Journal
THERANOSTICS
Volume 11, Issue 14, Pages 6905-6921Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.56882
Keywords
hepatocellular carcinoma; epithelial-mesenchymal transition; glycoproteome; FOLR1; core-fucosylation
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The study identified core-fucosylation as a key glycosylation modification linked to the promotion of EMT in HCC cells, with FOLR1 as a potential target for therapeutic interventions. The up-regulation of FUT8 was found to drive EMT induced by HGF/TGF-beta 1, highlighting the importance of glycosylation in cancer progression. Further experiments demonstrated that core-fucosylation on FOLR1 enhanced folate uptake, ultimately promoting EMT in HCC cells.
Rationale: Epithelial-mesenchymal transition (EMT) has been recognized as an important step toward high invasion and metastasis of many cancers including hepatocellular carcinoma (HCC), while the mechanism for EMT promotion is still ambiguous. Methods: The dynamic alterations of site-specific glycosylation during HGF/TGF-beta 1-induced EMT process of three HCC cell lines were systematically investigated using precision glycoproteomic methods. The possible roles of EMT-related glycoproteins and site-specific glycans were further confirmed by various molecular biological approaches. Results: Using mass spectrometry-based glycoproteomic methods, we totally identified 2306 unique intact glycopeptides from SMMC-7721 and HepG2 cell lines, and found that core-fucosylated glycans were accounted for the largest proportion of complex N-glycans. Through quantification analysis of intact glycopeptides, we found that the majority of core-fucosylated intact glycopeptides from folate receptor a (FOLR1) were up-regulated in the three HGF-treated cell lines. Similarly, core-fucosylation of FOLR1 were up-regulated in SMMC-7721 and Hep3B cells with TGF-beta 1 treatment. Using molecular approaches, we further demonstrated that FUT8 was a driver for HGF/TGF-beta 1-induced EMT. The silencing of FUT8 reduced core-fucosylation and partially blocked the progress of HGF-induced EMT. Finally, we confirmed that the level of core-fucosylation on FOLR1 especially at the glycosite Asn-201 positively regulated the cellular uptake capacity of folates, and enhanced uptake of folates could promote the EMT of HCC cells. Conclusions: Based on the results, we proposed a potential pathway for HGF or TGF-beta 1-induced EMT of HCC cells: HGF or TGF-beta 1 treatment of HCC cells can increase the expression of glycosyltransferase FUT8 to up-regulate the core-fucosylation of N-glycans on glycoproteins including the FOLR1; core-fucosylation on FOLR1 can then enhance the folate uptake capacity to finally promote the EMT progress of HCC cells.
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