Interaction of Hepatitis C Viral Proteins with Cellular Oncoproteins in the Induction of Liver Cancer

Figure 1

Interactions between HCV proteins and oncoproteins, YB-1 and p53 and other important host cells proteins implicated in hepatocellular carcinogenesis: the tumor suppressor gene p53 is more frequently inactivated in a variety of cancers. YB-1, a master regulator of several genes involved in cell proliferation and apoptosis, has also been shown to be activated in practically all types of cancer. The Core protein of HCV has been shown to bind to p53 and change its properties. NS5A interacts with p53 and cyclin D1 and this interaction prevents phosphorylation of RB and stimulates transcription of various cell cycle genes induced by the transcription factor E2F. YB-1 also activates E2F transcription factors by sequestering cyclin D1 and modulating RB gene expression. NS3/4 interacts with YB-1 and many host cell proteins involved in ribosomal RNA synthesis, and nucleolin, which binds to various RNAs and regulates their translation. NS2 has been shown to upregulate cyclin E. Additionally, YB-1 was shown to regulate major signaling pathways implicated in several tumors. YB-1 also is implicated in EMT through activation of cadherin genes and this phenotypic change is important for cancer. Also it has been shown that depending on the concentration of YB-1 and its cellular localization, it can directly activate or repress transcription of extracellular matrix components, which play a major role in fibrosis leading to cirrhosis. YB-1 also activates transcription of matrix metalloproteinases genes which are involved in tumor metastasis. YB-1 also regulates expression of Myc and Fos oncogenes. HCV proteins are shown in white with blue background.