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

• Wang, Liping ^[1] ; Chen, Xixi ^[1] ; Meng, Fanxu ^[1] ; Huang, Tianmiao ^[1] ; Wang, Shujing ^[2] ; Zheng, Zhichao ^[3] ; Zheng, Guoliang ^[3] ; Li, Wenli ^[1] ; Zhang, Jianing ^[1] ; Liu, Yubo ^[1]
  1. [1] Dalian University of Technology

     Dalian University of Technology

     China

     
  2. [2] Dalian Medical University

     Dalian Medical University

     China

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

  Mostrar afiliaciones +
• Localización: Journal of physiology and biochemistry, ISSN-e 1877-8755, ISSN 1138-7548, Vol. 79, Nº. 1, 2023, págs. 19-34
• Idioma: inglés
• Enlaces
  • Texto completo  1 (pdf)   2  
• Resumen

  • 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.