Open AccessHaem oxygenase 1 expression is associated with prognosis in cholangiocarcinoma patients and with drug sensitivity in xenografted mice
Author(s) -
Kongpetch S.,
Puapairoj A.,
Ong C. K.,
Senggunprai L.,
Prawan A.,
Kukongviriyapan U.,
ChanOn W.,
Siew E. Y.,
Khuntikeo N.,
Teh B. T.,
Kukongviriyapan V.
Publication year - 2016
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12228
Subject(s) - immunohistochemistry , cancer research , cell growth , in vitro , apoptosis , gene silencing , pathology , cytotoxicity , biology , medicine , chemistry , gene , biochemistry
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 si RNA . 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 (Zn PP ) enhanced cytotoxicity to GEM in CCA cells, validated in CCA xenografts. Treatment with GEM and Zn PP 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.