Expression of MicroRNA miR-122 Facilitates an Efficient Replication in Nonhepatic Cells upon Infection with Hepatitis C Virus

Fukuhara, Takasuke; Kambara, Hiroto; Mai, Sabine; Ono, Chikako; Katoh, Hiroshi; Morita, Eiji; Okuzaki, Daisuke; Maehara, Yoshihiko; Koike, Kazuhiko; Matsuura, Yoshiharu

doi:10.1128/jvi.00567-12

Cited by 113 publications

(103 citation statements)

References 68 publications

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“…Recently, several reports have shown that the exogenous expression of microRNA-122 (miR-122) facilitates the efficient propagation of HCVcc in HepG2 and Hep3B cells, which are nonpermissive for propagation of HCVcc (16,17). Furthermore, we reported that nonhepatic cell lines, including Hec1B cells derived from uterine endometrial adenocarcinoma, also permit replication of HCV RNA by exogenous expression of miR-122 (18). These reports indicate that miR-122 is one of the most important determinants for liver tropism of HCV infection.…”

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confidence: 77%

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Novel Permissive Cell Lines for Complete Propagation of Hepatitis C Virus

Mai

Fukuhara

Ono

et al. 2014

J Virol

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Hepatitis C virus (HCV) is a major etiologic agent of chronic liver diseases. Although the HCV life cycle has been clarified by studying laboratory strains of HCV derived from the genotype 2a JFH-1 strain (cell culture-adapted HCV [HCVcc]), the mechanisms of particle formation have not been elucidated. Recently, we showed that exogenous expression of a liver-specific microRNA, miR-122, in nonhepatic cell lines facilitates efficient replication but not particle production of HCVcc, suggesting that liver-specific host factors are required for infectious particle formation. In this study, we screened human cancer cell lines for expression of the liver-specific ␣-fetoprotein by using a cDNA array database and identified liver-derived JHH-4 cells and stomach-derived FU97 cells, which express liver-specific host factors comparable to Huh7 cells. These cell lines permit not only replication of HCV RNA but also particle formation upon infection with HCVcc, suggesting that hepatic differentiation participates in the expression of liver-specific host factors required for HCV propagation. HCV inhibitors targeting host and viral factors exhibited different antiviral efficacies between Huh7 and FU97 cells. Furthermore, FU97 cells exhibited higher susceptibility for propagation of HCVcc derived from the JFH-2 strain than Huh7 cells. These results suggest that hepatic differentiation participates in the expression of liver-specific host factors required for complete propagation of HCV. IMPORTANCEPrevious studies have shown that liver-specific host factors are required for efficient replication of HCV RNA and formation of infectious particles. In this study, we screened human cancer cell lines for expression of the liver-specific ␣-fetoprotein by using a cDNA array database and identified novel permissive cell lines for complete propagation of HCVcc without any artificial manipulation. In particular, gastric cancer-derived FU97 cells exhibited a much higher susceptibility to HCVcc/JFH-2 infection than observed in Huh7 cells, suggesting that FU97 cells would be useful for further investigation of the HCV life cycle, as well as the development of therapeutic agents for chronic hepatitis C. More than 170 million individuals worldwide are infected with hepatitis C virus (HCV), and the cirrhosis and hepatocellular carcinoma induced by HCV infection are life-threatening diseases (1). Current standard therapy combining pegylated-interferon (peg-IFN) and ribavirin (RBV) has achieved a sustained virological response (SVR) in 50% of individuals infected with HCV genotype 1 (2). Recently, directly acting antiviral (DAA) agents have been applied in a clinical setting (3). An SVR rate of over 80% has been realized by combination therapy with peg-IFN, RBV, and NS3/4A inhibitors in genotype 1 patients (4, 5). In addition, several DAAs, including inhibitors for NS3/4A protease, NS5A, and NS5B polymerase, are currently in clinical trials. Several reports have shown that in vitro replication of HCV RNA is significantly inhibited by treat...

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confidence: 77%

“…2A, bar graph). Recent reports have shown that exogenous expression of miR-122 enhances HCV RNA abundances in several hepatic or nonhepatic cell lines (16)(17)(18). Therefore, we examined the effect of miR-122 overexpression on HCV RNA abundances in both JHH-4 and FU97 cells.…”

Section: Jhh-4 and Fu97 Cells Express High Levels Of The Liver-specifmentioning

confidence: 99%

Novel Permissive Cell Lines for Complete Propagation of Hepatitis C Virus

Mai

Fukuhara

Ono

et al. 2014

J Virol

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“…The molecular mechanism by which miR-122 facilitates replication is still unknown, but it is critical for the HCV life cycle. miR-122 expression is sufficient to convert nonhepatic cells to become HCV permissive (61,62). On the other hand, silencing of miR-122 with an antisense locked nucleic acid oligonucleotide leads to long-lasting suppression of HCV in infected primate models (63).…”

Section: The Hijackermentioning

confidence: 99%

Virus Meets Host MicroRNA: the Destroyer, the Booster, the Hijacker

Guo

Steitz

2014

Molecular and Cellular Biology

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Virus-host interactions highlight key regulatory steps in the control of gene expression. MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein production via base pairing with mRNAs. Both DNA and RNA viruses have evolved mechanisms to degrade, boost, or hijack cellular miRNAs to benefit the viral life cycle. This minireview focuses on recent discoveries in virus-host miRNA interactions.

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“…These cells show viral titers of 10 4 -10 5 infectious units/ml of culture supernatant in the HCV-JFH1 infection system, and the virus can be serially passaged without loss of infectivity (8). Very recent studies have also shown other hepatic and nonhepatic cell lines that endogenously or that exogenously express higher miR-122 levels and support HCV infection (12)(13)(14)(15), although infection levels in these models are similar to or lower than those in Huh7-derived cells.…”

Section: Introductionmentioning

confidence: 99%