In this study, we found that HCV and its protein NS4B induced the expression of cancer-related NF-κB target genes (C-myc, Mcl-1, Cyclin D1 and MMP-9) in both human hepatoma cells and primary human hepatocytes and this induction was mediated by ER stress response pathway, EOR-Ca2+-ROS, implying that ER stress response pathway may be involved in carcinogenesis. Here, MMP9 is linked to hepatocellular carcinoma.