S Kongpetch1,2, A Puapairoj3, C K Ong4,5, L Senggunprai1,2, A Prawan1,2, U Kukongviriyapan6, W Chan-On4, E Y Siew4,5, N Khuntikeo2,7, B T Teh4,5,8, V Kukongviriyapan1,2. 1. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 2. Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, Thailand. 3. Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 4. Laboratory of Cancer Epigenome, National Cancer Centre of Singapore, Singapore. 5. Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore. 6. Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 7. Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 8. Cancer Science Institute of Singapore, National University of Singapore, Singapore.
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. MATERIALS AND 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. CONCLUSION: 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.
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. MATERIALS AND 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. CONCLUSION: 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: M Ferrando; G Gueron; B Elguero; J Giudice; A Salles; F Coluccio Leskow; E A Jares-Erijman; L Colombo; R Meiss; N Navone; A De Siervi; E Vazquez Journal: Angiogenesis Date: 2011-08-11 Impact factor: 9.596
Authors: Shahid A Khan; Brian R Davidson; Robert D Goldin; Nigel Heaton; John Karani; Stephen P Pereira; William M C Rosenberg; Paul Tait; Simon D Taylor-Robinson; Andrew V Thillainayagam; Howard C Thomas; Harpreet Wasan Journal: Gut Date: 2012-08-15 Impact factor: 23.059
Authors: Mariapaola Nitti; Sabrina Piras; Umberto M Marinari; Lorenzo Moretta; Maria A Pronzato; Anna Lisa Furfaro Journal: Antioxidants (Basel) Date: 2017-05-05
Authors: Marilina Mascaró; Eliana N Alonso; Exequiel G Alonso; Ezequiel Lacunza; Alejandro C Curino; María Marta Facchinetti Journal: Antioxidants (Basel) Date: 2021-01-11