具有肿瘤起始细胞的特征。高尔基 α-甘露糖苷酶 I 编码基因 MAN1C1 的缺失导致 iCCA 起始细胞中形成α-1,2-甘露糖化 CD133。在机制上，α-1,2-甘露糖化促进了 CD133 的细胞质分布，并增强了 CD133 与自噬基因 FIP200 之间的相互作用，随后促进了α-1,2-甘露糖化 CD133 细胞的肿瘤发生。对 iCCA 样本的分析表明，细胞质 CD133 的水平与 iCCA 的不良预后相关。总之，α-1,2-甘露糖化 CD133 是 iCCA 起始细胞的功能标志物。