title: Gene expression analysis for predicting gemcitabine resistance in human cholangiocarcinoma.
abstract: BACKGROUND
  Gemcitabine is a promising drug for cholangiocarcinoma treatment. However, the kinetics and metabolism of this drug in cholangiocarcinoma treatment are not well defined. We aimed to investigate the potential clinical role of gemcitabine metabolism-related genes in the gemcitabine sensitivity of cholangiocarcinoma and identify and characterize novel gemcitabine resistance-related genes.
  
  
  METHODS
  Expressions of genes related to gemcitabine sensitivity and gemcitabine metabolism were measured in 10 cholangiocarcinoma cell lines, and the association between gene expression and gemcitabine sensitivity was evaluated. Furthermore, gemcitabine-resistant cell lines were established from YSCCC cells and subjected to genome-wide microarray analysis. The 2-fold upregulated and downregulated genes were then subjected to pathway analysis.
  
  
  RESULTS
  p53R2 mRNA expression was significantly higher in gemcitabine-resistant cell lines (IC(50) > 1000 nM), and all subunits of ribonucleotide reductase were upregulated in the established gemcitabine-resistant cell lines. Microarray analysis revealed that the upregulated genes in the resistant cells belonged to the glutathione and pyrimidine metabolism pathways, and that the downregulated genes belonged to the N-glycan biosynthesis pathway.
  
  
  CONCLUSIONS
  Increased expression of p53R2 may predict gemcitabine resistance, and upregulated RNR activity may influence gemcitabine resistance in cholangiocarcinoma cells. Glutathione pathway-related genes were induced by continuous exposure to gemcitabine and may contribute to gemcitabine resistance.
authors: Department of Organ Regenerative Surgery, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan.
authors: Jun
authors: J
authors: Sato
authors: Takashi
authors: T
authors: Kimura
authors: Takuro
authors: T
authors: Saito
authors: Takayuki
authors: T
authors: Anazawa
authors: Akira
authors: A
authors: Kenjo
authors: Yoshihiro
authors: Y
authors: Sato
authors: Takao
authors: T
authors: Tsuchiya
authors: Mitsukazu
authors: M
authors: Gotoh
mesh_terms: D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012264:Ribonucleotide Reductases / Q000096:biosynthesis / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D018797:Cell Cycle Proteins; D007166:Immunosuppressive Agents; D012334:RNA, Neoplasm; D003841:Deoxycytidine; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine