Hepatitis C virus core protein activates Wnt/Œ≤-catenin signaling through multiple regulation of upstream molecules in the SMMC-7721 cell line
Authors: Ni Tang
Fan Zhou
Ailong Huang
Qingmei Chen
Jia Tang
Renkuan Tang
Wenlu Zhang
Zengchan Wang
Xiaoliang Shan
Jiao Liu
Ke Chen
Journal: Archives of Virology (2011)
Discipline: MICROBIOLOGY
Keywords: Hepatitis C virus; HCV core protein; Wnt/Œ≤-catenin signaling; hepatocellular carcinoma; transcriptional regulation
Affiliations: The Second Affiliated Hospital, Chongqing Medical University, Lin Jiang Road, No.74, Chongqing, 400010 Chongqing, China.

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/Œ≤-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/Œ≤-catenin signaling in the hepatoma cell line SMMC-7721. The effects of core protein on Wnt/Œ≤-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 Œ≤-catenin/Tcf-4-dependent transcriptional activity and increases active Œ≤-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 Œ≤-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 Œ≤-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/Œ≤-catenin-mediated liver pathogenesis. 

Retracted: No

PubPeer comments:
 Fig.1A: Two sets of two panels appear to show an area of overlap. Shown with red and blue boxes.  , 
 Figure 2: Three sets of three panels appear to show an area of overlap. Shown with green,yellow and blue boxes.  , 
 1# 2# Thank you for identifying these errors. Upon carefully examining of our original data, we found that two image assembly errors in Fig. 1A and Fig. 2 occurred during proof revision process when higher resolution images were required for article typeset and production. The corrected Fig. 1A and Fig. 2 are attached below. All authors were informed about the errors and approved the corrected figures. A formal correction has been submitted to Archives of Virology, and is expected to be published shortly. While these errors do not affect the overall conclusion of our reported work, we sincerely apologize for any inconvenience caused by these unintended errors to the readers. Corrected Fig. 1A  Corrected Fig. 2  ,