Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the leading causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide.Here we investigated the biological effects of proteins of HBV and HCV in association with cellular factors with the aims to define the molecular mechanisms involved in pathogenesis in response to the viral infection.We demonstrated that of HCV and its non-structural protein NS3 activate Cyclooxygenase-2 (COX-2) expression and enhances prostaglandin E2 (PGE2) production.Multiple signaling pathways are involved cooperatively in such regulation in a calcium-independent manner, which requires signaling components, including JNK, ERK, and PKD2, and transcription factor, NF-κB.We also demonstrated that NS3 played an important role in the activation of matrix metalloproteinase-9 (MMP-9) through p38 and ERK1/2.NS3 induced DNA-binding activity of NF-κB and ERK1/2 inhibitor or p38 inhibitor significantly blocked such binding.