title: Overexpression of tumor-associated trypsin inhibitor (SPINK1/TATI) in hepatitis C-associated hepatocellular carcinoma: potential implications for viral hepatocarcinogenesis.
abstract: 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 polymerase 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)/tumor-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 HCC. These data highlight the importance of SPINK1/TATI as a tumor marker for HCV-induced HCC and may lead to a better understanding of HCV-induced hepatocarcinogenesis.
authors.affiliation: Department of Oncology, Paracelsus Klinik, Scheidegg, Germany.
authors.forename: Holger G
authors.initials: HG
authors.lastname: Hass
authors.forename: Jürgen
authors.initials: J
authors.lastname: Jobst
authors.forename: Ulrich
authors.initials: U
authors.lastname: Vogel
authors.forename: Michael
authors.initials: M
authors.lastname: Scheurlen
authors.forename: Oliver
authors.initials: O
authors.lastname: Nehls
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology*; D002352:Carrier Proteins / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D016174:Hepacivirus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000821:virology*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D014359:Trypsin Inhibitor, Kazal Pancreatic / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic