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. 2001 Oct;49(4):565–576. doi: 10.1136/gut.49.4.565

Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression

N Shackel 1, P McGuinness 1, C Abbott 1, M Gorrell 1, G McCaughan 1
PMCID: PMC1728487  PMID: 11559656

Abstract

BACKGROUND—Primary biliary cirrhosis (PBC) is an autoimmune disease in which the pathogenesis of progressive liver injury is poorly understood.
AIM—To provide novel insights into the pathogenesis of PBC related liver injury using cDNA array analysis, which simultaneously examines expression of many genes.
METHODS—Utilising cDNA arrays of 874 genes, PBC was compared with primary sclerosing cholangitis (PSC) associated cirrhosis and non-diseased liver. Differential expression of 10 genes was confirmed by real time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).
RESULTS—Array analysis identified many differentially expressed genes that are important in inflammation, fibrosis, proliferation, signalling, apoptosis, and oxidative stress. PBC was associated with increased expression of both Th1 and Th2 type molecules of the immune response. Fibrosis related gene expression featured upregulation of connective tissue growth factor and transforming growth factor beta3. Many more apoptosis associated molecules exhibited increased expression, consistent with apoptosis being a more active and regulated process, in PSC associated cirrhosis than in PBC. Increased expression of many genes of the Wnt and notch pathways implicated these highly conserved and linked pathways in PBC pathogenesis. The observed increases in expression of c-jun, c-myc, and c-fos related antigen 1 are consistent with increased Wnt pathway activity in PBC. Differential expression of four components of the Wnt pathway, Wnt-5a, Wnt-13, FRITZ, and beta-catenin, was confirmed by quantitative RT-PCR.
CONCLUSION—Many genes implicated in intrahepatic inflammation, fibrosis, and regeneration were upregulated in PBC cirrhosis. In particular, increased expression of a number of Drosophila homologues was seen in PBC.


Keywords: primary sclerosing cholangitis; apoptosis; fibrosis; connective tissue growth factor; Wnt; Th1/Th2; brain derived neurotrophic factor; notch

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Figure 1  .

Figure 1  

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Examples of cDNA arrays. ATLAS Cytokine Receptor Array (268 genes and nine housekeeping genes) (A) and ATLAS Human Gene Array 1.0 (588 genes and nine housekeeping genes) (B), both probed with 32P-2' deoxy-cytidine 5' triphosphate (dCTP) labelled primary biliary cirrhosis (PBC) mRNA (pooled from four subjects). The magnified portion of the ATLAS Cytokine Receptor Array compares the 32P-dCTP signal from the PBC and normal liver probes. Upregulation of monocyte chemoattractant protein 1 (MCP-1) in PBC (in the small broken line boxes) is shown (C). Regression analysis (D); this example compares signals generated using the PBC probe with signals generated using a probe derived from non-diseased tissue (the normal liver probe) for each gene on the ATLAS Human Gene Array 1.0. The regression line equation was PBC=2.0684×non-diseased0.83854, r2=0.76, p<0.0001. The extent of differential expression for each gene was determined as a ratio of the raw array signal intensity to the signal intensity calculated from the regression line formula.

Figure 2  .

Figure 2  

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Clustering of the 874 genes. Each line across all comparisons represents a single gene with upregulation indicated in increasing red and downregulation indicated in increasing green. Genes were clustered according to the nature and extent of their differential expression over the three comparisons. There was more than 70% similarity in the patterns of expression in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) associated cirrhosis compared with non-diseased tissue (indicated by the broken lines with asterisks). This graphical depiction of the data identifies groups of genes, such as those that had increased expression in: PBC compared with both non-diseased tissue and PSC associated cirrhosis (A); both PBC and PSC associated cirrhosis compared with non-diseased liver (B, C); PBC compared with PSC associated cirrhosis in addition to both of these diseases compared with non-diseased liver (C); and PSC but not PBC compared with non-diseased liver (D).

Figure 3  .

Figure 3  

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Upregulation of inflammatory, fibrosis, and apoptosis associated genes. Inflammation associated genes (A), fibrosis associated genes (B), and apoptosis associated genes (C) that were upregulated 2.0-fold or greater in primary biliary cirrhosis (PBC) compared with non-diseased liver tissue. Apoptosis associated gene upregulation of 2.0-fold or greater in primary sclerosing cholangitis (PSC) associated cirrhosis compared with non-diseased liver tissue is also shown (D). Genes marked with an asterisk were upregulated greater than twofold in PBC compared with both non-diseased liver tissue and PSC associated cirrhosis (*A-C). Genes marked with two asterisks were upregulated greater than twofold in PSC associated cirrhosis compared with both non-diseased liver tissue and PBC (**D).    

Figure 4  .

Figure 4  

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Upregulation of Drosophila homologues. Drosophila homologues that were upregulated 2.0-fold or greater in primary biliary cirrhosis (PBC) compared with non-diseased liver tissue. Genes marked with an asterisk were upregulated greater than twofold in PBC compared with both non-diseased liver tissue and primary sclerosing cholangitis associated cirrhosis.

Figure 5  .

Figure 5  

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Differential gene expression examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Quantitative real-time RT-PCR data (mean (SEM)) on mRNA from primary biliary cirrhosis (PBC) (n=6), primary sclerosing cholangitis (PSC) associated cirrhosis (n=4), hepatitis C virus (HCV) cirrhosis (n=6), and non-diseased donor liver (n=4). The depicted differential expression data are in two groups: (A) follistatin, CXC chemokine receptor 4 (CXCR4), connective tissue growth factor (CTGF), and extracellular matrix metalloproteinase inducer (EMMPRIN) and (B) Drosophila homologues including Wnt-13, secreted frizzled related protein 3 (FRITZ), beta-catenin, and Jagged-1.

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