Abstract
Abnormal sialylation due to overexpression of sialyltransferases has been associated with tumorigenesis and tumor progression. Although ST6Gal-I influences cancer persistence and progression by affecting various receptors, the underlying mechanisms and mediators remain largely obscure, especially in hepatocellular carcinoma (HCC). We found that ST6Gal-I expression was markedly upregulated in HCC tissues and cells, high levels being associated with aggressive phenotype and poor prognosis. Furthermore, we examined the roles and mechanisms of ST6Gal-I in HCC tumorigenesis and metastasis in vitro and in vivo. ST6Gal-I overexpression promoted proliferation, migration and invasion of Huh-7 cells, whereas its knockdown restricted these abilities in MHCC97-H cells. Additionally, in a mouse xenograft model, ST6Gal-I-knockdown MHCC97-H cells formed significantly smaller tumors, implying that ST6Gal-I overexpression can induce HCC cell malignant transformation. Importantly, enhanced HCC tumorigenesis and metastasis by ST6Gal-I may be associated with Wnt/β-catenin signaling promotion, including β-catenin nuclear transition and upregulation of downstream molecules. Together, our results suggest a role for ST6Gal-I in promoting the growth and invasion of HCC cells through the modulation of Wnt/β-catenin signaling molecules, and that ST6Gal-I might be a promising marker for prognosis and therapy of HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed malignant tumor and the second leading cause ofD growing life-threatening cancer worldwide.[1]
E migration of MHCC97-H/shST6Gal-I cells (Figures 3j and k). These findings suggest that ST6Gal-I expression is positively correlated with the proliferation, migration and invasion potential of HCC cells
Abnormal sialylation was found in many cancers, potentially affecting tumor cell differentiation, adhesiveness and invasion.[28]
Summary
Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed malignant tumor and the second leading cause of. It has been reported that the high expression of ST6Gal-I increases in the levels of α2,6-sialylation, and correlates with tumorigenesis and tumor progression.[16,17,18] Lu et al.[19] showed that α2,6-sialylated glycans can promote the malignant phenotypes of many tumors by regulating the related signaling pathways. ST6Gal-I is known to regulate the interaction between galectin-1 and α2,6-sialylated N-glycans, and further prevents angiogenesis and tumor progression.[17,20,21] The Rabinovich lab showed that ST6Gal-I overexpression increased in the α2,6-sialylation levels of glycoproteins, and inhibited the binding of galectin-1 and promoted the cellular apoptosis.[22,23] In our previous study, we found that upregulation of ST6Gal-I increased the adhesive capability of mouse hepatocarcinoma cell to lymph node.[24]. Evaluation of the effects of ST6Gal-I knockdown on clonogenic capacity, colony formation was found to be reduced by shST6Gal-I
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