title: Haem oxygenase 1 expression is associated with prognosis in cholangiocarcinoma patients and with drug sensitivity in xenografted mice.
abstract: OBJECTIVE
  Haem oxygenase-1 (HO-1) plays important roles in cytoprotection and tumour growth. Cholangiocarcinoma (CCA) is a deadly malignancy with very poor prognosis. The role of HO-1 in tumour progression in CCA up to now has been relatively unexplored, thus, its possible therapeutic implications in CCA have been investigated here.
  
  
  METHODS
  HO-1 expression in tumour tissues from 50 CCA patients was determined by immunohistochemical analysis and its association with survival time was evaluated using the Kaplan-Meier method. Its role in CCA cells in vitro was evaluated by transwell and wound healing assays and suppression of HO-1 expression by siRNA. Effects of HO-1 inhibition on gemicitabine (GEM)-mediated tumour suppression was evaluated in nude mice xenografted with CCA cells.
  
  
  RESULTS
  HO-1 expression was inversely associated with median overall survival time. Hazard ratio of patients with high HO-1 expression was 2.42 (95% CI: 1.16-5.08) with reference to low expression and HO-1 knock-down expression inhibited transwell cell migration. Suppression of HO-1 by Zn-protoporphyrin (ZnPP) enhanced cytotoxicity to GEM in CCA cells, validated in CCA xenografts. Treatment with GEM and ZnPP almost completely arrested tumour growth, whereas treatment with only a single reagent, retarded it. Tumour inhibition was associated with reduction in expression of Ki-67 and microvascular density, and enhanced p53 and p21 immunohistochemical staining.
  
  
  CONCLUSIONS
  High HO-1 expression was associated with poor prognosis of CCA. Synergistic role of HO-1 inhibition in chemotherapy of CCA is a promising insight for treatment of this tumour and warrants further investigation.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: S
authors.initials: S
authors.lastname: Kongpetch
authors.affiliation: Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: A
authors.initials: A
authors.lastname: Puapairoj
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre of Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: C K
authors.initials: CK
authors.lastname: Ong
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: L
authors.initials: L
authors.lastname: Senggunprai
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: A
authors.initials: A
authors.lastname: Prawan
authors.affiliation: Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: U
authors.initials: U
authors.lastname: Kukongviriyapan
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre of Singapore, Singapore.
authors.forename: W
authors.initials: W
authors.lastname: Chan-On
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre of Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: E Y
authors.initials: EY
authors.lastname: Siew
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand.|Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: N
authors.initials: N
authors.lastname: Khuntikeo
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre of Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: B T
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.|Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: V
authors.initials: V
authors.lastname: Kukongviriyapan
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D015999:Multivariate Analysis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011524:Protoporphyrins; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D000093542:Gemcitabine