Inhibition of Fucosylation by 2-fluorofucose Suppresses Human Liver Cancer HepG2 Cell Proliferation, Migration, and Tumor Formation
Each year in the United States, about 24,000 men and 10,000 women get liver cancer, and about 18,000 men and 9,000 women die from the disease. Thus the treatment of liver cancer has been the focus of worldwide researchers.
The research team from Tohoku Medical and Pharmaceutical University and National Institute of Advanced Industrial Science and Technology shows us a new potential treatment for this disease. They found that cell proliferation and integrin-mediated cell migration were significantly suppressed in cells treated with 2-fluoro-L-fucose (2FF). Moreover, the treatment with 2FF decreased the core fucosylation levels of membrane glycoproteins, which in turn suppressed downstream signals, and this clearly described the roles of 2FF and the importance of core fucosylation in liver cancer progression, suggesting 2FF shows promise for use in the treatment of hepatoma.
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Relations Between Core Fucosylation and Hepatocellular Carcinoma
Glycosylation is the reaction in which a carbohydrate is attached to a hydroxyl or other functional group of another molecule, which plays an essential role in various biological processes such as inflammation, growth, differentiation, carcinogenesis, and cancer metastasis.
Core fucosylation is an important modification of the N-glycan core structure, forming the α1,6 fucosylation of the GlcNAc residue linked to the asparagine, catalyzed by FUT8. In regards to liver cancer, core fucosylation is a pre-eminent factor as it can be catalyzed to transfer fucose residue to the innermost asparagine-linked GlcNAc, and it is a process highly related to liver cancer, especially to hepatocellular carcinoma (HCC).
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2-fluoro-L-fucose May Enhance the Treatment of Hepatoma
In this study, the researchers examined the effects of 2FF in live cancer HepG2 cells and further clarified the underlying molecular mechanisms, using various kinds of technologies, such as western blot and lectin blot assay, RT-PCR, flow cytometry analysis, mass spectrometry, cell growth assay, transwell cell migration assays, and statistical analysis.
They found that treatment with 2FF greatly decreased core fucosylation levels and both suppressed downstream signaling and tumor formation, which suggested that 2FF might be a novel candidate for liver cancer therapy. Key results of this research are listed below:
1. 2FF suppressed fucosylation in HepG2 cells.
2. Alteration of the N-linked glycans of HepG2 cells treated with 2FF.
3. Treatment with 2FF inhibited cell proliferation and colony formation.
4. 2FF suppressed integrin-mediated cell migration.
5. 2FF inhibited core fucosylation of EGFR and integrin β1 and the related intracellular signaling.
6. Inhibitory effects of 2FF on tumorigenesis and core fucosylation in vivo.
Liver cancer ranks as the second leading cause of death from cancer. Effective therapy for liver cancer remains one of the biggest challenges for public health. Previous studies have suggested that core fucosylated alpha-fetoprotein (AFP) was a reliable marker to distinguish HCC from chronic hepatitis and liver cirrhosis. And this study clearly show that core fucosylation plays crucial roles in liver cancer, which enabled us to predict that the inhibition of core fucosylation could provide a novel strategy for liver cancer therapy.
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