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Is a Marker for an Unfavorable Prognosis in Early-Stage Invasive Cervical Cancer1
Institute of Clinical Pathology [P. B., C. P., G. B., G. O.] and Department of Gynecology and Obstetrics [M. S., A. O.], University of Vienna, A-1090 Vienna, Austria
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ABSTRACT |
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(HIF-1) is a transcriptional factor
that regulates genes involved in response to hypoxia and promotes
neoangiogenesis, which are considered essential for tumor growth and
progression. Using immunohistochemistry, we investigated the influence
of HIF-1 expression on prognosis in 91 patients with cervical cancer
stage pT1b. In univariate and multivariate analysis, patients with
strong expression of HIF-1 had a significantly shorter overall
survival time (P = 0.0307, log-rank test)
and disease-free survival time (P < 0.0001, log-rank test) compared with those with moderate to absent
HIF-1 expression. HIF-1 expression is a strong independent
prognostic marker in early stage cervical cancer. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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The mechanisms leading to adaptation of tumor cells to these
unfavorable environmental factors are still poorly understood
(5)
. One key factor in supporting adaptation may be
HIF-1,3
which is known to play an essential role in cellular
O2 homeostasis (6)
. HIF-1 is a
heterodimeric bHLH-PAS complex [PAS is an acronym that refers to the
first proteins in which this motif was identified, i.e., PER
(the protein product of the Drosophila period gene), ARNT
(the aryl hydrocarbon receptor nuclear translocator), and SIM (the
protein product of the Drosophila single-minded gene)]
composed of the two subunits HIF-1 and HIF-1ß (7)
.
The bHLH domain mediates dimerization and DNA binding in a large number
of transcription factors. PAS is an additional dimerization motif.
Whereas HIF-1ß is a common subunit of multiple bHLH proteins,
HIF-1 is the unique, O2-regulated subunit that
determines HIF-1 activity (6)
.
Cervical cancer is one of the most common cancers in women worldwide
(8)
. Because of nationwide screening programs in developed
countries, most patients are first seen with stage 1 disease. Stage 1
cervical cancer has a favorable outcome in most patients; nevertheless,
approximately 20–35% of patients are expected to die from their
disease (9)
. Until now, it is unknown which factors
influence the fate of these patients. Overexpression of HIF-1
protein has been demonstrated in a variety of human cancers by
immunohistochemistry (5)
; data on its impact on prognosis,
in particular in cervical cancer, do not exist thus far. The aim of our
study was to investigate the impact of immunohistochemically detected
HIF-1 expression on prognosis in human early-stage cervical cancer.
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Materials and Methods |
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Tumors were considered bulky when infiltrating the outer third of the
cervix or having a diameter of 40 mm or more. Vascular space
involvement was determined in slides routinely stained with H&E and was
considered positive if at least one tumor cell cluster was clearly
visible in a vascular space (10)
. Tissue of five cervices
histologically considered normal were used to compare HIF-1
expression in normal versus malignant epithelia. In
addition, 10 samples of CIN III were also immunostained for HIF-1
(mean patient age, 37.5 ± 10.5 years).
Immunohistochemistry.
The expression of HIF-1 was determined immunohistochemically in
paraffin-embedded specimens fixed in 4% buffered formalin.
Histological slides, 4 µm in thickness, were deparaffined in xylol.
Slides were heated in 0.01 M citrate buffer for 16 min in a
microwave oven, and endogenous peroxidase was blocked with methanol
containing 0.3% hydrogen peroxide for 30 min. For immunohistochemical
detection of HIF-1, specimens were incubated overnight at 4°C with
a monoclonal anti-HIF-1 antibody (Clone MAb H167, #NB 100–105;
Novus Biologicals, Littleton, CO; Ref. 5
) in a dilution of
1:60. According to the manufacturer’s specifications, this antibody
recognizes bands at Mr 120,000
in Western blot, representing HIF-1 in activated cells, and has also
been used to immunoprecipitate human HIF-1. Visualization of bound
antibodies was performed by using a Super Sensitive kit (#AP900-M;
BioGenex, San Ramon, CA), which is based on
streptavidin-biotin-horseradish peroxidase complex formation, according
to the manufacturer’s instructions. As chromogen,
3-amino-9-ethylcarbazole (BioGenex) was used. As positive control, a
specimen of colon adenocarcinoma with strong expression of HIF-1 was
used (5)
.
Expression of HIF-1 was determined by two independent observers
(P. B. and G. O.) by assessing semiquantitatively the percentage of
stained tumor cells and the staining intensity. The percentage of
positive cells was rated as follows: 2 points, 11–50% positive tumor
cells; 3 points, 51–80% positive cells; and 4 points, >81% positive
cells. The staining intensity was rated as follows: 1 point, weak
intensity; 2 points, moderate intensity; and 3 points, strong
intensity. Points for expression and percentage of positive cells were
added, and specimens were attributed to four groups according to their
overall score: negative, 
10% of cells stained positive, regardless
of intensity; weak expression, 3 points; moderate expression, 4–5
points; and strong expression, 6–7 points.
Expression of p53 was investigated using a standard protocol with the monoclonal antibody DO-7 (Dako, Glostrup, Denmark; Ref. 11 ). Detection was performed using a Super Sensitive kit (#AP900-M; BioGenex) and diaminobenzidine. As positive control, a specimen of colorectal cancer with a known mutation of p53 was used. A specimen was considered as "positive" for p53 expression if a vast majority of tumor cells showed distinct nuclear staining, suggesting accumulation of nonfunctional p53, otherwise as "negative" with regard to p53 expression. The negative control slides for both antibodies were prepared from the same tissue block. Instead of the primary antibody, a nonimmune serum was applied.
Statistical Methods.
Differences in HIF-1 expression between cervical cancer and
CIN III were investigated using the Mann-Whitney- test, as well as
differences in HIF-1 expression between tumors with and without
expression of p53. Correlation of HIF-1 expression with various
clinical and histopathological parameters was investigated using
Kruskal-Wallis test. OS was defined as the period from primary surgery
until the death of the patient. Death from a cause other than cervical
cancer or survival until the end of the observation period were
considered censoring events. DFS was defined from the end of primary
therapy until first evidence of progression of disease. Univariate
analysis of OS and DFS was performed as outlined by Kaplan and Meier
(12)
. The Cox proportional- hazards model was used for
multivariate analysis. HIF-1 expression, lymphatic node status,
vascular invasion, histological grading, and tumor size (bulky
versus nonbulky) were entered into Cox regression. For all
tests, a two-tailed P 0.05 was considered
significant.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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expression was recognized through a nuclear staining of
positive cells. There was no expression of this protein in normal
cervical samples. In contrast, immunohistochemistry revealed decoration
by the HIF-1 antibody in 81.3% of the tumor samples. In 16 (17.6%)
cases, there was a weak (Fig. 1)
, in 38 (41.8%) a moderate, and in 20 samples (22%) a strong
expression of HIF-1 (Fig. 2)
. In only
17 samples (18.7%), no HIF-1 was detected in tumor cells. In 77
cases, nondysplastic squamous cell epithelium directly adjacent to
invasive cancer was present, and in 15 cases, it showed weak expression
of HIF-1 in the basal and intermediate cells. In these cases, the
cancer cells also showed moderate to strong expression of HIF-1.
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, 2 weak, 4
moderate, and 2 strong expression of HIF-1. No significant
difference between HIF-1 expression between cervical cancer and CIN
III was observed (P = 0.83, Mann-Whitney
test).
In the Kruskal-Wallis test, no significant correlation between HIF-1
expression and lymphatic node involvement (P = 0.325), patients’ age (P = 0.442),
histological grading (P = 0.105), and tumor
size (P = 0.499) was found. Ten specimens of
invasive cancer (11%) were considered positive with regard to p53
expression, and 2 specimens (20%) of CIN III. No correlation of p53
and HIF-1 expression was observed (P = 0.453, Mann-Whitney test).
When survival of patients with strong expression of HIF-1 was
compared with survival of patients with moderate to absent expression
of HIF-1, Kaplan-Meier analysis (log-rank test) revealed a
significant influence of HIF-1 expression on OS
(P = 0.0307; Fig. 3A
) and DFS (P < 0.0001; Fig. 3B
). Expression of HIF-1 remained an independent
prognostic factor for OS (P = 0.0129) and DFS
(P = 0.0002) in multivariate analysis (Table 1)
.
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(median OS time, 103 months), whereas in
patients with strong HIF-1 expression, it was 75% (median OS time,
85 months). The 5-year DFS rate was 80% in patients with moderate to
absent expression of HIF-1 (median DFS time, 170 months), whereas in
patients with strong HIF-1 expression, it was only 34% (median DFS
time, 28 months). |
Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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as revealed by
immunohistochemistry can be observed in various intensities in 81.3%
of early-stage invasive cervical cancers and in 80% of CIN III but not
in "normal" cervical epithelia. We demonstrate for the first time
that HIF-1 expression is a strong prognostic marker mainly for DFS
in UICC stage pT1b cervical cancer.
How can this influence on prognosis be explained in cervical cancer?
HIF-1 probably has a dual function in early cancerogenesis. On the
one hand, it may stimulate angiogenesis via transactivation of the
VEGF gene, thus supporting tumor growth. On the other
hand, HIF-1 may associate with p53 protein, thus increasing the
stability of p53 (13)
. In this situation, cells have a
higher susceptibility to succumb because of hypoxia through p53-induced
apoptosis. This is supported by the fact that the loss of wild-type p53
is associated with a marked reduction in hypoxia-mediated apoptosis
(14)
. The interrelationship between HIF-1 and p53 is
also supported by the finding that HIF-1-/- ES cells show no
induction of p53 protein or apoptosis in response to
O2 and glucose deprivation (15)
.
Therefore, HIF-1 may support hypoxia-mediated apoptosis via
stabilization of p53. It therefore appears that the combination of p53
protein dysfunction, e.g., through somatic mutation, and
HIF-1 overexpression seem to be necessary to allow HIF-1 to
sufficiently stimulate tumor progression in early cancerogenesis
through mediating angiogenesis and inducing adaptive intracellular
responses to hypoxia without supporting proapoptotic mechanisms.
In the vast majority of patients, cervical cancer is caused by
infection with HPV types with high oncogenic risk (e.g., HPV
16, 18, and 33; Ref. 16
). HPV may be an important coplayer
for the development of tumorigenic properties of HIF-1. In cervical
cancer, p53 is most commonly inactivated by the viral oncoprotein E6
(17)
and not by mutations (18)
. Furthermore,
the E6 oncoprotein has been demonstrated to stimulate HIF-1
expression as a consequence of ubiquitin-dependent conjugation and
degradation of p53 (19)
. Therefore, in cervical cancer,
the tumor-suppressive functions of HIF-1 may be lost already in
initial stages in the majority of cases through the influence of HPV
infection and p53 protein inactivation. The function remaining is its
angiogenic property via activation of the VEGF gene
(19)
. The extent of neoangiogenesis, as assessed by
determination of microvessel density, is influenced by VEGF
(20)
and is considered to support progression of cervical
cancer (3)
. Consistent with this notion are results of
earlier studies on the collective presented here showing that a high
microvessel density had a negative impact on survival (9)
.
Presumably because of HPV infection, the impact of HIF-1 expression
on prognosis may be more clearly seen in cervical cancer as compared
with other cancers with functioning p53 in a high percentage of cases.
On the basis of our findings, we speculate that increased expression of
HIF-1 is an important event in the progression of cervical cancer at
least in a subgroup of patients. It may either increase
O2 availability or metabolic adaptation to
O2 deprivation. This notion is supported by the
fact that HIF-1 influences a number of genes that partly play a role
in tumor progression including erythropoietin, transferrin,
endothelin-1, inducible nitric oxide synthetase, heme oxygenase 1,
VEGF, insulin-like growth factor-2, insulin-like growth factor-binding
proteins -2 and -3, and 13 different glucose transporters and
glycolytic enzymes (6)
.
In conclusion, we have shown here for the first time that
overexpression of HIF-1 is a marker for tumor progression in
cervical cancer. Further studies will show whether HIF-1 has a
similar impact on prognosis in other forms of cancer. Furthermore, they
should reveal whether inactivation of p53, as it is known to exist in
cervical cancer through the viral protein E6, is essential for the
potential tumorigenic effects of HIF-1.
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FOOTNOTES |
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1 The study was supported by a grant from the
Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der
Bundeshauptstadt Wien. 
2 To whom requests for reprints should be
addressed, at the Institute of Clinical Pathology, University of
Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Phone:
43-1-40400-3650; Fax: 43-1-4053402; E-mail: peter.birner{at}akh-wien.ac.at
3 The abbreviations used are: HIF-1,
hypoxia-inducible factor 1; bHLH, basic helix-loop-helix; UICC,
International Union Against Cancer; CIN, cervical intraepithelial
neoplasia; OS, overall survival; DFS, disease-free survival; VEGF,
vascular endothelial growth factor; HPV, human papillomavirus.
Received 5/22/00. Accepted 7/20/00.
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REFERENCES |
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in common human cancers and their metastases. Cancer Res., 59: 5830-5835, 1999.. Nature (Lond.), 392: 405-408, 1998.[Medline]
in hypoxia mediated apoptosis, cell proliferation and tumor angiogenesis. Nature (Lond.), 394: 485-490, 1998.[Medline]
. Genes Dev., 14: 34-44, 2000.This article has been cited by other articles:
|
|
 |
|
  D. A. Tennant, R. V. Duran, H. Boulahbel, and E. Gottlieb Metabolic transformation in cancer Carcinogenesis, August 1, 2009; 30(8): 1269 - 1280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
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|
|
|
|
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|
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|
|
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|
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|
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|
|
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|
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|
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|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
E R Nijhuis, H W Nijman, K A Oien, A Bell, K A ten Hoor, N Reesink-Peters, H M Boezen, H Hollema, and A G J van der Zee Loss of MSH2 protein expression is a risk factor in early stage cervical cancer J. Clin. Pathol., July 1, 2007; 60(7): 824 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Tang, Q. Zhang, J. Nishitani, J. Brown, S. Shi, and A. D. Le Overexpression of Human Papillomavirus Type 16 Oncoproteins Enhances Hypoxia-Inducible Factor 1{alpha} Protein Accumulation and Vascular Endothelial Growth Factor Expression in Human Cervical Carcinoma Cells Clin. Cancer Res., May 1, 2007; 13(9): 2568 - 2576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
T. K. Lee, R. T.P. Poon, A. P. Yuen, M. T. Ling, X. H. Wang, Y. C. Wong, X. Y. Guan, K. Man, Z. Y. Tang, and S. T. Fan Regulation of Angiogenesis by Id-1 through Hypoxia-Inducible Factor-1{alpha}-Mediated Vascular Endothelial Growth Factor Up-regulation in Hepatocellular Carcinoma Clin. Cancer Res., December 1, 2006; 12(23): 6910 - 6919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Lim, J.-W. Park, M.-S. Kim, S.-K. Park, R. S. Johnson, and Y.-S. Chun Bafilomycin Induces the p21-Mediated Growth Inhibition of Cancer Cells under Hypoxic Conditions by Expressing Hypoxia-Inducible Factor-1{alpha} Mol. Pharmacol., December 1, 2006; 70(6): 1856 - 1865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Choi, Y.-S. Chun, S.-W. Kim, M.-S. Kim, and J.-W. Park Curcumin Inhibits Hypoxia-Inducible Factor-1 by Degrading Aryl Hydrocarbon Receptor Nuclear Translocator: A Mechanism of Tumor Growth Inhibition Mol. Pharmacol., November 1, 2006; 70(5): 1664 - 1671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Melillo Inhibiting Hypoxia-Inducible Factor 1 for Cancer Therapy Mol. Cancer Res., September 1, 2006; 4(9): 601 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Li, X. Lin, A. R. Shoemaker, D. H. Albert, S. W. Fesik, and Y. Shen Hypoxia-Inducible Factor-1 Inhibition in Combination with Temozolomide Treatment Exhibits Robust Antitumor Efficacy In vivo Clin. Cancer Res., August 1, 2006; 12(15): 4747 - 4754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.-J. Yeo, J.-H. Ryu, Y.-S. Chun, Y.-S. Cho, I.-J. Jang, H. Cho, J. Kim, M.-S. Kim, and J.-W. Park YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases. Cancer Res., June 15, 2006; 66(12): 6345 - 6352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Zhang, X. Tang, Q. Lu, Z. Zhang, J. Rao, and A. D. Le Green tea extract and (-)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1{alpha} protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells Mol. Cancer Ther., May 1, 2006; 5(5): 1227 - 1238. [Abstract] [Full Text] [PDF]
|
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L. M. Brown, R. L. Cowen, C. Debray, A. Eustace, J. T. Erler, F. C. D. Sheppard, C. A. Parker, I. J. Stratford, and K. J. Williams Reversing Hypoxic Cell Chemoresistance in Vitro Using Genetic and Small Molecule Approaches Targeting Hypoxia Inducible Factor-1 Mol. Pharmacol., February 1, 2006; 69(2): 411 - 418. [Abstract] [Full Text] [PDF]
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Q. Zhang, X. Tang, Q. Y. Lu, Z. F. Zhang, J. Brown, and A. D. Le Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1{alpha} and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells Mol. Cancer Ther., October 1, 2005; 4(10): 1465 - 1474. [Abstract] [Full Text] [PDF]
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|
 J.-Y. Han, S. H. Oh, F. Morgillo, J. N. Myers, E. Kim, W. K. Hong, and H.-Y. Lee Hypoxia-inducible Factor 1{alpha} and Antiangiogenic Activity of Farnesyltransferase Inhibitor SCH66336 in Human Aerodigestive Tract Cancer J Natl Cancer Inst, September 7, 2005; 97(17): 1272 - 1286. [Abstract] [Full Text] [PDF]
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K. Nakanishi, S. Hiroi, S. Tominaga, S. Aida, H. Kasamatsu, S. Matsuyama, T. Matsuyama, and T. Kawai Expression of Hypoxia-Inducible Factor-1{alpha} Protein Predicts Survival in Patients with Transitional Cell Carcinoma of the Upper Urinary Tract Clin. Cancer Res., April 1, 2005; 11(7): 2583 - 2590. [Abstract] [Full Text] [PDF]
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A. Lidgren, Y. Hedberg, K. Grankvist, T. Rasmuson, J. Vasko, and B. Ljungberg The Expression of Hypoxia-Inducible Factor 1{alpha} Is a Favorable Independent Prognostic Factor in Renal Cell Carcinoma Clin. Cancer Res., February 1, 2005; 11(3): 1129 - 1135. [Abstract] [Full Text] [PDF]
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G. J. Hutchison, H. R. Valentine, J. A. Loncaster, S. E. Davidson, R. D. Hunter, S. A. Roberts, A. L. Harris, I. J. Stratford, P. M. Price, and C. M. L. West Hypoxia-Inducible Factor 1{alpha} Expression as an Intrinsic Marker of Hypoxia: Correlation with Tumor Oxygen, Pimonidazole Measurements, and Outcome in Locally Advanced Carcinoma of the Cervix Clin. Cancer Res., December 15, 2004; 10(24): 8405 - 8412. [Abstract] [Full Text] [PDF]
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H. Yoshimura, D. K. Dhar, H. Kohno, H. Kubota, T. Fujii, S. Ueda, S. Kinugasa, M. Tachibana, and N. Nagasue Prognostic Impact of Hypoxia-Inducible Factors 1{alpha} and 2{alpha} in Colorectal Cancer Patients: Correlation with Tumor Angiogenesis and Cyclooxygenase-2 Expression Clin. Cancer Res., December 15, 2004; 10(24): 8554 - 8560. [Abstract] [Full Text] [PDF]
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 M. F. McCarty Targeting Multiple Signaling Pathways as a Strategy for Managing Prostate Cancer: Multifocal Signal Modulation Therapy Integr Cancer Ther, December 1, 2004; 3(4): 349 - 380. [Abstract] [PDF]
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H. D. Skinner, J. Z. Zheng, J. Fang, F. Agani, and B.-H. Jiang Vascular Endothelial Growth Factor Transcriptional Activation Is Mediated by Hypoxia-inducible Factor 1{alpha}, HDM2, and p70S6K1 in Response to Phosphatidylinositol 3-Kinase/AKT Signaling J. Biol. Chem., October 29, 2004; 279(44): 45643 - 45651. [Abstract] [Full Text] [PDF]
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 T. Koike, N. Kimura, K. Miyazaki, T. Yabuta, K. Kumamoto, S. Takenoshita, J. Chen, M. Kobayashi, M. Hosokawa, A. Taniguchi, et al. Hypoxia induces adhesion molecules on cancer cells: A missing link between Warburg effect and induction of selectin-ligand carbohydrates PNAS, May 25, 2004; 101(21): 8132 - 8137. [Abstract] [Full Text] [PDF]
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A M Jubb, T Q Pham, A M Hanby, G D Frantz, F V Peale, T D Wu, H W Koeppen, and K J Hillan Expression of vascular endothelial growth factor, hypoxia inducible factor 1{alpha}, and carbonic anhydrase IX in human tumours J. Clin. Pathol., May 1, 2004; 57(5): 504 - 512. [Abstract] [Full Text] [PDF]
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S. Welsh, R. Williams, L. Kirkpatrick, G. Paine-Murrieta, and G. Powis Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1{alpha} Mol. Cancer Ther., March 1, 2004; 3(3): 233 - 244. [Abstract] [Full Text]
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A. Rapisarda, B. Uranchimeg, O. Sordet, Y. Pommier, R. H. Shoemaker, and G. Melillo Topoisomerase I-Mediated Inhibition of Hypoxia-Inducible Factor 1: Mechanism and Therapeutic Implications Cancer Res., February 15, 2004; 64(4): 1475 - 1482. [Abstract] [Full Text] [PDF]
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J. Li, G. Davidson, Y. Huang, B.-H. Jiang, X. Shi, M. Costa, and C. Huang Nickel Compounds Act through Phosphatidylinositol-3-kinase/Akt-Dependent, p70S6k-Independent Pathway to Induce Hypoxia Inducible Factor Transactivation and Cap43 Expression in Mouse Epidermal Cl41 Cells Cancer Res., January 1, 2004; 64(1): 94 - 101. [Abstract] [Full Text] [PDF]
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Y.-S. Chun, K.-H. Lee, E. Choi, S.-Y. Bae, E.-J. Yeo, L. E. Huang, M.-S. Kim, and J.-W. Park Phorbol Ester Stimulates the Nonhypoxic Induction of a Novel Hypoxia-Inducible Factor 1{alpha} Isoform: Implications for Tumor Promotion Cancer Res., December 15, 2003; 63(24): 8700 - 8707. [Abstract] [Full Text] [PDF]
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T. K.-W. Lee, K. Man, M.-T. Ling, X.-H. Wang, Y.-C. Wong, C.-M. Lo, R. T.-P. Poon, I. O.-L. Ng, and S.-T. Fan Over-expression of Id-1 induces cell proliferation in hepatocellular carcinoma through inactivation of p16INK4a/RB pathway Carcinogenesis, November 1, 2003; 24(11): 1729 - 1736. [Abstract] [Full Text] [PDF]
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N. J. Mabjeesh, M. T. Willard, C. E. Frederickson, H. Zhong, and J. W. Simons Androgens Stimulate Hypoxia-inducible Factor 1 Activation via Autocrine Loop of Tyrosine Kinase Receptor/Phosphatidylinositol 3'-Kinase/Protein Kinase B in Prostate Cancer Cells Clin. Cancer Res., July 1, 2003; 9(7): 2416 - 2425. [Abstract] [Full Text] [PDF]
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B. Bachtiary, M. Schindl, R. Potter, B. Dreier, T. H. Knocke, J. A. Hainfellner, R. Horvat, and P. Birner Overexpression of Hypoxia-inducible Factor 1{alpha} Indicates Diminished Response to Radiotherapy and Unfavorable Prognosis in Patients Receiving Radical Radiotherapy for Cervical Cancer Clin. Cancer Res., June 1, 2003; 9(6): 2234 - 2240. [Abstract] [Full Text] [PDF]
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E.-J. Yeo, Y.-S. Chun, Y.-S. Cho, J. Kim, J.-C. Lee, M.-S. Kim, and J.-W. Park YC-1: A Potential Anticancer Drug Targeting Hypoxia-Inducible Factor 1 J Natl Cancer Inst, April 2, 2003; 95(7): 516 - 525. [Abstract] [Full Text] [PDF]
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B. Krishnamachary, S. Berg-Dixon, B. Kelly, F. Agani, D. Feldser, G. Ferreira, N. Iyer, J. LaRusch, B. Pak, P. Taghavi, et al. Regulation of Colon Carcinoma Cell Invasion by Hypoxia-Inducible Factor 1 Cancer Res., March 1, 2003; 63(5): 1138 - 1143. [Abstract] [Full Text] [PDF]
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M. Schindl, S. F. Schoppmann, T. Strobel, H. Heinzl, C. Leisser, R. Horvat, and P. Birner Level of Id-1 Protein Expression Correlates with Poor Differentiation, Enhanced Malignant Potential, and More Aggressive Clinical Behavior of Epithelial Ovarian Tumors Clin. Cancer Res., February 1, 2003; 9(2): 779 - 785. [Abstract] [Full Text] [PDF]
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S. J. Welsh, W. T. Bellamy, M. M. Briehl, and G. Powis The Redox Protein Thioredoxin-1 (Trx-1) Increases Hypoxia-inducible Factor 1{alpha} Protein Expression: Trx-1 Overexpression Results in Increased Vascular Endothelial Growth Factor Production and Enhanced Tumor Angiogenesis Cancer Res., September 1, 2002; 62(17): 5089 - 5095. [Abstract] [Full Text] [PDF]
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J. S. Isaacs, Y.-J. Jung, E. G. Mimnaugh, A. Martinez, F. Cuttitta, and L. M. Neckers Hsp90 Regulates a von Hippel Lindau-independent Hypoxia-inducible Factor-1alpha -degradative Pathway J. Biol. Chem., August 9, 2002; 277(33): 29936 - 29944. [Abstract] [Full Text] [PDF]
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E. P. Hui, A. T. C. Chan, F. Pezzella, H. Turley, K.-F. To, T. C. W. Poon, B. Zee, F. Mo, P. M. L. Teo, D. P. Huang, et al. Coexpression of Hypoxia-inducible Factors 1{alpha} and 2{alpha}, Carbonic Anhydrase IX, and Vascular Endothelial Growth Factor in Nasopharyngeal Carcinoma and Relationship to Survival Clin. Cancer Res., August 1, 2002; 8(8): 2595 - 2604. [Abstract] [Full Text] [PDF]
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H. Lu, R. A. Forbes, and A. Verma Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis J. Biol. Chem., June 21, 2002; 277(26): 23111 - 23115. [Abstract] [Full Text] [PDF]
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M. Schindl, S. F. Schoppmann, H. Samonigg, H. Hausmaninger, W. Kwasny, M. Gnant, R. Jakesz, E. Kubista, P. Birner, and G. Oberhuber Overexpression of Hypoxia-inducible Factor 1{alpha} Is Associated with an Unfavorable Prognosis in Lymph Node-positive Breast Cancer Clin. Cancer Res., June 1, 2002; 8(6): 1831 - 1837. [Abstract] [Full Text] [PDF]
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N. J. P. Beasley, R. Leek, M. Alam, H. Turley, G. J. Cox, K. Gatter, P. Millard, S. Fuggle, and A. L. Harris Hypoxia-inducible Factors HIF-1{alpha} and HIF-2{alpha} in Head and Neck Cancer: Relationship to Tumor Biology and Treatment Outcome in Surgically Resected Patients Cancer Res., May 1, 2002; 62(9): 2493 - 2497. [Abstract] [Full Text] [PDF]
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G. Hopfl, R. H. Wenger, U. Ziegler, T. Stallmach, O. Gardelle, R. Achermann, M. Wergin, B. Kaser-Hotz, H. M. Saunders, K. J. Williams, et al. Rescue of Hypoxia-inducible Factor-1{alpha}-deficient Tumor Growth by Wild-Type Cells Is Independent of Vascular Endothelial Growth Factor Cancer Res., May 1, 2002; 62(10): 2962 - 2970. [Abstract] [Full Text] [PDF]
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 C. N. Coleman, J. B. Mitchell, and K. Camphausen Tumor Hypoxia: Chicken, Egg, or a Piece of the Farm? J. Clin. Oncol., February 1, 2002; 20(3): 610 - 615. [Full Text] [PDF]
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A. Fyles, M. Milosevic, D. Hedley, M. Pintilie, W. Levin, L. Manchul, and R. P. Hill Tumor Hypoxia Has Independent Predictor Impact Only in Patients With Node-Negative Cervix Cancer J. Clin. Oncol., February 1, 2002; 20(3): 680 - 687. [Abstract] [Full Text] [PDF]
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M. Schindl, G. Oberhuber, A. Obermair, S. F. Schoppmann, B. Karner, and P. Birner Overexpression of Id-1 Protein Is a Marker for Unfavorable Prognosis in Early-Stage Cervical Cancer Cancer Res., August 1, 2001; 61(15): 5703 - 5706. [Abstract] [Full Text] [PDF]
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M. S. Wiesener, P. M. Munchenhagen, I. Berger, N. V. Morgan, J. Roigas, A. Schwiertz, J. S. Jurgensen, G. Gruber, P. H. Maxwell, S. A. Loning, et al. Constitutive Activation of Hypoxia-inducible Genes Related to Overexpression of Hypoxia-inducible Factor-1{{alpha}} in Clear Cell Renal Carcinomas Cancer Res., July 1, 2001; 61(13): 5215 - 5222. [Abstract] [Full Text] [PDF]
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 E. Laughner, P. Taghavi, K. Chiles, P. C. Mahon, and G. L. Semenza HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression Mol. Cell. Biol., June 15, 2001; 21(12): 3995 - 4004. [Abstract] [Full Text]
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P. Birner, M. Schindl, A. Obermair, G. Breitenecker, and G. Oberhuber Expression of Hypoxia-inducible Factor 1{{alpha}} in Epithelial Ovarian Tumors: Its Impact on Prognosis and on Response to Chemotherapy Clin. Cancer Res., June 1, 2001; 7(6): 1661 - 1668. [Abstract] [Full Text] [PDF]
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D. M. Aebersold, P. Burri, K. T. Beer, J. Laissue, V. Djonov, R. H. Greiner, and G. L. Semenza Expression of Hypoxia-inducible Factor-1{{alpha}}: A Novel Predictive and Prognostic Parameter in the Radiotherapy of Oropharyngeal Cancer Cancer Res., April 1, 2001; 61(7): 2911 - 2916. [Abstract] [Full Text]
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M. I. Koukourakis, A. Giatromanolaki, J. Skarlatos, L. Corti, S. Blandamura, M. Piazza, K. C. Gatter, and A. L. Harris Hypoxia Inducible Factor (HIF-1a and HIF-2a) Expression in Early Esophageal Cancer and Response to Photodynamic Therapy and Radiotherapy Cancer Res., March 1, 2001; 61(5): 1830 - 1832. [Abstract] [Full Text]
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R. Bos, H. Zhong, C. F. Hanrahan, E. C. M. Mommers, G. L. Semenza, H. M. Pinedo, M. D. Abeloff, J. W. Simons, P. J. van Diest, and E. van der Wall Levels of Hypoxia-Inducible Factor-1{{alpha}} During Breast Carcinogenesis J Natl Cancer Inst, February 21, 2001; 93(4): 309 - 314. [Abstract] [Full Text] [PDF]
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