Hepatitis C Virus NS5A Protein Down-regulates the Expression of Spindle Gene Aspm through PKR-p38 Signaling Pathway

Wu, Shun-Chi; Chang, Shih‐Chieh; Wu, Hung‐Yi; Liao, Pei-Ju; Chang, Shan‐Chwen

doi:10.1074/jbc.m802821200

Cited by 47 publications

(38 citation statements)

References 40 publications

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“…HBV basal core promoter mutations (A1762T/G1764A) are found to be associated with the occurrence of HCC in several cross-sectional (Baptista et al ., 1999; Kao et al ., 2003) and longitudinal studies (Chou et al ., 2008; Fang et al ., 2008; Wu et al ., 2008; Yuan et al ., 2009). The REVEAL-HBV study from Taiwan found that the multivariable-adjusted hazard ratio of developing HCC was 1.73 for basal core promoter mutations and that the risk was highest among participants infected with genotype C HBV and who harbored the precore 1896 variant and mutations for the basal core promoter (Yang et al ., 2008).…”

Section: Hbv Proteinsmentioning

confidence: 99%

Viral hepatocarcinogenesis

2010

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Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Despite recent advances in the diagnosis and treatment of HCC, its prognosis remains dismal. Infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major risk factors for HCC. Although both are hepatotropic viral infections, there are important differences between the oncogenic mechanisms of these two viruses. In addition to the oncogenic potential of its viral proteins, HBV, as a DNA virus, can integrate into host DNA and directly transform hepatocytes. In contrast, HCV, an RNA virus, is unable to integrate into the host genome, and viral protein expression has a more critical function in hepatocarcinogenesis. Both HBV and HCV proteins have been implicated in disrupting cellular signal transduction pathways that lead to unchecked cell growth. Most HCC develops in the cirrhotic liver, but the linkage between cirrhosis and HCC is likely multifactorial. In this review, we summarize current knowledge regarding the pathogenetic mechanisms of viral HCC.

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Section: Hbv Proteinsmentioning

confidence: 99%

Viral hepatocarcinogenesis

2010

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“…For DMSO treatment, HuS-E/2 cells were seeded at 60% confluence for 18 h and DMSO was added to a final concentration of 2% (vol/ vol), and then the DMSO-containing culture medium was changed every 3 days for 10 to 12 days, when the differentiated HuS-E/2 cells were used for HBV infection experiments in the continued presence of 2% DMSO. Cells of the cell lines Huh7 (a human hepatoma cell line), HepG2 (a human hepatocellular carcinoma cell line), and 293 (a human embryonic kidney cell line) were maintained as described previously (54).…”

Section: Methodsmentioning

confidence: 99%

Entry of Hepatitis B Virus into Immortalized Human Primary Hepatocytes by Clathrin-Dependent Endocytosis

Huang

Chen

Chang

et al. 2012

J Virol

144

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The lack of a suitable in vitro hepatitis B virus (HBV) infectivity model has limited examination of the early stages of the virus-cell interaction. In this study, we used an immortalized cell line derived from human primary hepatocytes, HuS-E/2, to study the mechanism of HBV infection. HBV infection efficiency was markedly increased after dimethyl sulfoxide (DMSO)-induced differentiation of the cells. Transmission electron microscopy demonstrated the presence of intact HBV particles in DMSO-treated HBV-infected HuS-E/2 cells, which could be infected with HBV for up to at least 50 passages. The pre-S1 domain of the large HBsAg (LHBsAg) protein specifically interacted with clathrin heavy chain (CHC) and clathrin adaptor protein AP-2. Short hairpin RNA knockdown of CHC or AP-2 in HuS-E/2 cells significantly reduced their susceptibility to HBV, indicating that both are necessary for HBV infection. Furthermore, HBV entry was inhibited by chlorpromazine, an inhibitor of clathrin-mediated endocytosis. LHBsAg also interfered with the clathrin-mediated endocytosis of transferrin by human hepatocytes. This infection system using an immortalized human primary hepatocyte cell line will facilitate investigations into HBV entry and in devising therapeutic strategies for manipulating HBV-associated liver disorders.

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“…Among them, the expression of 31 upregulated and 7 downregulated genes were positive both in HCC and liver-cirrhosis nodules (Nagai et al, 2004). Wu et al showed that the NS5A protein downregulated the expression of the mitotic spindle protein ASPM and induced an aberrant mitotic cell cycle, which was associated with chromosome instability and subsequently HCC (Wu et al, 2008). Wu et al studied human osteopontin positive and negative HCC tissues and found some tumor-related genes, such as SMR3B, MUC7, EPHA5, SPP1, and CLDN10 to have significantly higher expression in osteopontin positive HCC than in osteopontin negative HCC (Wu et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…If so, they may be useful as candidate genes for the diagnosis and treatment of HCC. The ASPM (abnormal spindle-like microcephaly) gene that encodes a mitotic spindle protein is widely expressed in fetal and proliferating adult tissues (Kouprina et al, 2005;Wu et al, 2008). The SCFCN2 (Ficolin 2) gene encodes ficolin-2 (L-ficolin), which regulates innate immunity (Munthe-Fog et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…However, this method has not been widely used for documenting differences in gene expression in HCC. Only a few such studies have been reported (Yim et al, 2003;Nagai et al, 2004;Wu et al, 2008Wu et al, , 2010. In this study, we identified genes that are differentially expressed in HCC as compared to normal liver tissue using LCM combined with microarray analysis in order to explore the relationship between the genotype and phenotype of HCC in humans.…”

Section: Introductionmentioning

confidence: 99%

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Aberrant gene expression profiles in hepatocellular carcinoma detected by microdissection

Wei

Li²,

Zhang³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to identify genomic aberrations in hepatocellular carcinoma (HCC) by using laser capture microdissection (LCM) combined with microarray analysis. Samples were procured by LCM from HCC and patient-matched normal liver tissue surgically resected from 4 patients. RNA was isolated from the samples and reverse transcribed into cDNA. After 2-cycle linear amplification and 2-color fluorescent labeling, the cRNA was hybridized onto a whole genome microarray. All genes expressed in the normal and HCC samples were counted and analyzed. Differentially expressed genes were identified and the top 10 up and downregulated genes (totally 20 genes) were further evaluated. LCM was able to accurately capture 50-200 cells from HCC and control tissues. The microarray spectrum showed satisfactory detection of HCC-enriched genes. A total of 1361 differentially expressed genes were identified, among which, 607 were upregulated and 754 were downregulated. Among the top 20 up and downregulated genes, 4 genes had not been documented in the literature as being differentially expressed in any tumors. Thus, LCM is an effective approach for identifying aberrantly expressed genes in HCC, and may lead to the discovery of biomarkers for diagnostic and therapeutic applications.

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Hepatitis C Virus NS5A Protein Down-regulates the Expression of Spindle Gene Aspm through PKR-p38 Signaling Pathway

Cited by 47 publications

References 40 publications

Viral hepatocarcinogenesis

Viral hepatocarcinogenesis

Entry of Hepatitis B Virus into Immortalized Human Primary Hepatocytes by Clathrin-Dependent Endocytosis

Aberrant gene expression profiles in hepatocellular carcinoma detected by microdissection

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