Abstract
BackgroundLiver cirrhosis is the most important risk factor for hepatocellular carcinoma (HCC) but the role of liver disease aetiology in cancer development remains under-explored. We investigated global gene expression profiles from HCC arising in different liver diseases to test whether HCC development is driven by expression of common or different genes, which could provide new diagnostic markers or therapeutic targets.Methodology and Principal FindingsGlobal gene expression profiling was performed for 4 normal (control) livers as well as 8 background liver and 7 HCC from 3 patients with hereditary haemochromatosis (HH) undergoing surgery. In order to investigate different disease phenotypes causing HCC, the data were compared with public microarray repositories for gene expression in normal liver, hepatitis C virus (HCV) cirrhosis, HCV-related HCC (HCV-HCC), hepatitis B virus (HBV) cirrhosis and HBV-related HCC (HBV-HCC). Principal component analysis and differential gene expression analysis were carried out using R Bioconductor. Liver disease-specific and shared gene lists were created and genes identified as highly expressed in hereditary haemochromatosis HCC (HH-HCC) were validated using quantitative RT-PCR. Selected genes were investigated further using immunohistochemistry in 86 HCC arising in liver disorders with varied aetiology. Using a 2-fold cut-off, 9 genes were highly expressed in all HCC, 11 in HH-HCC, 270 in HBV-HCC and 9 in HCV-HCC. Six genes identified by microarray as highly expressed in HH-HCC were confirmed by RT qPCR. Serine peptidase inhibitor, Kazal type 1 (SPINK1) mRNA was very highly expressed in HH-HCC (median fold change 2291, p = 0.0072) and was detected by immunohistochemistry in 91% of HH-HCC, 0% of HH-related cirrhotic or dysplastic nodules and 79% of mixed-aetiology HCC.ConclusionHCC, arising from diverse backgrounds, uniformly over-express a small set of genes. SPINK1, a secretory trypsin inhibitor, demonstrated potential as a diagnostic HCC marker and should be evaluated in future studies.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and lies third as a cause of death from cancer [1]
The population most at risk for hepatocellular carcinoma (HCC) are those with cirrhosis; the highest risk, estimated at 3 to 8% per year, is associated with cirrhosis due to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection [4,5,6]
We identified and curated 259 liver, liver disease and HCC gene expression profiles from public microarray data repositories ArrayExpress and Gene Expression Omnibus that had used the U133Plus2.0 microarray
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and lies third as a cause of death from cancer [1]. Liver cirrhosis is the most important risk factor for hepatocellular carcinoma (HCC) but the role of liver disease aetiology in cancer development remains under-explored. MRN = macroregenerative nodule LGN = low grade dysplastic nodules HGN = high grade dysplastic nodule HH = hereditary haemochromatosis, NASH = non-alcoholic steatohepatitis, HCV = hepatitis C virus, HBV = hepatitis B virus, ALD = alcohol-related liver disease. Functional studies in breast, prostate and liver cancer cell lines have suggested SPINK1 might inhibit apoptosis [39,40,41]. The prostate cancer cell line 22Rv1 has an aggressive phenotype and highly expresses SPINK1. In this cell line, high SPINK1 expression increased cell proliferation and invasion both in vitro and in tumour xenografts [55]. SPINK1 can activate the EGF receptor and treatment of tumour xenograft-bearing mice with antibodies to SPINK1 or EGR receptor reduced tumour growth [55], suggesting SPINK is a potential therapeutic target
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