Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans.
MicroRNAs (miRNAs) are small RNAs that regulate gene expression pathways. Previous studies have shown interactions between hepatitis C virus (HCV) and host miRNAs. We measured miR-122 and miR-21 levels in HCV-infected human liver biopsies relative to uninfected human livers and correlated these with clinical patient data. miR-122 is required for HCV replication in vitro, and miR-21 is involved in cellular proliferation and tumorigenesis. We found that miR-21 expression correlated with viral load, fibrosis and serum liver transaminase levels. miR-122 expression inversely correlated with fibrosis, liver transaminase levels and patient age. miR-21 was induced ∼twofold, and miR-122 was downregulated on infection of cultured cells with the HCV J6/JFH infectious clone, thus establishing a link to HCV. To further examine the relationship between fibrosis and the levels of miR-21 and miR-122, we measured their expression levels in a mouse carbon tetrachloride fibrosis model. As in the HCV-infected patient samples, fibrotic stage positively correlated with miR-21 and negatively correlated with miR-122 levels. Transforming growth factor β (TGF-β) is a critical mediator of fibrogenesis. We identified SMAD7 as a novel miR-21 target. SMAD7 is a negative regulator of TGF-β signaling, and its expression is induced by TGF-β. To confirm the relationship between miR-21 and the TGF-β signaling pathway, we measured the effect of miR-21 on a TGF-β-responsive reporter. We found that miR-21 enhanced TGF-β signaling, further supporting a relationship between miR-21 and fibrosis. We suggest a model in which miR-21 targeting of SMAD7 could increase TGF-β signaling, leading to increased fibrogenesis.
Marquez
Rebecca T
RT
Department of Internal Medicine, University of Iowa School of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Bandyopadhyay
Sarmistha
S
Wendlandt
Erik B
EB
Keck
Kathy
K
Hoffer
Brandon A
BA
Icardi
Michael S
MS
Christensen
Randolph N
RN
Schmidt
Warren N
WN
McCaffrey
Anton P
AP
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001706:Biopsy; D002460:Cell Line; D002478:Cells, Cultured; D002999:Clone Cells; D015536:Down-Regulation; D005260:Female; D005355:Fibrosis / Q000473:pathology; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D015398:Signal Transduction / Q000235:genetics; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019562:Viral Load
C531907:MIRN122 microRNA, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase