Abstract
Hepatocellular carcinoma (HCC) is most common malignant cancer worldwide; however, the mortality rate of HCC remains high due to the invasion and metastasis of HCC. Thus, exploring novel treatments to prevent the invasion of HCC is needed for improving clinical outcome of this fatal disease. In this study, we identified lectin from Bandeiraea simplicifolia seeds (BS‐I) binds to metastasis‐associated HCC cell surface glycans by a lectin microarray and inhibits HCC cell migration and invasion through downregulating the matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9) and urokinase‐type plasminogen activator (uPA) production. These effects of BS‐I were mediated by inhibiting the activation of AKT/GSK‐3β/β‐catenin pathway and depended on specificity of lectin BS‐I binding to GalNAc. GSK3β inhibitors rescued BS‐I‐mediated inhibition of migration and invasion of HCC cell. Further, we identified that lectin BS‐I interacts with sGrp78, affects membrane localization of sGrp78 and attenuates the binding of sGrp78 and p85 to inhibit the activation of AKT/GSK‐3β/β‐catenin pathway. Overexpression of Grp78 or P85 rescues BS‐I‐mediated inhibition of migration and invasion of HCC cell. These findings demonstrated for the first time that BS‐I can act as a novel potential drug to prevent the invasion of HCC.
Highlights
Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide and the second leading cause of cancer death in men of developing country, causes 745,500 deaths each year [1]
We screened normal liver cell 7702 and four HCC cell lines (Hep3B, MHCC97L, MHCC97H and HCCLM3), which were different in metastatic capacity by a lectin microarray and found lectin Bandeiraea simplicifolia seeds (BS-I) binds to metastasis-associated HCC cell surface glycans
To identify the cell surface glycan profiles, the harvested cells were firstly fixed by 3% glutaraldehyde and incubated on 1% BSA blocked lectin microarray containing 37 lectins and each lectin was present in triplicate [28] (Fig. 1A)
Summary
Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide and the second leading cause of cancer death in men of developing country, causes 745,500 deaths each year [1]. New therapeutic strategies such as liver resection, transplantation, radiofrequency ablation and transcatheter arterial chemoembolization have been continuously developed and applied to clinical treatment of HCC; the prognosis is still very poor due to the invasion and metastasis of HCC [2]. It was found that cell surface GRP78 (sGRP78) regulates the invasion and metastasis of many human cancers by forming complexes with specific cell surface proteins and regulates signal transduction [13,14,15]. It was found that cell surface GRP78 (sGRP78) regulates the invasion and metastasis of many human cancers by forming complexes with specific cell surface proteins and regulates signal transduction [13,14,15]. sGRP78 activated the p21-activated kinase-2 (PAK2) signalling pathway and facilitated the invasion and metastasis by binding with a2macroglobulin in prostate [16], and promoted the invasion and metastasis of cancer cells by activating the uPA/uPAR protease a 2017 The Authors
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