Journal
ONCOLOGY RESEARCH AND TREATMENT
Volume 37, Issue 12, Pages 732-738Publisher
KARGER
DOI: 10.1159/000369151
Keywords
Hepatocarcinogenesis; SPINK1; TATI; Metalloproteinases; Gene expression
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Funding
- fortune program of the University of Tuebingen
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Background: The molecular pathomechanisms leading to hepatitis C virus (HCV)-induced hepatocarcinogenesis remain unclear. This study investigated the molecular pathways and key genes underlying HCV-positive hepatocellular carcinoma (HCC) using gene expression profiling. Methods: Oligonucleotide arrays (Affymetrix HU133A) were used to determine and compare the tissue-specific gene expression profiles in 39 cases of HCV-positive or -negative HCC and non-malignant liver tissue. The expression values of the most overexpressed genes were validated by real-time polyrnerase chain reaction (RT-PCR). Results: 837 genes or expressed sequence tags (ESTs) were significantly differently expressed in HCV-positive HCC versus healthy tissue: 414 were upregulated and 423 were downregulated (p < 0.05; > 2-fold change in >= 70% of the samples). A specific gene expression profile for HCV-positive HCC was obtained using 2-dimensional cluster analysis and was confirmed using supervised neuronal network modeling. The most consistently overexpressed gene coded for serine protease inhibitor Kazal-type 1 (SPINK1)/turnor-associated trypsin inhibitor (TATI) (median fold change, 19.7; significantly overexpressed in 90% of the samples). SPINK1/TATI was coregulated with matrix metalloproteinases (MMPs) and their natural inhibitors (tissue inhibitors of metalloproteinases (TIMPs)). Conclusions: Gene expression profiling identified specific dysregulated molecular pathways and SPINK1/TATI as the most overexpressed gene in HCV-positive HOC. These data highlight the importance of SPINK1/TATI as a tumor marker for HCV-induced HOC and may lead to a better understanding of HCV-induced hepatocarcinogenesis.
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