title: Hepatitis C virus core protein activates Wnt/β-catenin signaling through multiple regulation of upstream molecules in the SMMC-7721 cell line.
abstract: The core protein of hepatitis C virus (HCV) has been implicated in HCV-induced liver pathogenesis. Previous data have shown that the HCV core protein has pleiotropic functions, including transcriptional regulation of a number of cellular genes, although the mechanism of gene regulation remains unclear. Wnt/β-catenin signaling is also involved in hepatocellular carcinoma (HCC) tumorigenesis. To elucidate the molecular mechanism of HCV pathogenesis, we examined whether HCV core protein activates Wnt/β-catenin signaling in the hepatoma cell line SMMC-7721. The effects of core protein on Wnt/β-catenin signaling cascades were investigated by luciferase reporter gene assay, immunofluorescence, western blot and RT-PCR analysis. Here, we demonstrate that HCV core protein plays an essential role in activating β-catenin/Tcf-4-dependent transcriptional activity and increases active β-catenin expression and nuclear accumulation in SMMC-7721 cells. An RT-PCR assay indicated that core protein upregulates gene expression of canonical Wnt ligands, such as Wnt2, Wnt3, Wnt3a, Wnt8b, Wnt10a, Wnt10b, frizzled receptors Fzd1, 2, 5, 6, 7, 9, and LRP5/6 co-receptors. However, Wnt antagonists SFRP3, 5 and Dkk1 were moderately repressed. Furthermore, ectopic expression of core protein markedly promoted cell proliferation. The soluble Fzd molecule FrzB or the β-catenin inhibitor siBC efficiently blocked cell growth stimulation by the core gene. Our present findings demonstrate that the HCV core protein activates canonical Wnt signaling through tight regulation of several important molecules upstream of β-catenin and presumably results in promotion of cell proliferation in the SMMC-7721 cell line. Taken together, these data suggested that the core protein may be directly involved in Wnt/β-catenin-mediated liver pathogenesis.
authors.affiliation: The Second Affiliated Hospital, Chongqing Medical University, Lin Jiang Road, No.74, Chongqing, 400010 Chongqing, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.forename: Zengchan
authors.initials: Z
authors.lastname: Wang
authors.forename: Jia
authors.initials: J
authors.lastname: Tang
authors.forename: Renkuan
authors.initials: R
authors.lastname: Tang
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Shan
authors.forename: Wenlu
authors.initials: W
authors.lastname: Zhang
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Chen
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Ailong
authors.initials: A
authors.lastname: Huang
authors.forename: Ni
authors.initials: N
authors.lastname: Tang
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D051157:Frizzled Receptors / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D017930:Genes, Reporter; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D014758:Viral Core Proteins / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000099274:Frizzled-Related Proteins
chemical_list: D051157:Frizzled Receptors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D014758:Viral Core Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins