Expression of prolyl-hydroxylases PHD-1, 2 and 3 and of the asparagine hydroxylase FIH in non-small cell lung cancer relates to an activated HIF pathway

被引:21
作者
Giatromanolaki, Alexandra [1 ,2 ,3 ]
Koukourakis, Michael I. [1 ,2 ,3 ]
Pezzella, Francesco [4 ,5 ]
Turley, Helen [4 ,5 ]
Sivridis, Efthimlos [1 ,2 ,3 ]
Bouros, Demosthenes [1 ,2 ,3 ]
Bougioukas, George [1 ,2 ,3 ]
Harris, Adrian L. [4 ,5 ]
Gatter, Kevin C. [4 ,5 ]
机构
[1] Democritus Univ Thrace, Dept Pathol, Alexandroupolis 68100, Greece
[2] Democritus Univ Thrace, Dept Radiotherapy Oncol, Alexandroupolis 68100, Greece
[3] Democritus Univ Thrace, Dept Pneumol & Thorac Surg, Alexandroupolis 68100, Greece
[4] John Radcliffe Hosp, Canc Res UK Mol Oncol Lab, Inst Mol Med, Oxford OX3 9DU, England
[5] Univ Oxford, Nuffield Dept, Clin Sci Lab, Oxford OX3 9DU, England
关键词
lung cancer; hypoxia inducible factors; prolyl-hydroxylases; asparagine hydroxylases; lactate dehydrogenase;
D O I
10.1016/j.canlet.2007.11.041
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The oxygen sensitive prolyl-hydroxylase domain enzymes (PHDs) and the asparagines hydroxylase (FIH, factor inhibiting HIF) regulate the transcriptional activity of HIFs. We assessed the expression of these enzymes in a series of 73 non-small cell lung carcinomas (NSCLC). A direct association of PHDs with FIH and of the PHDs/FIH with HIFs expression was noted. Thirty three of 73 cases had high HIF/PHD expression, predicting intense HIF activity; 19/73 cases had low H IF and high PHD expression mimicking the normal bronchial pattern-, and 18/73 cases had low HIF/PHD (inactive HIF pathway). High lactate dehydrogenase LDH5 expression was noted in cases with high HIF/PHD phenotype. The value of such a classification in defining different metabolic phenotypes of NSCLC deserves further evaluation. (C) 2007 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:87 / 93
页数:7
相关论文
共 19 条
[11]   C2028T polymorphism in exon 12 and dinucleotide repeat polymorphism in intron 13 of the HIF-1α gene define HIF-1α protein expression in non-small cell lung cancer [J].
Koukourakis, Michael I. ;
Papazoglou, Dimitrios ;
Giatromanolaki, Alexandra ;
Panagopoulos, Ioannis ;
Maltezos, Efstratios ;
Harris, Adrian L. ;
Gatter, Kevin C. ;
Sivridis, Efthimios .
LUNG CANCER, 2006, 53 (03) :257-262
[12]   FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor [J].
Lando, D ;
Peet, DJ ;
Gorman, JJ ;
Whelan, DA ;
Whitelaw, ML ;
Bruick, RK .
GENES & DEVELOPMENT, 2002, 16 (12) :1466-1471
[13]   FIH-1:: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity [J].
Mahon, PC ;
Hirota, K ;
Semenza, GL .
GENES & DEVELOPMENT, 2001, 15 (20) :2675-2686
[14]   HIF hydroxylation and cellular oxygen sensing [J].
Metzen, E ;
Ratcliffe, PJ .
BIOLOGICAL CHEMISTRY, 2004, 385 (3-4) :223-230
[15]   The tumor bed effect: Increased metastatic dissemination from hypoxia-induced up-regulation of metastasis-promoting gene products [J].
Rofstad, EK ;
Mathiesen, B ;
Henriksen, K ;
Kindem, K ;
Galappathi, K .
CANCER RESEARCH, 2005, 65 (06) :2387-2396
[16]  
SERNENZA GL, 1996, J BIOL CHEM, V271, P32529
[17]   Use of novel monoclonal antibodies to determine the expression and distribution of the hypoxia regulatory factors PHD-1, PHD-2, PHD-3 and FIH in normal and neoplastic human tissues [J].
Soilleux, EJ ;
Turley, H ;
Tian, YM ;
Pugh, CW ;
Gatter, KC ;
Harris, AL .
HISTOPATHOLOGY, 2005, 47 (06) :602-610
[18]   Genetic analysis of the role of the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (HIF) in regulating HIF transcriptional target genes [J].
Stolze, IP ;
Tian, YM ;
Appelhoff, RJ ;
Turley, H ;
Wykoff, CC ;
Gleadle, JM ;
Ratcliffe, PJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (41) :42719-42725
[19]   Oxygenation status of malignant tumors:: Pathogenesis of hypoxia and significance for tumor therapy [J].
Vaupel, P ;
Kelleher, DK ;
Höckel, M .
SEMINARS IN ONCOLOGY, 2001, 28 (02) :29-35