Hepatitis C Virus Mediated Changes in miRNA-449a Modulates Inflammatory Biomarker YKL40 through Components of the NOTCH Signaling Pathway

Sarma, Nayan J.; Tiriveedhi, Venkataswarup; Subramanian, Vijay; Shenoy, Surendra; Crippin, Jeffrey S.; Chapman, William C.; Mohanakumar, Thalachallour

doi:10.1371/journal.pone.0050826

Cited by 54 publications

(50 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…HCV infection has been shown to result in aberrant miRNA expression that regulates HCV particle entry, propagation, and gene expression mechanisms, thus playing a pivotal role in host immune evasion and inflammatory responses (22,23). In this report, we demonstrate that HCV-mediated regulation of miRNA-449a and miRNA-107 results in upregulation of CCL2 and modulates components of the IL-6R complex, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis.…”

mentioning

confidence: 55%

“…pCMV-XL4-PU.1 (SC315715) and pCMV-XL4-STAT3 (SC124165), Hsa-miRNA-449a (SC400399), Hsa-miRNA-107 (SC400023), and controls were obtained from Origene, MD. The construction of pcDNA-CEBP␣ is described elsewhere (23). Small interfering RNAs (siRNAs) specific for PU.1 (sc-36330), STAT3 (sc-29493), CEBP␣ (sc-37047), IL-6R (sc-35663), JAK1 (sc-35719), and a control (sc-37007) were purchased from Santa Cruz Biotechnology, CA.…”

Section: Methodsmentioning

confidence: 99%

“…miRNA-449a and miRNA-107 levels were determined using TaqMan miRNA assays and TaqMan Universal Master Mix-II (Life Technologies, NY) with predesigned primers. Quantitative PCR (qPCR) to analyze CCL2, PU.1, STAT3, CEBP␣, JAK1, and IL-6R was performed as described previously (23). Each TaqMan assay was run in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…Primary human hepatocytes (Life Technologies) and HEPG2 (ATCC) cells were grown and gene/siRNA transfections were carried out as described previously (23). The cytokine IL-6 (50 ng/ml; Sigma, MO) was added for 6 h wherever indicated.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

Sarma

Tiriveedhi

Crippin

et al. 2014

J Virol

Self Cite

View full text Add to dashboard Cite

Hepatitis C virus (HCV)-mediated liver diseases are one of the major health issues in the United States and worldwide. HCV infection has been reported to modulate microRNAs (miRNAs) that control various cell surface receptors and gene-regulatory complexes involved in hepatic inflammation and liver diseases. We report here that specific downregulation of miRNA-107 and miRNA-449a following HCV infection in patients with HCV-mediated liver diseases modulates expression of CCL2, an inflammatory chemokine upregulated in patients with chronic liver diseases, by targeting components of the interleukin-6 receptor (IL-6R) complex. Computational analysis for DNA-bound transcription factors in the CCL2 promoter identified adjacent binding sites for CCAAT/CEBP␣, spleen focus-forming virus, proviral integration oncogene (SPI1/PU.1), and STAT3. We demonstrate that CEBP␣, PU.1, and STAT3 interacted with each other physically to cooperatively bind to the promoter and activate CCL2 expression. Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR showed significant upregulation when there was impaired miRNA-107 and miRNA-449a expression, along with upregulation of PU.1 and STAT3, but not CEBP␣. miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes. Taken together, our results demonstrate a novel gene-regulatory mechanism in which HCV-induced changes in miRNAs (miRNA449a and miRNA-107) regulate CCL2 expression by activation of the IL-6-mediated signaling cascade, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis. IMPORTANCEHepatitis C virus (HCV)-induced hepatitis is a major health concern worldwide. HCV infection results in modulation of noncoding microRNAs affecting major cellular pathways, including inflammatory responses. In this study, we have identified a microRNA-regulated pathway for the chemokine CCL2 in HCV-induced hepatitis. Understanding microRNA-mediated transcriptional-regulatory pathways will result in development of noninvasive biomarkers for better disease prediction and development of effective therapeutics.

show abstract

mentioning

confidence: 55%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

Sarma

Tiriveedhi

Crippin

et al. 2014

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…MiR-449a plays an important role in modulating expression of YKL40 (an inflammatory marker) through targeting the components of the NOTCH signaling pathway following HCV infection. 86 In HCV patients, miR-449a was down-regulated, thereby up-regulating its target-NOTCH1, which further leads to up-regulation of TNFa mediated YKL40 expression. Thus, HCV induced down-regulation of miR-449a in human livers can up-regulate transcriptional factors leading to increased inflammatory response, promoting cell proliferation that can result in HCC.…”

Section: Hepatitis Cmentioning

confidence: 99%

MicroRNAs in Liver Disease: Bench to Bedside

Shah

Nelson

Kowdley

2013

Journal of Clinical and Experimental Hepatology

View full text Add to dashboard Cite

MicroRNAs (miRs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3 0 UTRs of mRNAs to promote degradation and/or block translation. Aberrant miR expression is associated with development of multiple diseases including hepatic diseases. The role of miRs in the regulation of gene expression and rapid progress in the field of microRNA research are resulting in momentum toward development of diagnostic markers and novel therapeutic strategies for human liver diseases. Recent studies provide clear evidence that miRs are abundant in the liver and modulate a diverse spectrum of biological functions, thereby supporting an association between alterations of miR homeostasis and pathological liver diseases. Here we review the role of miRs in liver as their physiological and pathological importance has been demonstrated in metabolism, immunity, viral hepatitis, oncogenesis, fatty liver diseases (alcoholic and non-alcoholic), drug-induced liver injury, fibrosis as well as acute liver failure. ( J CLIN EXP HEPATOL 2013;3:231-242)

show abstract

Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

Patra¹,

Meyer²,

Ray³

et al. 2019

Hepatology

View full text Add to dashboard Cite

Background and Aims Hepatitis C virus (HCV) infection promotes hepatocyte growth and progress to hepatocellular carcinoma. We previously observed that HCV infection of hepatocytes transcriptionally down‐regulates miR‐181c expression through CCAAT/enhancer binding protein β (C/EBP‐β). Here, we examined the role of miR‐181c in the regulation of cell cycle progression in relation to HCV infection. In silico analysis suggested that ataxia‐telangiectasia mutated (ATM) protein, a protein kinase, is a direct target of miR‐181c. ATM is a central mediator of response for cellular DNA double‐strand break. Approach and Results Our results demonstrated that ATM expression is higher in HCV‐infected hepatocytes and chronic HCV‐infected liver biopsy specimens. We have shown a direct interaction of miR‐181c with the 3′ untranslated region of ATM, and the presence of ATM in miR‐181c‐associated RNA‐induced silencing complex. Exogenous expression of miR‐181c inhibited ATM expression and activation of its downstream molecules, Chk2 and Akt. On the other hand, introduction of anti‐miR‐181c restored ATM and phosphorylated Akt. Furthermore, introduction of miR‐181c significantly inhibited phospho–cyclin‐dependent kinase 2 (CDK2) and cyclin‐A expression, arresting cell cycle progression, whereas overexpression of miR‐181c promoted apoptosis of HCV‐infected hepatocytes and can be inhibited by overexpression of ATM from a clone lacking miR‐181c binding sites. In addition, miR‐181c significantly regressed tumor growth in the xenograft human hepatocellular carcinoma mouse model. Conclusions Together, our results suggest that HCV infection suppresses miR‐181c in hepatocytes, resulting in ATM activation and apoptosis inhibition for promotion of cell cycle progression. The results provide mechanistic insight into understanding the role of miR‐181c in HCV‐associated hepatocyte growth promotion, and may have the potential for therapeutic intervention.

show abstract

Hepatitis C Virus Mediated Changes in miRNA-449a Modulates Inflammatory Biomarker YKL40 through Components of the NOTCH Signaling Pathway

Cited by 54 publications

References 45 publications

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

MicroRNAs in Liver Disease: Bench to Bedside

Hepatitis C Virus Mediated Inhibition of miR‐181c Activates ATM Signaling and Promotes Hepatocyte Growth

Contact Info

Product

Resources

About