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α2,6-Sialylation promotes hepatocellular carcinoma cells migration and invasion via enhancement of nSmase2-mediated exosomal miRNA sorting

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Abstract

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.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by the National Natural Science Foundation of China (31971214, 32171282, 31870793) and the Fundamental Research Funds for the Central Universities (DUT20YG116 and DUT20YG130).

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Authors and Affiliations

  1. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, 122406, China

    Liping Wang, Xixi Chen, Fanxu Meng, Tianmiao Huang, Wenli Li, Jianing Zhang & Yubo Liu

  2. Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China

    Shujing Wang

  3. Department of Gastric Surgery, Cancer Hospital of China Medical University (Liaoning Cancer Hospital and Institute), Liaoning, China

    Zhichao Zheng & Guoliang Zheng

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  1. Liping Wang
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Contributions

Liping Wang, Jianing Zhang, and Yubo Liu conceived and designed the study. Liping Wang, Xixi Chen, Fanxu Meng, Tianmiao Huang, Shujing Wang, Zhichao Zheng, Guoliang Zheng performed the experiments. Liping Wang and Liu Yubo wrote the paper. Wenli Li and Jianing Zhang reviewed and edited the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Jianing Zhang or Yubo Liu.

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Key points

• ST6Gal-I silencing affects the release of exosomal miRNAs from HCC cells.

• nSmase2 is a target for ST6Gal-I α2,6-sialylation.

• α2,6-sialylation regulates exosomal sorting by interfering with nSmase2 activity.

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Wang, L., Chen, X., Meng, F. et al. α2,6-Sialylation promotes hepatocellular carcinoma cells migration and invasion via enhancement of nSmase2-mediated exosomal miRNA sorting. J Physiol Biochem 79, 19–34 (2023). https://doi.org/10.1007/s13105-022-00917-1

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