Molecular Mechanism Of Asialoglycoprotein Receptor In Inhibiting Metastasis Of Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC),which is one of the most common malignant tumors,has a poor prognosis,and metastasis is one of the main reasons for its treatment failure.Therefore,to explore molecular mechanisms of HCC metastasis could help to find effective therapeutic strategies and improve prognosis of patients.Asialoglycoprotein receptor(ASGR)is mainly expressed in the liver parenchyma cells,and its role in HCC is largely unknown.This study is to investigate the clinical significance of ASGR in HCC,as well as its effect on the metastatic potentials of hepatoma cells and its molecular mechanisms.In this study,expression of ASGR1 was detected in 71 pairs of HCC tissues and their corresponding adjacent nontumoral liver tissues by real time PCR.Results showed that m RNA level of ASGR1 was significantly lower in HCC than that in the corresponding adjacent nontumoral liver tissues.Data from Kaplan-Meier analysis in 146 HCC patients exhibited that the patients with low expression of ASGR1 had shorter overall survival(OS)and shorter disease-free survival(DFS)than those with high expression of ASGR1.Moreover,low expression of ASGR1 was significantly correlated with advanced TNM stage and microvascular invasion in HCC.Meanwhile,the role of ASGR1 in HCC was explored in vitro and in vivo by establishing stable hepatoma cell lines with ASGR1 overexpression or ASGR1 knockdown.Gain-of-function and loss-of-function experiments indicated that ASGR1 overexpression or ASGR1 knockdown had no effect on the proliferation of hepatoma cells,but ASGR1 overexpression could inhibit the migration and invasion of hepatoma cells in vitro as well as suppress the experimental lung metastasis of hepatoma cells in nude mice,and ASGR1 knockdown had the reverse effect.Co-immunoprecipitation revealed that ASGR1 could directly interact with longevity assurance 2 of yeast LAG1(LASS2).And LASS2 knockdown by si RNA interference could attenuate the inhibitory effect of ASGR1 on the metastatic potentials of hepatoma cells.The activity of V-ATPases was detected by using a p H sensitive probe.Results suggested that ASGR1 might suppress the activity of V-ATPases through LASS2.Conclusion: In this study,we found that asialoglycoprotein receptor 1(ASGR1)was down-regulated in HCC.Low expression of ASGR1 was significantly correlated with advanced TNM stage,microvascular invasion and poor prognosis.At the same time,ASGR1 could directly interact with LASS2,which led to the inhibition of V-ATPases activity,thereby inhibited the metastatic potentials of hepatoma cells.These results indicate that ASGR1 may act as a negative regulatory factor in HCC metastasis,and suggest that ASGR1 may serve as one of the potential predictors of prognosis in HCC patients.