α2,6-Sialylation promotes hepatocellular carcinoma cells migration and invasion via enhancement of nSmase2-mediated exosomal miRNA sorting.
α2,6-Sialylation promotes hepatocellular carcinoma cells migration and invasion via enhancement of nSmase2-mediated exosomal miRNA sorting.
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α2,6-Sialylation 通过增强 nSmase2 介导的外泌体 miRNA 分选促进肝细胞癌细胞迁移和侵袭。
DOI：
10.1007/s13105-022-00917-1
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发表时间：
2022
影响因子：
3.4
通讯作者：
Yubo Liu
中科院分区：
文献类型：
--
作者：
Liping Wang;Xixi Chen;Fanxu Meng;Tianmiao Huang;Shujing Wang;Zhichao Zheng;Guoliang Zheng;Wenli Li;Jianing Zhang;Yubo Liu
外泌体在肝细胞癌（HCC）的细胞间通讯和转移进展中发挥着关键作用。最近，我们的研究小组表明，α2,6-唾液酸化在癌症来源的外泌体的增殖和迁移促进作用中发挥着重要作用。然而，分子基础仍然难以捉摸。在这项研究中，阐明了 α2, 6-唾液酸化介导的特定 microRNA (miRNA) 分选到外泌体中的机制。我们进行了 miRNA 谱分析，以比较来自仅 α2, 6-唾液酸化状态不同的 HCC 细胞系的外泌体。在野生型和 β-半乳糖苷 α2, 6-唾液酸转移酶 I (ST6Gal-I) 敲低的 MHCC-97H 细胞衍生的外泌体中总共鉴定出 388 个差异分布的 miRNA。中性鞘磷脂酶-2 (nSmase2) 是介导外泌体 miRNA 排序的重要调节因子，被发现是 ST6Gal-I 的靶标。 α2, 6-唾液酸化的减少可能会损害 nSmase2 的活性以及 nSmase2 依赖性的外泌体 miRNA 分选。这种 α2,6-唾液酸化依赖性分选增强了受体 HCC 细胞的运动能力。我们的数据进一步证明，α2,6-唾液酸化介导的外泌体miR-100-5p分选通过PI3K/AKT信号通路促进受体HepG2细胞的迁移和侵袭。细胞转移相关基因 CLDN11 被证实是外泌体 miR-100-5p 的直接靶标，可提高受体 HCC 细胞的迁移率。总之，我们的结果表明 α2,6-唾液酸化调节 nSmase2 依赖性外泌体 miRNA 分选并促进 HCC 进展。
Exosomes have a critical role in the intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). Recently, our group showed that α2, 6-sialylation played an important role in the proliferation- and migration-promoting effects of cancer-derived exosomes. However, the molecular basis remains elusive. In this study, the mechanism of α2, 6-sialylation-mediated specific microRNAs (miRNA) sorting into exosomes was illustrated. We performed miRNA profiling analysis to compare exosomes from HCC cell lines that differ only in α2, 6-sialylation status. A total of 388 differentially distributed miRNAs were identified in wild-type and β-galactoside α2, 6-sialyltransferase I (ST6Gal-I) knockdown MHCC-97H cells-derived exosomes. Neutral sphingomyelinase-2 (nSmase2), an important regulator mediating the sorting of exosomal miRNAs, was found to be a target of ST6Gal-I. The reduction of α2, 6-sialylation could impair the activity of nSmase2, as well as the nSmase2-dependent exosomal miRNAs sorting. This α2,6-sialylation-dependent sorting exerted an augmentation of motility on recipient HCC cells. Our data further demonstrated that α2,6-sialylation-mediated sorting of exosomal miR-100-5p promoted the migration and invasion of recipient HepG2 cells via the PI3K/AKT signaling pathway. The cellular metastasis-related gene CLDN11 was confirmed as a direct target of exosomal miR-100-5p, which elevated the mobility of recipient HCC cells. In conclusion, our results showed that α2,6-sialylation modulates nSmase2-dependent exosomal miRNAs sorting and promotes HCC progression.