title: Correlation of gene expression of ATP-binding cassette protein and tyrosine kinase signaling pathway in patients with hepatocellular carcinoma.
abstract: BACKGROUND
  Recent evidence suggests an involvement of the tyrosine kinase signaling pathway in the development of ATP-binding cassette (ABC) protein-mediated multidrug resistance in cancer. The aim of our study was to determine the relevance of kinase and multidrug-resistance protein expression in human hepatocellular carcinoma (HCC).
  
  
  METHODS
  Paired tissue samples of HCC and corresponding peri-neoplastic tissue from 15 patients undergoing surgical resection were analyzed. The gene expression of ABC proteins and mitogen-activated protein kinase (MAPK) signaling cascade kinases was evaluated by real-time PCR and correlated with a series of clinicopathological parameters. In vitro effects of MAPK Kinase (MEK) inhibition were evaluated in HepG2 cells.
  
  
  RESULTS
  Overexpression of ABC proteins, tyrosine kinases, or both was detectable in 40%, 86% and 33% of HCC samples, respectively. ABCC1, -2 and -3-mRNA levels were significantly increased in 13%, 20% and 33% of the HCC samples compared to the corresponding peri-neoplastic tissue (p≤0.05). There was an association of ABCC1 and ABCC2 overexpression in HCC tissue (p≤0.05). EGFR, RAF, MEK, ERK and MAPK mRNA were overexpressed in 33%, 33%, 40%, 50% and 50%, respectively compared to the peri-neoplastic tissue (p≤0.05). The expression of ABCC1, ABCC2 and P-glycoprotein correlated statistically with the MEK gene expression. Patients with tyrosine kinase overexpression had significantly higher angioinvasion (p≤0.05). RAF overexpression correlated statistically with increased tumor size (p=0.052). In vitro, MEK inhibition led to a reduced ABCC1 mRNA and protein expression.
  
  
  CONCLUSIONS
  ABC proteins and tyrosine kinases are significantly overexpressed in HCC tissue. The multidrug-resistance phenotype is associated with the MEK expression in HCC. Inhibition of MEK might be a new therapeutic approach to restore chemosensitivity in patients with highly resistant tumors.
authors: Department of General and Transplantation Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.
authors: Katrin
authors: K
authors: Hoffmann
authors: Lin
authors: L
authors: Shibo
authors: Zhi
authors: Z
authors: Xiao
authors: Thomas
authors: T
authors: Longerich
authors: Markus W
authors: MW
authors: Büchler
authors: Peter
authors: P
authors: Schemmer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D048490:raf Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases