Study On Mechanisms Underlying The Involvement Of CIAP2 In HBV-induced Liver Cancer And Sorafenib Resistance

Liver cancer is the second leading cause of cancer worldwide,and more than half of the liver cancer cases are caused by hepatitis B virus(HBV)infection.However,up to now,mechanism underlying HBV induced liver cancer has not yet been fully elucidated.Furthermore,HBV infection can also lead the liver cancer resistant to sorafenib,the only approved chemotherapy reagent.Therefore,it is of great importance to in-depth investigate the mechanism underlying HBV-induced liver cancer,which can not only give better understanding between HBV infection and liver cancer,but also can provide valuable information for the diagnosis and treatment of the disease.The cellular inhibitor of apoptosis protein 2(cIAP2)is involved in the pathogenesis of various cancers,but its relation to HBV-induced liver cancer has remained to be investigated.This study investigated in-depth about the relationship between HBV and cIAP2 on both clinical tissue and cell line level,and also investigated the importance of cIAP2 in HBV-induced sorafenib resistance in liver cancer on both cell line and animal models.The analysis on clinical HBV infected and non-infected liver cancer tissue samples,showed that cIAP2 expression was increased in HBV positive tissue comparing to HBV negative tissue.In HBV positive tissue,the expression of cIAP2 was higher in cancer tissue comparing to adjacent noncancerous tissue.The data on cell lines also confirmed that HBV infection upregulated cIAP2 expression on both mRNA and protein levels.Analysis on cIAP2 promoter revealed that HBV could enhance NF-?B phosphorylation and its translocation into nucleus and binding onto cIAP2 promoter,leading to promoter activation and cIAP2 transcription.Further signaling pathway analysis showed that PI3K/AKT/NF-?B pathway was involved in HBV-induced cIAP2 expression.Cell viability and detection of cleaved Caspase 3 showed that HBV positive cell line HepG2.215 was more resistant to sorafenib than HBV negative cell line HepG2.Upregulation of cIAP2 in HepG2 cells enhanced resistance to sorafenib,while knockdown of cIAP2 in HepG2.215 cells enhanced sensitivity to sorafenib,indicating that cIAP2 might be involved in HBV-induced sorafenib resistance in liver cancer.Treatment of HepG2.215 cells with the combination of sorafenib and anti-HBV drug lamivudine partially restored cancer cell sensitivity to sorafenib,namely the enhancement of cell apoptosis.The treatment with the combination of sorafenib and AKT inhibitor showed similar effect.In the xenotransplantation nude mouse model,the combination treatment with sorafenib and lamivudine also effectively suppressed tumor growth.Taken together,the study reveals that HBV can enhance NF-?B phosphorylation and its binding to cIAP2 promoter through PI3K/AKT/NF-?B signaling pathway,which leads to elevated cIAP2 expression.Consistent high cIAP2 expression may contribute to liver cancer pathogenesis.In addition,cIAP2 is involved in HBV-induced sorafenib resistance in liver cancer,and inhibition of HBV replication and AKT signaling pathway can decrease cIAP2 and consequently partially restore cell sensitivity to sorafenib.The findings of the study provide new potential mechanism underlying HBV-induced liver cancer pathogenesis and sorafenib resistance,and also offer valuable targets for the diagnosis and treatment of HBV positive liver cancer.