Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C.
OBJECTIVE
The molecular mechanisms of hepatocellular carcinoma have been studied, but little is known of the changes in liver gene expression during the different stages of chronic hepatitis C virus (HCV) infection, in particular the transition from mild to moderate fibrosis.


METHODS
We used real-time quantitative RT PCR to study the messenger RNA expression of 240 selected genes in 2 pools of liver specimens according to the stages of fibrosis (Metavir score; mild fibrosis = F1 and septal fibrosis = F2). Genes whose expression differed between pools (F2 vs F1) by at least 2-fold were selected. In addition, the expression level of these selected genes then was assessed in each of the 62 individual samples (F4, n = 6; F3, n = 17; F2, n = 21; vs F1, n = 18).


RESULTS
The 22 genes that were up-regulated in the 21 F2 samples relative to the 18 F1 samples mainly encoded genes involved in cytoskeleton (KRT 19 and SCG 10), growth factors/cytokines (CXCL6, interleukin 8 [IL8], IL1A, IL2, and CXCL10), or growth factor receptors (CCR2, CXCR3, and CXCR4), or were involved in extracellular matrix production (COL1A1, CHI3L, and SPP1), in extracellular matrix remodeling (TIMP1, MMP7, and MMP9), and in cell junction (ITGA2 and CLDN 4). When hierarchically clustering the F2 and F1 samples according to the expression of the 11 most discriminatory genes (KRT 19, COL1A1, STMN2, CXCL6, CCR2, TIMP1, IL8, IL1A, ITGA2, CLDN 4, and IL2), the patient population was categorized into 2 subgroups: F1 and F2. Specifically, 15 of 18 F1 (83%) and 19 of 21 F2 (90%) were classified correctly (P < 10(-5)). We also studied the messenger RNA expression of these 240 selected genes in normal liver in comparison with F1. Genes dysregulated in the transition from normal liver to F1 mainly were interferon-inducible genes, and therefore were very different from those dysregulated in the transition from F1 to F2.


CONCLUSIONS
Genes involved in extracellular matrix turnover and immune response are implicated in the transition from mild to moderate fibrosis. Eleven of the genes could form the basis for the gene expression signature of mild versus moderate fibrosis in patients with chronic hepatitis C.
Asselah
Tarik
T
Service d'Hépatologie and INSERM CRB3, AP-HP Hôpital Beaujon, University of Paris VII, Paris, France. tarikasselah@hotmail.com
Bièche
Ivan
I
Laurendeau
Ingrid
I
Paradis
Valérie
V
Vidaud
Dominique
D
Degott
Claude
C
Martinot
Michelle
M
Bedossa
Pierre
P
Valla
Dominique
D
Vidaud
Michel
M
Marcellin
Patrick
P
D000328:Adult; D000368:Aged; D001706:Biopsy; D016000:Cluster Analysis; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D019698:Hepatitis C, Chronic / Q000145:classification / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000473:pathology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism
D012333:RNA, Messenger