Molecular Pathways: Hepatitis C Virus, CXCL10, and the Inflammatory Road to Liver Cancer

Brownell, Jessica; Polyak, Stephen J.

doi:10.1158/1078-0432.ccr-12-0928

Cited by 60 publications

(49 citation statements)

References 61 publications

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“…These findings may be of relevance in inflammatory diseases since enhanced tissue expression of CXCL10 has been associated with many autoimmune diseases. 44 Furthermore, CXCL10 over-expression has been shown to correlate with disease progression in several chronic infectious diseases such as HCV 20,45,46 and human immunodeficiency virus-1 (HIV-1) infections. 47 Thus, natural products like silymarin may be useful tools to dissect how stress signaling regulates pro-inflammatory signaling and cytokine production.…”

Section: The Second Phase: Inhibition Of Inflammationmentioning

confidence: 99%

Silymarin suppresses cellular inflammation by inducing reparative stress signaling

Lovelace¹,

Wagoner²,

Macdonald

et al. 2015

Planta Med

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Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Antiinflammatory effects arose with prolonged (i.e. 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-* Corresponding Author: (S.J. Polyak). . polyak@uw.edu. Supporting Information. Primer-probe sets for RT-PCR validation of microarray data and antibodies used in Western blotting are in Tables S1 and S2, respectively. Figures S1-S9 provide microarray heat map, microarray RT-PCR validation, protein validation, supporting IPA pinwheels, metabolomics heat map, AMPK knockout validation, and IPA legend. This material is available free of charge via the Internet at http://pubs.acs.org. Author ContributionsThe manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, while silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.Natural products are used to prevent and treat a plethora of chronic, debilitating, and inflammatory diseases. Over one-third of adults in the US reported self-medicating with complementary and alternative medicines (CAM). 1 Defining precise mechanisms of action is a critical barrier to the optimal application of botanicals as CAMs and as pharmaceuticals. Natural products, like the compounds contained in silymarin (a.k.a. milk thistle extract; from the plant Silybum marianum [L.] Gaertn.[Asteraceae]), protect cells by various antioxidant, anti-inflammatory, antiviral, immunomodulatory, proliferative, and metabolic effects, 2,3 resulting in diverse protective phenotypes, both in vitro and in vivo. For example, silymarin and silymarin-derived flavonolignans inhibit in vitro hepatitis C virus (HCV) infection of hu...

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Section: The Second Phase: Inhibition Of Inflammationmentioning

confidence: 99%

Silymarin suppresses cellular inflammation by inducing reparative stress signaling

Lovelace¹,

Wagoner²,

Macdonald

et al. 2015

Planta Med

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“…Several factors controlling inflammation and immune response have been identified to play regulatory actions in melanoma, such as Platelet Activating Factor (PAF) [9], microphthalmia-associated transcription factor (MITF) [13], granulocyte-macrophage colony-stimulating factor [14], TNF-alpha [15], transforming growth factor [16]. CXCL10/IP-10 has a clear controlling role on immune response and inflammation [17–20] and has been recently found to be involved in liver and renal cancer development [21, 22]. It has been reported to inhibit melanoma growth and angiogenensis [23–26] and melanoma represses its expression in a nitric oxide-related manner [27].…”

Section: Introductionmentioning

confidence: 99%

PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10: a multi-omicsapproach

et al. 2016

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Melanoma is the most aggressive skin-cancer, showing high mortality at advanced stages. Platelet Derived Growth Factor Receptor-alpha (PDGFR-alpha) potently inhibits melanoma- and endothelium-proliferation and its expression is significantly reduced in melanoma-biopsies, suggesting that melanoma progression eliminates cells expressing PDGFR-alpha. In the present study transient overexpression of PDGFR-alpha in endothelial (HUVEC) and melanoma (SKMel-28, A375, Preyer) human-cells shows strong anti-proliferative effects, with profound transcriptome and miRNome deregulation. PDGFR-alpha overexpression strongly affects expression of 82 genes in HUVEC (41 up-, 41 down-regulated), and 52 genes in SKMel-28 (43 up-, 9 down-regulated). CXCL10/IP-10 transcript showed up to 20 fold-increase, with similar changes detectable at the protein level. miRNA expression profiling in cells overexpressing PDGFR-alpha identified 14 miRNAs up- and 40 down-regulated, with miR-503 being the most down-regulated (6.4 fold-reduction). miR-503, miR-630 and miR-424 deregulation was confirmed by qRT-PCR. Interestingly, the most upregulated transcript (i.e., CXCL10/IP-10) was a validated miR-503 target and CXCL10/IP-10 neutralization significantly reverted the anti-proliferative action of PDGFR-alpha, and PDGFR-alpha inhibition by Dasatinb totally reverted the CXCL10/IP10 induction, further supporting a functional interplay of these factors. Finally, integration of transcriptomics and miRNomics data highlighted several pathways affected by PDGFR-alpha.This study demonstrates for the first time that PDGFR-alpha strongly inhibits endothelial and melanoma cells proliferation in a CXCL10/IP-10 dependent way, via miR-503 down-regulation.

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“…Worldwide, approximately 170 million people are chronically infected with HCV [3]. HCV is a single-stranded RNA virus ~9600 nt in size, and it belongs to the Flaviviridae family .…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Hepatitis C Virus Subgenotypes 1a and 1b in Japanese Patients: Ultra-Deep Sequencing Analysis of HCV NS5B Genotype-Specific Region

Nakamoto

Jiang

et al. 2013

PLoS ONE

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BackgroundHepatitis C virus (HCV) subgenotypes 1a and 1b have different impacts on the treatment response to peginterferon plus ribavirin with direct-acting antivirals (DAAs) against patients infected with HCV genotype 1, as the emergence rates of resistance mutations are different between these two subgenotypes. In Japan, almost all of HCV genotype 1 belongs to subgenotype 1b.Methods and FindingsTo determine HCV subgenotype 1a or 1b in Japanese patients infected with HCV genotype 1, real-time PCR-based method and Sanger method were used for the HCV NS5B region. HCV subgenotypes were determined in 90% by real-time PCR-based method. We also analyzed the specific probe regions for HCV subgenotypes 1a and 1b using ultra-deep sequencing, and uncovered mutations that could not be revealed using direct-sequencing by Sanger method. We estimated the prevalence of HCV subgenotype 1a as 1.2-2.5% of HCV genotype 1 patients in Japan.ConclusionsAlthough real-time PCR-based HCV subgenotyping method seems fair for differentiating HCV subgenotypes 1a and 1b, it may not be sufficient for clinical practice. Ultra-deep sequencing is useful for revealing the resistant strain(s) of HCV before DAA treatment as well as mixed infection with different genotypes or subgenotypes of HCV.

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Molecular Pathways: Hepatitis C Virus, CXCL10, and the Inflammatory Road to Liver Cancer

Cited by 60 publications

References 61 publications

Silymarin suppresses cellular inflammation by inducing reparative stress signaling

Silymarin suppresses cellular inflammation by inducing reparative stress signaling

PDGFR-alpha inhibits melanoma growth via CXCL10/IP-10: a multi-omicsapproach

Prevalence of Hepatitis C Virus Subgenotypes 1a and 1b in Japanese Patients: Ultra-Deep Sequencing Analysis of HCV NS5B Genotype-Specific Region

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