Molecular profiling of early stage liver fibrosis in patients with chronic hepatitis C virus infection.
The molecular mechanisms of acute hepatitis C virus (HCV) infection, end-stage hepatitis (cirrhosis), and hepatocellular carcinoma have been extensively studied, but little is known of the changes in liver gene expression during the early stages of liver fibrosis associated with chronic HCV infection, that is, the transition from normal liver (NL) of uninfected patients to the first stage of liver fibrosis (F1-CH-C). To obtain insight into the molecular pathogenesis of F1-CH-C, we used real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to study the mRNA expression of 240 selected genes in liver tissue with F1-CH-C, in comparison with NL. The expression of 54 (22.5%) of the 240 genes was significantly different between F1-CH-C and NL; 46 genes were upregulated and 8 were downregulated in F1-CH-C. The most noteworthy changes in gene expression mainly affected the transcriptional network regulated by interferons (IFNs), including both IFN-alpha/beta-inducible genes (STAT1, STAT2, ISGF3G/IRF9, IFI27, G1P3, G1P2, OAS2, MX1) and IFN-gamma-inducible genes (CXCL9, CXCL10, CXCL11). Interesting, upregulation of IFN-alpha/beta-inducible genes (but not IFN-gamma-inducible genes) was independent of histological scores (grade and stage of fibrosis) and HCV characteristics (hepatic HCV mRNA levels and the HCV genotype), and was specific to HCV (as compared to hepatitis B virus (HBV)). Other genes dysregulated in F1-CH-C, albeit less markedly than IFN-alpha/beta- and IFN-gamma-inducible genes, were mainly involved in the activation of lymphocytes infiltrating the liver (IFNG, TNF, CXCL6, IL6, CCL8, CXCR3, CXCR4, CCR2), cell proliferation (p16/CDKN2A, MKI67, p14/ARF), extracellular matrix remodeling (MMP9, ITGA2), lymphangiogenesis (XLKD1/LYVE), oxidative stress (CYP2E1), and cytoskeleton microtubule organization (STMN2/SCG10). Thus, a limited number of signaling pathways, and particularly the transcriptional network regulated by interferons, are dysregulated in the first stage of HCV-induced liver fibrosis. Some of the genes identified here could form the basis for new approaches aimed at refining IFN-based therapies for chronic HCV infection.
Bièche
Ivan
I
Laboratoire de Génétique Moléculaire-UPRES EA 3618, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, Paris, France. ivan.bieche@univ-paris5.fr
Asselah
Tarik
T
Laurendeau
Ingrid
I
Vidaud
Dominique
D
Degot
Claude
C
Paradis
Valérie
V
Bedossa
Pierre
P
Valla
Dominique-Charles
DC
Marcellin
Patrick
P
Vidaud
Michel
M
D015870:Gene Expression; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators
D015534:Trans-Activators