Haem oxygenase 1 expression is associated with prognosis in cholangiocarcinoma patients and with drug sensitivity in xenografted mice

S. KongpetchA. PuapairojC. K. OngL. SenggunpraiA. PrawanU. KukongviriyapanW. Chan-OnE. Y. SiewN. KhuntikeoB. T. TehV. KukongviriyapanKhon Kaen UniversityNational Cancer Centre, SingaporeNational University of SingaporeCancer Science Institute of SingaporeMahidol University2018-12-112019-03-142018-12-112019-03-142016-02-01Cell Proliferation. Vol.49, No.1 (2016), 90-10113652184096077222-s2.0-84958866770https://repository.li.mahidol.ac.th/handle/20.500.14594/43108© 2016 John Wiley & Sons Ltd. 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyHaem oxygenase 1 expression is associated with prognosis in cholangiocarcinoma patients and with drug sensitivity in xenografted miceArticleSCOPUS10.1111/cpr.12228