Long Non-coding RNAs in Hepatitis C Virus-Infected Cells

Barriocanal, Marina; Fortes, Puri

doi:10.3389/fmicb.2017.01833

Cited by 20 publications

(25 citation statements)

References 223 publications

(278 reference statements)

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“…In contrast, the world of infection-induced lncRNAs is widely unexplored and HCV-related lncRNAs are not an exception. The few studies performed clearly indicate that, similar to what has been described for miRNAs, several cellular lncRNAs are deregulated in response to HCV replication or to the antiviral response induced by viral infection ( Barriocanal and Fortes, 2017 ). The function of some of them has been studied.…”

Section: Interaction Of the Non-coding Transcriptome And Rna Viruses:mentioning

confidence: 86%

Regulation of the Interferon Response by lncRNAs in HCV Infection

Valadkhan

Fortes

2018

Front. Microbiol.

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The interferon (IFN) response is a critical component of the innate immunity antiviral pathways in mammalians. IFN signaling results in increased expression of cellular factors that block key steps in the viral replication cycle. Many IFN-induced antiviral factors act through decreasing viral entry, replication, transcription, translation, packaging and release. However, these effects are also deleterious for the viability of the cell, which necessitates a tight control over the magnitude and duration of the IFN response. This is partially achieved through the IFN-mediated activation of negative regulatory factors that help in termination of the IFN response and return to a normal homeostatic state. Such built-in negative regulatory mechanisms are frequently hijacked by viruses such as the Hepatitis C virus (HCV) to increase viral replication and productive infections. We and others have shown that long non-coding RNAs (lncRNAs) play prominent roles in regulation of the IFN response. Activation of the IFN cascade alters the expression of a large number of lncRNAs, many of which are directly induced by the JAK/STAT pathway and thus, resemble the well-studied protein-coding interferon-stimulated genes (ISGs). While only a handful of IFN- and virally induced lncRNAs have been characterized, recent studies have identified several lncRNAs that act as positive or negative regulators of expression of ISGs during the IFN response. A number of such regulatory lncRNAs have multiple ISG targets, while others act on a single neighboring ISG. Another group of studied lncRNAs act further upstream and regulate the expression of IFN genes or factors that sense the presence of viral genome or replication products. The large number of unstudied IFN- and virally induced lncRNAs makes it highly likely that future studies will reveal a much greater share for this class of transcripts in regulation of the antiviral response. In addition to their physiological roles, the expression of such lncRNAs is frequently modulated by virally encoded factors to interfere with the antiviral response and promote viral replication, thus making them ideal targets for therapeutic intervention.

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Section: Interaction Of the Non-coding Transcriptome And Rna Viruses:mentioning

confidence: 86%

Regulation of the Interferon Response by lncRNAs in HCV Infection

Valadkhan

Fortes

2018

Front. Microbiol.

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“…miRNAs are responsible for regulating many cellular processes, and viruses modulate the miRNA milieu in different ways to facilitate pathogenesis. Several lncRNAs are involved in HCV replication and modulation of the antiviral response (18); however, their role in pathogenesis is poorly understood. miR-373 has been implicated in the regulation of several cellular functions, including cell proliferation, invasion, and DNA damage repair in different cancers (10).…”

Section: Discussionmentioning

confidence: 99%

Association between MicroRNA-373 and Long Noncoding RNA NORAD in Hepatitis C Virus-Infected Hepatocytes Impairs Wee1 Expression for Growth Promotion

Sur

Sasaki

Devhare

et al. 2018

J Virol

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Chronic hepatitis C virus (HCV) infection may lead to end-stage liver disease, including hepatocellular carcinoma (HCC). We have shown previously that microRNA-373 (miR-373) is upregulated in HCV-infected human liver biopsy specimens. To gain insight into the role of miR-373 in HCV-mediated pathogenesis, we investigated its interacting partner for hepatocyte growth regulation. Transcriptome sequencing (RNA-seq) data revealed that Wee1 is associated with miR-373 and is a direct target. Interestingly, higher expression of Wee1 was noted in HCV-infected hepatocytes than in uninfected hepatocytes, suggesting that other factors may block miR-373-mediated Wee1 inhibition. We subsequently found an association between the long noncoding RNA NORAD (LINC00657) and miR-373, and we demonstrated that NORAD binds to miR-373 and Wee1 independently. However, the high level of Wee1 expression in HCV-infected hepatocytes suggested that miR-373 forms a complex with NORAD. Depletion of miR-373 or the inhibitor Wee1 reduces the growth of Huh7.5 cells harboring the HCV genome as well as reducing Wee1 expression. Taken together, our data demonstrate a novel mechanism of hepatocyte growth promotion during HCV infection involving a miR-373-NORAD-Wee1 axis, which may be a target for future therapy against HCV-associated HCC. The mechanism of HCV-mediated liver pathogenesis is poorly understood. In this study, we observed that HCV infection upregulates miR-373 and Wee1, a pivotal player in the G checkpoint in the cell cycle, although Wee1 is a direct target for miR-373. Subsequent investigation demonstrated that miR-373 forms a complex with the long noncoding RNA NORAD, resulting in the release of their common target, Wee1, in HCV-infected cells, which, in turn, favors uncontrolled cell growth. Our study suggested a previously unknown mechanism for hepatocyte growth promotion following HCV infection, and this pathway can be targeted for future therapy against HCV-mediated liver pathogenesis.

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“…There, they are bound by IRF9 to constitute the ISGF3 (IFN-stimulated gene factor 3) complex, in charge of activating the transcription of the vast ISG (IFN-stimulated genes) repertoire [21,22]. Several ISGs have been shown to decrease HCV replication by affecting virus infection (Mx, TRIM, IFITM, CH25H), viral RNA translation, replication, stability (OAS, IFIT, GBP1), or virus packaging and release (tetherin/BST2, viperin) [23,24]. These effects are reinforced by ISGs that contribute to IFN synthesis or signaling.…”

Section: Hcv and The Antiviral Responsementioning

confidence: 99%

LncRNAs in HCV Infection and HCV-Related Liver Disease

Unfried¹,

Fortes²

2020

IJMS

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Long non-coding RNAs (lncRNAs) are transcripts with poor coding capacity that may interact with proteins, DNA, or other RNAs to perform structural and regulatory functions. The lncRNA transcriptome changes significantly in most diseases, including cancer and viral infections. In this review, we summarize the functional implications of lncRNA-deregulation after infection with hepatitis C virus (HCV). HCV leads to chronic infection in many patients that may progress to liver cirrhosis and hepatocellular carcinoma (HCC). Most lncRNAs deregulated in infected cells that have been described function to potentiate or block the antiviral response and, therefore, they have a great impact on HCV viral replication. In addition, several lncRNAs upregulated by the infection contribute to viral release. Finally, many lncRNAs have been described as deregulated in HCV-related HCC that function to enhance cell survival, proliferation, and tumor progression by different mechanisms. Interestingly, some HCV-related HCC lncRNAs can be detected in bodily fluids, and there is great hope that they could be used as biomarkers to predict cancer initiation, progression, tumor burden, response to treatment, resistance to therapy, or tumor recurrence. Finally, there is high confidence that lncRNAs could also be used to improve the suboptimal long-term outcomes of current HCC treatment options.

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Long Non-coding RNAs in Hepatitis C Virus-Infected Cells

Cited by 20 publications

References 223 publications

Regulation of the Interferon Response by lncRNAs in HCV Infection

Regulation of the Interferon Response by lncRNAs in HCV Infection

Association between MicroRNA-373 and Long Noncoding RNA NORAD in Hepatitis C Virus-Infected Hepatocytes Impairs Wee1 Expression for Growth Promotion

LncRNAs in HCV Infection and HCV-Related Liver Disease

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