Hepatitis C Virus Core Protein Down-Regulates p21(Waf1/Cip1) and Inhibits Curcumin-Induced Apoptosis through MicroRNA-345 Targeting in Human Hepatoma Cells.

Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C.
PLoS ONE (Impact Factor: 3.53). 04/2013; 8(4):e61089. DOI: 10.1371/journal.pone.0061089
Source: PubMed

ABSTRACT Hepatitis C virus (HCV) has been reported to regulate cellular microRNAs. The HCV core protein is considered to be a potential oncoprotein in HCV-related hepatocellular carcinoma, but HCV core-modulated cellular microRNAs are unknown. The HCV core protein regulates p21(Waf1/Cip1) expression. However, the mechanism of HCV core-associated p21(Waf1/Cip1) regulation remains to be further clarified. Therefore, we attempted to determine whether HCV core-modulated cellular microRNAs play an important role in regulating p21(Waf1/Cip1) expression in human hepatoma cells.
Cellular microRNA profiling was investigated in core-overexpressing hepatoma cells using TaqMan low density array. Array data were further confirmed by TaqMan real-time qPCR for single microRNA in core-overexpressing and full-length HCV replicon-expressing cells. The target gene of microRNA was examined by reporter assay. The gene expression was determined by real-time qPCR and Western blotting. Apoptosis was examined by annexin V-FITC apoptosis assay. Cell cycle analysis was performed by propidium iodide staining. Cell proliferation was analyzed by MTT assay.
HCV core protein up- or down-regulated some cellular microRNAs in Huh7 cells. HCV core-induced microRNA-345 suppressed p21(Waf1/Cip1) gene expression through targeting its 3' untranslated region in human hepatoma cells. Moreover, the core protein inhibited curcumin-induced apoptosis through p21(Waf1/Cip1)-targeting microRNA-345 in Huh7 cells.
HCV core protein enhances the expression of microRNA-345 which then down-regulates p21(Waf1/Cip1) expression. It is the first time that HCV core protein has ever been shown to suppress p21(Waf1/Cip1) gene expression through miR-345 targeting.

  • [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma (HCC) initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or as tools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus-related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs.
    World Journal of Gastroenterology 10/2014; 20(37):13477-13492. DOI:10.3748/wjg.v20.i37.13477 · 2.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interaction between microRNA (miRNA) and messenger RNA of target genes at the posttranscriptional level provides fine-tuned dynamic regulation of cell signaling pathways. Each miRNA can be involved in regulating hundreds of protein-coding genes, and, conversely, a number of different miRNAs usually target a structural gene. Epigenetic gene inactivation associated with methylation of promoter CpG-islands is common to both protein-coding genes and miRNA genes. Here, data on functions of miRNAs in development of tumor-cell phenotype are reviewed. Genomic organization of promoter CpG-islands of the miRNA genes located in inter- and intragenic areas is discussed. The literature and our own results on frequency of CpG-island methylation in miRNA genes from tumors are summarized, and data regarding a link between such modification and changed activity of miRNA genes and, consequently, protein-coding target genes are presented. Moreover, the impact of miRNA gene methylation on key oncogenetic processes as well as affected signaling pathways is discussed.
    Biochemistry (Moscow) 02/2015; 80(2):145-162. DOI:10.1134/S0006297915020029 · 1.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) infection represents an important public health problem worldwide. Reduction of HCV morbidity and mortality is a current challenge owned to several viral and host factors. Virus molecular evolution plays an important role in HCV transmission, disease progression and therapy outcome. The high degree of genetic heterogeneity characteristic of HCV is a key element for the rapid adaptation of the intrahost viral population to different selection pressures (e.g., host immune responses and antiviral therapy). HCV molecular evolution is shaped by different mechanisms including a high mutation rate, genetic bottlenecks, genetic drift, recombination, temporal variations and compartmentalization. These evolutionary processes constantly rearrange the composition of the HCV intrahost population in a staging manner. Remarkable advances in the understanding of the molecular mechanism controlling HCV replication have facilitated the development of a plethora of direct-acting antiviral agents against HCV. As a result, superior sustained viral responses have been attained. The rapidly evolving field of anti-HCV therapy is expected to broad its landscape even further with newer, more potent antivirals, bringing us one step closer to the interferon-free era.

Full-text (2 Sources)

Available from
Jun 5, 2014