Small heterodimer partner 1 directly interacts with NS5A viral protein and has a key role in HCV related liver cell transformation

Conti, Beatrice; Porcu, Cristiana; Viscomi, C.; Minutolo, Antonella; Costantini, Susan; Corazzari, Marco; Iannucci, Gino; Barbaro, Barbara; Balsano, Clara

doi:10.18632/oncotarget.12144

Cited by 9 publications

(9 citation statements)

References 31 publications

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“…The lab of Volker Lohmann has shown that cell culture (i.e., Huh7)-adapted strains of HCV have, thus, evolved to lose PI4KIIIα stimulating activity in order to cope with the situation found in these cells, and non-adapted HCV variants can only replicate in Huh7 cells upon (siRNA-mediated or pharmacological) inhibition of PI4KIIIα [99]. In line with a previous report [74], which further showed a direct interaction of NS5A with NR0B2, we have found our cell culture-derived HCV to mildly induce expression of NR0B2 (see Figure S9); however, conflicting observations have been published as well [17,100]. In the light of these findings, it will be very interesting to investigate the situation in primary human hepatocytes and non-adapted HCV isolates in future studies.…”

Section: Discussionsupporting

confidence: 81%

“…NR0B2 showed a mainly nuclear localization consistent with its described role as a nuclear receptor and transcriptional repressor, but also a diffuse signal with some rare speckles in the cytoplasm (white arrows, Figure S6E). This partially cytoplasmic localization is in line with the reported finding of direct interaction between NR0B2 and HCV NS5A, an important ER-membrane-associated component of the viral replication machinery [74]. Unexpectedly, overexpression of HA-NR0B2 in lowly permissive Huh7-LP cells lead to a significant 3.4-fold decrease in HCV replication ( Figure 5A); the same was observed for a C-terminally FLAG-tagged version of NR0B2 ( Figure S6A,B).…”

Section: Nr0b2 Expression Levels Sensitively Modulate Hcv Replicationsupporting

confidence: 89%

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Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

Dächert

Gladilin

Binder

2019

Viruses

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Chronic Hepatitis C virus (HCV) infection still constitutes a major global health problem with almost half a million deaths per year. To date, the human hepatoma cell line Huh7 and its derivatives is the only cell line that robustly replicates HCV. However, even different subclones and passages of this single cell line exhibit tremendous differences in HCV replication efficiency. By comparative gene expression profiling using a multi-pronged correlation analysis across eight different Huh7 variants, we identified 34 candidate host factors possibly affecting HCV permissiveness. For seven of the candidates, we could show by knock-down studies their implication in HCV replication. Notably, for at least four of them, we furthermore found that overexpression boosted HCV replication in lowly permissive Huh7 cells, most prominently for the histone-binding transcriptional repressor THAP7 and the nuclear receptor NR0B2. For NR0B2, our results suggest a finely balanced expression optimum reached in highly permissive Huh7 cells, with even higher levels leading to a nearly complete breakdown of HCV replication, likely due to a dysregulation of bile acid and cholesterol metabolism. Our unbiased expression-profiling approach, hence, led to the identification of four host cellular genes that contribute to HCV permissiveness in Huh7 cells. These findings add to an improved understanding of the molecular underpinnings of the strict host cell tropism of HCV.

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Section: Discussionsupporting

confidence: 81%

Section: Nr0b2 Expression Levels Sensitively Modulate Hcv Replicationsupporting

confidence: 89%

Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

Dächert

Gladilin

Binder

2019

Viruses

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“…It is believed that an important role is given by viral persistence in immune stimulus incessant exercise. Consequently, the HCV core protein plays a pivotal role in the development of direct mechanisms of HCC; in fact, the core deregulates the pathways by inhibiting retinoblastoma protein (RB) and p53 tumor suppressor [ 33 ]. Furthermore, HCV NS5 inhibits the apoptosis regulators BCL-2, and it is the cause of abnormal activation of signaling pathways that promote growth, such as Wnt/beta catenin and mammalian target of rapamycin (mTOR) [ 34 ].…”

Section: Viral and Non-viral Factors Involved In Hcv-related Hccmentioning

confidence: 99%

Hepatitis C Virus and Hepatocellular Carcinoma: Pathogenetic Mechanisms and Impact of Direct-Acting Antivirals

Schietroma¹,

Scheri²,

Pinacchio³

et al. 2018

TOVJ

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Introduction:Globally, between 64 and 103 million people are chronically infected with Hepatitis C virus (HCV), with more than 4.6 million people in the United States and is associated with more than 15.000 deaths annually. Chronic infection can result in cirrhosis and hepatocellular carcinoma.Explanation:Epidemiological studies have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC), mainly through chronic inflammation, cell deaths, and proliferation. Despite the new direct-acting antiviral drugs (DAA’s) being able to clear the HCV, HCC recurrence rate in these patients is still observed.Conclusion:In this review we highlighted some aspects that could be involved in the onset of HCV-induced HCC such as immune system, viral factors and host genetics factors.Moreover, we focused on some of the last reports about the effects of DAA’s on the HCV clearance and their potential implications in HCC recurrence.

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“…Chronic viral hepatitis is a substantial contributing factor for liver cancer development and progression (51). HCV infection was shown to increase NR0B2 gene expression in human liver cells (52), and NR0B2 gene silencing or an excessive overexpression all reduced HCV replication in Huh7 cells (27). This study found an interesting correlation of NR0B2 expression with over survival in liver cancer patients with viral hepatitis history (HR = 0.52, p = 0.0416), which was more significant in Asian male patients (HR = 0.33, p = 0.0157).…”

Section: Discussionmentioning

confidence: 99%

The Orphan Nuclear Receptor Gene NR0B2 Is a Favorite Prognosis Factor Modulated by Multiple Cellular Signal Pathways in Human Liver Cancers

Zhu

Chang

et al. 2021

Front. Oncol.

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BackgroundLiver cancer is a leading cause of cancer death worldwide, and novel prognostic factor is needed for early detection and therapeutic responsiveness monitoring. The orphan nuclear receptor NR0B2 was reported to suppress liver cancer development in a mouse model, and its expression levels were reduced in liver cancer tissues and cell lines due to hypermethylation within its promoter region. However, it is not clear if NR0B2 expression is associated with cancer survival or disease progression and how NR0B2 gene expression is regulated at the molecular level.MethodsMultiple cancer databases were utilized to explore NR0B2 gene expression profiles crossing a variety of human cancers, including liver cancers, on several publicly assessable bioinformatics platforms. NR0B2 gene expression with or without kinase inhibitor treatment was analyzed using the qPCR technique, and NR0B2 protein expression was assessed in western blot assays. Two human hepatocellular carcinoma cell lines HepG2 and Huh7, were used in these experiments. NR0B2 gene activation was evaluated using NR0B2 promoter-driven luciferase reporter assays.ResultsNR0B2 gene is predominantly expressed in liver tissue crossing human major organs or tissues, but it is significantly downregulated in liver cancers. NR0B2 expression is mostly downregulated in most common cancers but also upregulated in a few intestinal cancers. NR0B2 gene expression significantly correlated with patient overall survival status in multiple human malignancies, including lung, kidney, breast, urinary bladder, thyroid, colon, and head-neck cancers, as well as liposarcoma and B-cell lymphoma. In liver cancer patients, higher NR0B2 expression is associated with favorite relapse-free and progression-free survival, especially in Asian male patients with viral infection history. In addition, NR0B2 expression negatively correlated with immune infiltration and PIK3CA and PIK3CG gene expression in liver cancer tissues. In HepG2 and Huh7 cells, NR0B2 expression at the transcription level was drastically reduced after MAPK inhibition but was significantly enhanced after PI3K inhibition.ConclusionNR0B2 gene expression is altered mainly in most human malignancies and significantly reduced in liver cancers. NR0B2 is a prognosis factor for patient survival in liver cancers. MAPK and PI3K oppositely modulate NR0B2 expression, and NR0B2 gene upregulation might serve as a therapeutic responsiveness factor in anti-PI3K therapy for liver cancer.

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Small heterodimer partner 1 directly interacts with NS5A viral protein and has a key role in HCV related liver cell transformation

Cited by 9 publications

References 31 publications

Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

Hepatitis C Virus and Hepatocellular Carcinoma: Pathogenetic Mechanisms and Impact of Direct-Acting Antivirals

The Orphan Nuclear Receptor Gene NR0B2 Is a Favorite Prognosis Factor Modulated by Multiple Cellular Signal Pathways in Human Liver Cancers

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