Expression of key hypoxia sensing prolyl-hydroxylases PHD1, -2 and -3 in pancreaticobiliary cancer.
OBJECTIVE
Tumour hypoxia is associated with an aggressive phenotype and resistance to chemotherapy and radiotherapy. The aim was to investigate whether key hypoxia sensing prolyl hydroxylases PHD1, PHD2 and PHD3 are dysregulated in pancreaticobiliary cancers, and to evaluate their potential clinical significance.


RESULTS
Formalin-fixed human pancreatic tissue from 120 consecutive patients undergoing pancreatic resections between June 2001 and June 2006 was constructed into tissue microarrays. Expression of PHD1, PHD2 and PHD3 was analysed using immunohistochemistry and correlated with clinicopathological variables and disease-specific overall survival. PHD1, PHD2 and PHD3 were significantly overexpressed in pancreaticobiliary tumours compared with normal pancreatic ductal tissues (P = 0.03, P < 0.0001 and P < 0.0001, respectively). PHD3 expression in tumour tissue was associated with a trend towards worse overall disease-specific survival in ampullary adenocarcinomas (P = 0.035) and pancreatic adenocarcinomas (P = 0.084). Absence of PHD1 expression was significantly associated with perineural invasion in pancreatic adenocarcinomas (P = 0.02) and a trend towards significance was also seen for absence of PHD2 expression in pancreatic adenocarcinomas (P = 0.04).


CONCLUSIONS
Our results provide the first clinical evidence that PHD1, PHD2 and PHD3 may be involved in pancreaticobiliary tumorigenesis.
Gossage
Lucy
L
Laboratory of Molecular Oncology, Academic Unit of Oncology, Faculty of Medicine & Health Sciences, School of Molecular Medical Sciences, University of Nottingham, Nottingham, UK.
Zaitoun
Abed
A
Fareed
Khaleel R
KR
Turley
Helen
H
Aloysius
Mark
M
Lobo
Dileep N
DN
Harris
Adrian L
AL
Madhusudan
Srinivasan
S
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D001661:Biliary Tract Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016009:Chi-Square Distribution; D049308:Dioxygenases / Q000378:metabolism*; D005260:Female; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D011379:Prognosis; D046888:Tissue Array Analysis
D049308:Dioxygenases; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases