Conclusion: These results indicate that the HCV core protein potentiates chemically induced HCC through c-Jun and STAT3 activation, which in turn, enhances cell proliferation, suppresses apoptosis, and impairs oxidative DNA damage repair, leading to hepatocellular transformation. Hepatology 2010 Hepatitis C virus (HCV) causes chronic hepatitis and liver cirrhosis and greatly increases the risk

for hepatocellular carcinoma (HCC).1-3 In both HCC and chronic hepatitis, the transcription factor activator protein-1 (AP-1) is activated and implicated.4 The ectopic expression of HCV core protein in cell cultures also activates AP-1 (c-Jun)5 via the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated see more protein kinase,6, 7 and HCV core transgenic (Tg) mice develop liver tumors,8 suggesting the role of c-Jun in core-induced oncogenesis. The transcription activator c-Jun is required for cell proliferation in postnatal hepatocytes.9 Mice deficient in c-Jun die between embryonic days E12.5 and E13.5 from massive apoptosis of hepatoblasts, erythroblasts, and other cell types, indicating the requirement of c-Jun in normal liver development and hematopoiesis.10, 11 To rescue embryonic lethality,

a “floxed” c-jun allele is deleted in a designated cell type upon expression of the Cre recombinase under the control of a cell-type–specific promoter. Using this conditional gene disruption, the requirement for c-jun is also shown for chemically-induced HCC in mice where c-Jun deficiency in hepatocytes reduces both the number and size of Fulvestrant solubility dmso HCC after tumor initiation with diethylnitrosamine (DEN), while increasing apoptosis.12 HCV

core protein induces reactive oxygen species (ROS), and HCV core Tg mice have higher hepatic levels of 8-oxo-2′-deoxyguanosine (8-oxodG), which is indicative of DNA damage by ROS.13 In fact, HCV core Tg mice show increased mutation frequencies of tumor suppressor and proto-oncogenes.13, 14 ROS also activates c-Jun and signal transducer and activator of transcription 3 (STAT3).15 Therefore, the core protein may increase Digestive enzyme the growth and survival of initiated tumor cells via activation of c-Jun and STAT3. However, the mechanisms by which c-Jun and STAT3 specifically contribute to liver oncogenesis induced by interactions of HCV core and environmental carcinogens remain to be elucidated. Furthermore, whether HCV core protein works as a tumor initiator or promoter has not been determined.16 The present study demonstrates that the mitogenic and antiapoptotic effects mediated by c-Jun/AP-1 and STAT3 are both required for hepatocyte susceptibility to HCV core-initiated hepatocellular transformation, and that this is caused by fixation of genetic mutations induced by oxidative stress and impaired DNA repair, resulting from activation of c-Jun and nitric oxide (NO).