PDF(Pubmed)
Abstract：
C-mannosylation is a post-translational modification that occurs intracellularly in the endoplasmic reticulum. In humans, biosynthesis of C-mannosylation in proteins containing thrombospondin type 1 repeat is catalyzed by the DPY19 family; nonetheless, biological functions of protein C-mannosylation are not yet fully understood, especially in tumor progression. Vasculogenic mimicry (VM) is the formation of fluid-conducting channels by highly invasive and genetically deregulated tumor cells, enabling the tumors to form matrix-embedded vasculogenic structures, containing plasma and blood cells to meet the metabolic demands of rapidly growing tumors. In this study, we focused on DPY19L3, a C-mannosyltransferase, and aimed to unravel its role in VM. Knockout of DPY19L3 inhibited the formation of VM in HT1080 human fibrosarcoma cells. Re-expression of wild-type DPY19L3 recovered VM formation; however, DPY19L3 isoform2, an enzymatic activity-defect mutant, did not restore it, suggesting that the C-mannosyltransferase activity of DPY19L3 is crucial to its function. Furthermore, the knockdown of DPY19L3 in MDA-MB-231 breast cancer cells hindered its network formation ability. Altogether, our findings suggest that DPY19L3 is required for VM formation and stipulate the relevance of C-mannosylation in oncogenesis.
摘要：
C-甘露糖基化是在内质网细胞内发生的翻译后修饰。在人类中,含有血小板反应蛋白1型重复蛋白的C-甘露糖基化的生物合成是由DPY19家族催化的；尽管如此，蛋白质C-甘露糖基化的生物学功能尚未完全了解，尤其是在肿瘤进展中。血管生成拟态（VM）是由高度侵袭性和遗传失调的肿瘤细胞形成的流体传导通道，使肿瘤形成基质嵌入的血管生成结构，含有血浆和血细胞，以满足快速生长的肿瘤的代谢需求。在这项研究中,我们专注于DPY19L3，一种C-甘露糖基转移酶，并旨在揭示其在VM中的作用。敲除DPY19L3抑制HT1080人纤维肉瘤细胞中VM的形成。野生型DPY19L3的再表达恢复了VM的形成；然而，DPY19L3isoform2，一种酶活性缺陷突变体，没有恢复它，表明DPY19L3的C-甘露糖基转移酶活性对其功能至关重要。此外，MDA-MB-231乳腺癌细胞中DPY19L3的敲低阻碍了其网络形成能力。总之,我们的研究结果表明,DPY19L3是VM形成所必需的,并规定了C-甘露糖基化在肿瘤发生中的相关性.
