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Tumor Biology |
in Common Human Cancers and Their Metastases1
The Johns Hopkins Oncology Center, Brady Urological Institute [H. Z., M. L., W. B. I., J. W. S.], Department of Pathology [A. M. D.], Departments of Pediatrics and Medicine, and Institute of Genetic Medicine [E. L., G. L. S.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Histopathology, Derriford Hospital, Plymouth PL6 8DH, United Kingdom [D. A. H.]; Department of Pathology, Division of Neuropathology, New York University Medical Center, New York, New York 10016 [D. Z.]; and Division of General Surgery, University of California-Los Angeles School of Medicine, Los Angeles, California 90095-6904 [P. B.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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subunit. In this study, HIF-1 expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1 was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1 expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1, whereas benign tumors in breast and uterus did not. HIF-1 overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1 immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1 may play an important role in human cancer progression. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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HIF-1 is a bHLH-PAS transcription factor that plays an essential role in O2 homeostasis (10, 11, 12, 13)
. HIF-1 is a heterodimer composed of HIF-1 and HIF-1
subunits (10)
. Whereas HIF-1 (also known as the aryl hydrocarbon receptor nuclear translocator) is a common subunit of multiple bHLH-PAS proteins, HIF-1 is the unique, O2-regulated subunit that determines HIF-1 activity (14
, 15)
. HIF-1 transactivates genes whose protein products function either to increase O2 availability or to allow metabolic adaptation to O2 deprivation. Included among these are genes encoding erythropoietin, transferrin, endothelin-1, inducible nitric oxide synthase, heme oxygenase 1, VEGF, IGF-2, IGF-binding proteins -2 and -3, and 13 different glucose transporters and glycolytic enzymes (15
, 16)
. Remarkably, most of these proteins are implicated in tumor progression (17)
. Analysis of isogenic tumor cell lines injected into nude mice revealed a dramatic correlation of HIF-1 expression levels with tumor growth and angiogenesis (18
, 19)
.
Recently, we found that HIF-1 mRNA was overexpressed in six rat PCA cell lines compared with the normal prostate, and metastatic potential was correlated with HIF-1 mRNA levels in those cell lines (20)
. A human PCA cell line derived from a bone metastasis was found to overexpress HIF-1 protein under nonhypoxic culture conditions (20)
. Because HIF-1 expression was dysregulated in PCA cell lines, we tested the hypothesis that HIF-1 is generally overexpressed in solid tumors. In this study, we screened HIF-1 protein expression by immunohistochemistry in normal tissues and human cancers, including lung, prostate, breast, and colon carcinoma, which are the leading causes of U.S. cancer mortality.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MAb H167. cDNA fragment encoding amino acids 432–528 was cloned into pGEX2T. The GST/HIF-1 fusion protein was purified from bacteria (14)
and used to immunize BALB/c mice. Spleen cells from immunized mice were fused with P3X63- Ag8-653 myeloma cells. Hybridoma supernatants were screened by ELISA against GST and GST/HIF-1. Supernatant from clone 67 was affinity-purified using protein G-Sepharose (Pharmacia). The adsorbed protein was eluted with 0.1 M glycine-HCl (pH 2.7) and neutralized with 1 M Tris-HCl (pH 9.0). Nuclear extracts, prepared from human Hep3B and mouse ES cells (11)
, were subjected to immunoblot analysis as described previously (14)
except that the primary MAb was H167 (1:500), and the secondary MAb was horseradish peroxidase-conjugated sheep antimouse immunoglobulin (1:2000).
Transient Transfection Assays.
Human embryonic kidney 293 cells, growing exponentially on 10-cm dishes, were transfected by calcium phosphate coprecipitation with 10 µg of pCEP4 (Invitrogen), pCEP4/HIF-1 (21
, 22)
, or PL477 (23)
, a HIF-2 expression vector that was generously provided by Dr. Christopher Bradfield (University of Wisconsin, Madison, WI). For reporter gene assays, the cells were cotransfected with pSVgal and 2xWT33-luciferase, which contains two copies of a 33-bp hypoxia-response element from the human erythropoietin gene cloned upstream of a basal SV40 promoter (22)
.
Immunohistochemistry.
Formalin-fixed, paraffin-embedded tissue specimens were obtained and handled by standard surgical oncology procedures. Serial 4-µm sections were prepared, and one was stained with H&E. Flanking sections were stained for HIF-1 using Catalyzed Signal Amplification System (DAKO) which is based on streptavidin-biotin-horseradish peroxidase complex formation. In brief, after deparaffinization and rehydration, slides were treated with target retrieval solution (DAKO) at 97°C for 45 min, and the manufacturer’s instructions were followed. MAb H167 (1 mg/ml) was used at a dilution of 1:1000. Nuclei were lightly counterstained with hematoxylin. Negative controls were performed using nonimmune serum or PBS instead of the MAb. A preadsorption test was also performed using GST/HIF-1 protein. Twenty-four-well plates were coated with GST/HIF-1 protein (2.9 mg/ml), air-dried, and incubated with H167 (1:1,000 dilution), followed by immunohistochemistry. Automated immunohistochemistry was performed using a BioTek-Tech Mate 100 Automated Stainer (Ventana-BioTek Solutions, Inc., Tucson, AZ) with the following MAbs: (a) anti-Ki67 (MAb MIB-1, Immunotech, 1:100); (b) antihuman p53 protein (MAb DO-7, DAKO, 1:250); (c) antihuman bcl-2 (MAb 124, DAKO, 1:25); (d) anticytokeratin (AE1/AE3, Boerhinger Mannheim, 1:2000); and (e) anti-prostate-specific antigen (MAb 5126, Immunotech, dilution 1:50).
Three investigators (H. Z., A. M. D., and J. W. S) independently evaluated the immunohistochemistry. All of the PCA bone metastases were verified by cytokeratin and prostate-specific antigen staining. The immunohistochemical results for HIF-1 protein were classified as follows: -, no staining; +, nuclear staining in less than 1% of cells; ++, nuclear staining in 1–10% of cells and/or with weak cytoplasmic staining; +++, nuclear staining in 10–50% of cells and/or with distinct cytoplasmic staining; ++++, nuclear staining in more than 50% of cells and/or with strong cytoplasmic staining. When independent scoring of a case differed, the case was rechecked, and the final score was determined by recounting HIF-1 positive cells using a multiheaded microscope with all of the three reviewers simultaneously viewing the slide. For Ki67 analysis, nuclei from approximately 1000 tumor cells from 10 randomly selected fields were counted, and the LI was determined as the percentage of positive nuclei. Bcl-2 reactivity was scored positive if >10% of tumor cells showed distinct cytoplasmic staining. Aberrant p53 accumulation was scored positive if nuclear staining was present in >10% of tumor cells.
Nonparametric statistical analyses were conducted by Dr. Steven Piantadosi, Johns Hopkins Oncology Center Biostatistics Center, using Microsoft Excel (Microsoft Corporation, Redmond, WA) and STAT-XACT, Version 4 for Windows (Cytel Software, Berkeley CA, 1998). As a singly ordered table, the Kruskal-Wallis test was used to evaluate the correlation between HIF-1 and aberrant p53 or bcl-2 expression. As a doubly ordered table, the correlation between HIF-1 protein expression and Ki67 LI was analyzed by Jonkchere-Terpstra test (24)
.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MAb H167. was used as immunogen for MAb production. Five hybridoma clones were identified that reacted with GST/HIF-1 but not with GST. Clone 67 was chosen for further characterization. MAb H167 was identified as IgG2b/
subtype and purified from hybridoma supernatants by protein-G affinity chromatography. Immunoblot assays demonstrated that MAb H167 recognized a hypoxia-induced protein of approximately Mr 120,000 that was identical in size to HIF-1, in Hep3B cells and wild-type ES cells, but not in HIF-1-null (11)
ES cells (Fig. 1A)
. MAb H167 showed reactivity against human, monkey, sheep, mouse, bovine, rat, and ferret HIF-1 (data not shown).
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67 also recognized human HIF-1 purified 11,250-fold by anion-exchange and DNA-affinity chromatography (25)
at concentrations too low to allow protein quantitation (data not shown). As a final test of its specificity, cells were transfected with expression vectors encoding no protein, HIF-1, or HIF-2 (Fig. 1B)
. MAb H167 detected overexpressed HIF-1 (Lanes 3–4), whereas cells overexpressing HIF-2 (Lanes 5–6) gave the same pattern as cells transfected with the empty vector (Lanes 1–2). HIF-2 expression in the transfected cells was confirmed by cotransfection of a reporter gene containing a hypoxia response element, which was activated 9- to 13-fold over background in cells transfected with HIF-1 expression vector and 33- to 106-fold over background in cells transfected with the HIF-2 expression vector (data not shown). These highly stringent tests provide convincing evidence that MAb H167 specifically recognizes HIF-1.
Screening of HIF-1 Protein Expression in Normal and Malignant Human Tissues.
HIF-1 expression was extensively screened in normal tissues and human cancers resected during routine surgical oncology procedures. Twenty-one normal human tissues (174 specimens), 19 primary malignant cancers (131 specimens), and 36 metastases from 6 tumor types were interrogated (Tables 1
and 2
). Most normal human tissues (14 types) showed no HIF-1 immunoreactivity (153 of 174 clinical specimens, 88% negative). In some autopsy specimens, weak staining was detected in adrenal cortical cells (3 of 8), renal distal tubular epithelium (3 of 9), pancreatic acinar cells (4 of 11), fetal hepatocytes (1 of 1), proliferating B cells from tonsil (2 of 3) and spleen (1 of 9), and seminiferous tubules of testis (7 of 7; Table 1
).
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protein was found in 69 (53%) of 131 primary malignant tumors representing 13 of 19 tumor types screened (Table 2)
. Cases of human prostate, breast, lung, colon, pancreas, brain, gastric, ovarian, and renal cell carcinomas, mesothelioma, and melanoma were positive. Immunohistochemistry was performed on adjacent sections of vena caval invasion from a renal cell carcinoma using MAb H167 that was preadsorbed with GST/HIF-1 protein. Whereas nonadsorbed MAb resulted in strong (++++) staining, preadsorbed MAb resulted in no (-) staining (data not shown).
Two-thirds of all of the regional lymph node and bone metastases were also positive for HIF-1 overexpression. HIF-1 was overexpressed in only 29% of primary breast cancers, whereas 69% of breast metastases were positive. All four of the preneoplastic and premalignant lesions found incidentally within biopsy specimens were positive for HIF-1 immunoreactivity, including two cases of breast comedo-type ductal carcinoma in situ, one case of prostatic intraepithelial neoplasia, and one case of colonic adenoma (Fig. 3, a and b)
. In contrast, all 12 of the benign tumors (breast fibroadenoma and uterine leiomyoma) were negative (Table 2)
.
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immunostaining was heterogeneous with signal concentrated primarily within the nucleus (Figs. 2
and 3
). Cytoplasmic staining was also detected in colon (Fig. 2e)
, breast, pancreas, and prostate adenocarcinomas. The results were reproducible, and cytoplasmic staining was not observed in flanking normal tissue. Within tumors, clusters of HIF-1 positive cells were most dense at the invading edge of tumor margins, the periphery of necrotic regions, and surrounding areas of neovascularization (Fig. 2, b and f)
. Some lymphocytes in lymph nodes containing metastatic cancer cells were positive for HIF-1 immunostaining (Fig. 3d)
, but expression was not detected in nonmalignant stromal cells under the assay conditions used for this study.
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expression levels correlated with the degree of tumor angiogenesis and/or disease progression, we evaluated nine brain tumors of different grades and degrees of neovascularization. HIF-1 expression was strongest in glioblastomas multiforme and hemangioblastomas (Fig. 2, f and g)
, which are respectively the most malignant and most highly vascularized primary tumors arising in the central nervous system. In glioblastomas, the staining was especially intense in pseudopalisading tumor cells surrounding areas of necrosis.
Comparison of HIF-1 Expression with the Expression of p53, bcl-2, and Ki67.
On the basis of tissue availability, most tumor samples used for HIF-1 staining were also stained with anti-Ki67 MAb; some tumor samples, the majority of which were colon and breast cancers, were also stained with anti-p53 and/or anti-bcl-2 MAbs. These markers were scored in a blinded manner relative to the HIF-1 staining. Expression of HIF-1 protein was positively correlated with aberrant p53 accumulation (P < 0.01), but the correlation with bcl-2 expression was of marginal statistical significance (P = 0.05; Table 3
). Nonparametric statistical analyses demonstrated a highly significant correlation of HIF-1 protein expression with Ki67 LI as a marker of cellular proliferation (P < 0.001; Table 3
). HIF-1 expression also correlated with Ki67 LI in some normal cell types. Fetal hepatocytes, proliferating B cells in tonsil and spleen, and seminiferous tubules of testis demonstrated weak HIF-1 expression, and these cell types manifested high Ki67 LI relative to other normal tissue types.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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protein was overexpressed in multiple types of human cancer and in regional and distant metastases. This study has identified increased HIF-1 expression (relative to adjacent normal tissue) in 13 tumor types including lung, prostate, breast, and colon carcinoma, which are the leading causes of U.S. cancer mortality. HIF-1 protein was also overexpressed in preneoplastic and premalignant lesions such as colonic adenoma, breast ductal carcinoma in situ, and prostate intraepithelial neoplasia. These data suggest that overexpression of HIF-1 can occur very early in carcinogenesis, before histological evidence of angiogenesis or invasion. Additional studies are under way to assess whether HIF-1 may represent a novel biomarker for precancerous lesions that warrant clinical surveillance or therapeutic intervention. It is provocative that every benign noninvasive tumor analyzed was negative for HIF-1 overexpression.
HIF-1 activates the transcription of genes encoding transferrin, VEGF, endothelin-1, and inducible nitric oxide synthase, which are implicated in vasodilation, neovascularization, and tumor metastasis (15
, 17)
. Particularly strong HIF-1 expression was observed in glioblastoma multiforme and hemangioblastoma. High VEGF mRNA expression has been reported in these highly malignant and vascularized brain tumors (26)
. HIF-1-positive cells were prominent at tumor margins and surrounding areas of neovascularization. In colonic adenocarcinoma, cancer cells at the leading edge of infiltrating carcinoma manifested the most intense HIF-1 immunostaining. Comparison of tumor and flanking normal tissue allows the patient to serve as his own control and supports the hypothesis that HIF-1 overexpression is associated with angiogenesis, invasion, and metastasis. Experimentally, xenografts of mutant mouse hepatoma cells lacking HIF-1 expression manifested significantly reduced growth rates and vascularization compared with parental and revertant cells that expressed HIF-1 (18
, 19)
. Conversely, human colon carcinoma cells transfected with a HIF-1 expression vector manifested significantly increased growth rates in nude mice as compared with parental cells.4
The patterns of immunohistochemical staining in different human cancers suggest that HIF-1 overexpression may result from both physiological (hypoxia) and nonphysiological mechanisms. It is clear from previous studies that many human tumors have regions of significant hypoxia (6, 7, 8)
. This pattern was most obvious in glioblastoma multiforme in which HIF-1 was detected in viable tumor cells that were closest to areas of necrosis and farthest from a blood vessel, as previously demonstrated for the expression of VEGF mRNA in these tumors (26
, 27)
. In contrast, expression of HIF-1 in hemangioblastoma could not be attributed to hypoxia because tumor cells immediately adjacent to patent blood vessels stained intensely, which indicated that factors other than hypoxia may contribute to HIF-1 expression in human cancers.
A growing number of observations indicate that genetic alterations also affect HIF-1 expression in cancer cells:
(a) we have correlated HIF-1 expression with cell proliferation, both in cultured PCA cells (20)
and in vivo (Table 3)
. Treatment of cultured cells with insulin, IGF-1, or IGF-2 induced expression of HIF-1 protein, which was in turn required for expression of IGF-2 mRNA (16)
, suggesting the involvement of HIF-1 in an autocrine growth factor loop. Remarkably, all of the 22 primary colon cancers analyzed overexpressed HIF-1, and the most highly up-regulated gene in colon cancer encodes IGF-2 (28)
;
(b) cells transfected with the v-Src oncogene overexpressed HIF-1, HIF-1 DNA-binding and transcriptional activity, and downstream genes including VEGF (18)
;
(c) HIF-1 overexpression was associated with aberrant p53 accumulation in human tumors (Table 3)
. The anti-p53 MAb used in this study recognizes an epitope in the NH2 terminus of the wild-type and mutant forms of human p53 protein. Point mutations in the TP53 gene occur frequently in human cancers, leading to increased expression of a nonfunctional p53 protein with a prolonged half-life that is detectable by immunohistochemistry. Thus, the presence of strong nuclear staining in the majority of cancer cells is frequently observed (29)
. Expression of HIF-1 protein, HIF-1 DNA-binding activity, and VEGF mRNA are increased in p53-/- knockout colon carcinoma cells as compared with the parental p53+/+ cells4
; and
(d) in renal clear cell carcinoma cell lines, the loss of von Hippel-Lindau tumor suppressor function results in constitutive high-level expression of HIF-1 (30)
. The primary (Fig. 2i)
and metastatic (Fig. 3f)
renal clear cell carcinomas analyzed here represent the first demonstration of this overexpression in vivo. Thus, in addition to hypoxia, both oncogene activation and tumor suppressor gene inactivation are associated with increased HIF-1 expression.
Some tumors did not stain positive for HIF-1 in this study. These tumors may overexpress HIF-1 but at levels that were below the limits of detection by immunohistochemistry using current methodology. Alternatively, other bHLH-PAS transcription factors that may have similar biological properties to HIF-1, such as HIF-2 (also known as EPAS1, HLF, HRF, and MOP2) or HIF-3 (23
, 31, 32, 33)
, may also mediate hypoxic adaptation. Nevertheless, HIF-1 was overexpressed in the majority of preneoplastic, malignant, and metastatic cancers analyzed. Given the overexpression of HIF-1 in common human cancers relative to normal tissues and its vital importance in mediating hypoxic adaptation, additional investigations of HIF-1 as a biomarker of metastatic potential and as a novel target for therapeutics are warranted.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by NIH Grant R01-HL55338 (to G. L. S.), NIH Prostate Cancer SPORE Grant CA-58236, CaP CURE Foundation, and Department of Defense Prostate Cancer Grant DAMD 17-98-1-8475 (to J. W. S.). Under a licensing agreement between the Johns Hopkins University and Novus Biologicals, Inc., G. L. S. is entitled to a share of royalties received by the University from sales of the technology described in this publication. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies. 
2 To whom requests for reprints should be addressed, at The Johns Hopkins Hospital, CMSC 1004, 600 North Wolfe Street, Baltimore, MD 21287. Phone: (410) 955-1619; Fax: (410) 955-0484; E-mail: gsemenza{at}jhmi.edu
3 The abbreviations used are: VEGF, vascular endothelial growth factor; HIF-1, hypoxia-inducible factor 1; IGF, insulin-like growth factor; MAb, monoclonal antibody; bHLH, basic helix-loop-helix; PCA, prostate cancer; GST, glutathione S-transferase; ES, embryonic stem; LI, labeling index.
4 R. Ravi, A. Bedi, and G. L. Semenza, unpublished data.
Received 6/18/99. Accepted 10/ 6/99.
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K. Raina, S. Rajamanickam, R. P. Singh, G. Deep, M. Chittezhath, and R. Agarwal Stage-Specific Inhibitory Effects and Associated Mechanisms of Silibinin on Tumor Progression and Metastasis in Transgenic Adenocarcinoma of the Mouse Prostate Model Cancer Res., August 15, 2008; 68(16): 6822 - 6830. [Abstract] [Full Text] [PDF]
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G.-M. Zou and A. Maitra Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration Mol. Cancer Ther., July 1, 2008; 7(7): 2012 - 2021. [Abstract] [Full Text] [PDF]
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A. Mayer, M. Hockel, A. Wree, C. Leo, L.-C. Horn, and P. Vaupel Lack of Hypoxic Response in Uterine Leiomyomas despite Severe Tissue Hypoxia Cancer Res., June 15, 2008; 68(12): 4719 - 4726. [Abstract] [Full Text] [PDF]
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M.-T. Lin, I-H. Kuo, C.-C. Chang, C.-Y. Chu, H.-Y. Chen, B.-R. Lin, M. Sureshbabu, H.-J. Shih, and M.-L. Kuo Involvement of Hypoxia-inducing Factor-1{alpha}-dependent Plasminogen Activator Inhibitor-1 Up-regulation in Cyr61/CCN1-induced Gastric Cancer Cell Invasion J. Biol. Chem., June 6, 2008; 283(23): 15807 - 15815. [Abstract] [Full Text] [PDF]
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C. Calabrese, A. Pisi, G. Di Febo, G. Liguori, G. Filippini, M. Cervellera, V. Righi, P. Lucchi, A. Mucci, L. Schenetti, et al. Biochemical Alterations from Normal Mucosa to Gastric Cancer by Ex vivo Magnetic Resonance Spectroscopy Cancer Epidemiol. Biomarkers Prev., June 1, 2008; 17(6): 1386 - 1395. [Abstract] [Full Text] [PDF]
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K. Lee, J. D. Lynd, S. O'Reilly, M. Kiupel, J. J. McCormick, and J. J. LaPres The Biphasic Role of the Hypoxia-Inducible Factor Prolyl-4-Hydroxylase, PHD2, in Modulating Tumor-Forming Potential Mol. Cancer Res., May 1, 2008; 6(5): 829 - 842. [Abstract] [Full Text] [PDF]
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X. Li, Y. Lu, K. Liang, T. Pan, J. Mendelsohn, and Z. Fan Requirement of hypoxia-inducible factor-1{alpha} down-regulation in mediating the antitumor activity of the anti-epidermal growth factor receptor monoclonal antibody cetuximab Mol. Cancer Ther., May 1, 2008; 7(5): 1207 - 1217. [Abstract] [Full Text] [PDF]
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C. Sahlgren, M. V. Gustafsson, S. Jin, L. Poellinger, and U. Lendahl Notch signaling mediates hypoxia-induced tumor cell migration and invasion PNAS, April 29, 2008; 105(17): 6392 - 6397. [Abstract] [Full Text] [PDF]
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R. Seifeddine, A. Dreiem, E. Blanc, M.-C. Fulchignoni-Lataud, M.-A. L. F. Belda, F. Lecuru, T. H. Mayi, N. Mazure, V. Favaudon, C. Massaad, et al. Hypoxia Down-regulates CCAAT/Enhancer Binding Protein-{alpha} Expression in Breast Cancer Cells Cancer Res., April 1, 2008; 68(7): 2158 - 2165. [Abstract] [Full Text] [PDF]
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L. Yang, Y. Jiang, S.F. Wu, M.Y. Zhou, Y.L. Wu, and G.Q. Chen CCAAT/enhancer-binding protein {alpha} antagonizes transcriptional activity of hypoxia-inducible factor 1 {alpha} with direct protein-protein interaction Carcinogenesis, February 1, 2008; 29(2): 291 - 298. [Abstract] [Full Text] [PDF]
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B. L. Lee, W. H. Kim, J. Jung, S. J. Cho, J.-W. Park, J. Kim, H.-Y. Chung, M. S. Chang, and S. Y. Nam A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angiogenesis in human gastric cancer Carcinogenesis, January 1, 2008; 29(1): 44 - 51. [Abstract] [Full Text] [PDF]
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J. H. Baek, Y. V. Liu, K. R. McDonald, J. B. Wesley, H. Zhang, and G. L. Semenza Spermidine/Spermine N1-Acetyltransferase-1 Binds to Hypoxia-inducible Factor-1{alpha} (HIF-1{alpha}) and RACK1 and Promotes Ubiquitination and Degradation of HIF-1{alpha} J. Biol. Chem., November 16, 2007; 282(46): 33358 - 33366. [Abstract] [Full Text] [PDF]
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S. A. Lang, C. Moser, A. Gaumann, D. Klein, G. Glockzin, F. C. Popp, M. H. Dahlke, P. Piso, H. J. Schlitt, E. K. Geissler, et al. Targeting Heat Shock Protein 90 in Pancreatic Cancer Impairs Insulin-like Growth Factor-I Receptor Signaling, Disrupts an Interleukin-6/Signal-Transducer and Activator of Transcription 3/Hypoxia-Inducible Factor-1{alpha} Autocrine Loop, and Reduces Orthotopic Tumor Growth Clin. Cancer Res., November 1, 2007; 13(21): 6459 - 6468. [Abstract] [Full Text] [PDF]
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P. Brader, C. C. Riedl, Y. Woo, V. Ponomarev, P. Zanzonico, B. Wen, S. Cai, H. Hricak, Y. Fong, R. Blasberg, et al. Imaging of hypoxia-driven gene expression in an orthotopic liver tumor model Mol. Cancer Ther., November 1, 2007; 6(11): 2900 - 2908. [Abstract] [Full Text] [PDF]
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Q. Cai, M. Murakami, H. Si, and E. S. Robertson A Potential {alpha}-Helix Motif in the Amino Terminus of LANA Encoded by Kaposi's Sarcoma-Associated Herpesvirus Is Critical for Nuclear Accumulation of HIF-1{alpha} in Normoxia J. Virol., October 1, 2007; 81(19): 10413 - 10423. [Abstract] [Full Text] [PDF]
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L. A. Kingsley, P. G.J. Fournier, J. M. Chirgwin, and T. A. Guise Molecular Biology of Bone Metastasis Mol. Cancer Ther., October 1, 2007; 6(10): 2609 - 2617. [Abstract] [Full Text] [PDF]
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C.-L. Sun, J.-M. Yuan, W. P. Koh, H.-P. Lee, and M. C. Yu Green tea and black tea consumption in relation to colorectal cancer risk: the Singapore Chinese Health Study Carcinogenesis, October 1, 2007; 28(10): 2143 - 2148. [Abstract] [Full Text] [PDF]
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J. H. Baek, Y. V. Liu, K. R. McDonald, J. B. Wesley, M. E. Hubbi, H. Byun, and G. L. Semenza Spermidine/Spermine-N1-Acetyltransferase 2 Is an Essential Component of the Ubiquitin Ligase Complex That Regulates Hypoxia-inducible Factor 1{alpha} J. Biol. Chem., August 10, 2007; 282(32): 23572 - 23580. [Abstract] [Full Text] [PDF]
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H. R. Rezvani, S. Dedieu, S. North, F. Belloc, R. Rossignol, T. Letellier, H. de Verneuil, A. Taieb, and F. Mazurier Hypoxia-inducible Factor-1{alpha}, a Key Factor in the Keratinocyte Response to UVB Exposure J. Biol. Chem., June 1, 2007; 282(22): 16413 - 16422. [Abstract] [Full Text] [PDF]
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T. Hiraga, S. Kizaka-Kondoh, K. Hirota, M. Hiraoka, and T. Yoneda Hypoxia and Hypoxia-Inducible Factor-1 Expression Enhance Osteolytic Bone Metastases of Breast Cancer Cancer Res., May 1, 2007; 67(9): 4157 - 4163. [Abstract] [Full Text] [PDF]
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 R. A. Cardone, A. Bellizzi, G. Busco, E. J. Weinman, M. E. Dell'Aquila, V. Casavola, A. Azzariti, A. Mangia, A. Paradiso, and S. J. Reshkin The NHERF1 PDZ2 Domain Regulates PKA-RhoA-p38-mediated NHE1 Activation and Invasion in Breast Tumor Cells Mol. Biol. Cell, May 1, 2007; 18(5): 1768 - 1780. [Abstract] [Full Text] [PDF]
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D. L. Gillespie, K. Whang, B. T. Ragel, J. R. Flynn, D. A. Kelly, and R. L. Jensen Silencing of Hypoxia Inducible Factor-1{alpha} by RNA Interference Attenuates Human Glioma Cell Growth In vivo Clin. Cancer Res., April 15, 2007; 13(8): 2441 - 2448. [Abstract] [Full Text] [PDF]
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H.-J. Kim, H. Chung, Y.-G. Yoo, H. Kim, J.-Y. Lee, M.-O. Lee, and G. Kong Inhibitor of DNA Binding 1 Activates Vascular Endothelial Growth Factor through Enhancing the Stability and Activity of Hypoxia-Inducible Factor-1{alpha} Mol. Cancer Res., April 1, 2007; 5(4): 321 - 329. [Abstract] [Full Text] [PDF]
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K. Horii, Y. Suzuki, Y. Kondo, M. Akimoto, T. Nishimura, Y. Yamabe, M. Sakaue, T. Sano, T. Kitagawa, S. Himeno, et al. Androgen-Dependent Gene Expression of Prostate-Specific Antigen Is Enhanced Synergistically by Hypoxia in Human Prostate Cancer Cells Mol. Cancer Res., April 1, 2007; 5(4): 383 - 391. [Abstract] [Full Text] [PDF]
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J. Fang, Q. Zhou, L.-Z. Liu, C. Xia, X. Hu, X. Shi, and B.-H. Jiang Apigenin inhibits tumor angiogenesis through decreasing HIF-1{alpha} and VEGF expression Carcinogenesis, April 1, 2007; 28(4): 858 - 864. [Abstract] [Full Text] [PDF]
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M. Ben-Shoshan, S. Amir, D. T. Dang, L. H. Dang, Y. Weisman, and N. J. Mabjeesh 1{alpha},25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells Mol. Cancer Ther., April 1, 2007; 6(4): 1433 - 1439. [Abstract] [Full Text] [PDF]
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J. D.W. van der Bilt, M. E. Soeters, A. M.M.J. Duyverman, M. W. Nijkamp, P. O. Witteveen, P. J. van Diest, O. Kranenburg, and I. H.M. Borel Rinkes Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases Am. J. Pathol., April 1, 2007; 170(4): 1379 - 1388. [Abstract] [Full Text] [PDF]
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J.-H. Lim, J.-W. Park, S. J. Kim, M.-S. Kim, S.-K. Park, R. S. Johnson, and Y.-S. Chun ATP6V0C Competes with Von Hippel-Lindau Protein in Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}) Binding and Mediates HIF-1{alpha} Expression by Bafilomycin A1 Mol. Pharmacol., March 1, 2007; 71(3): 942 - 948. [Abstract] [Full Text] [PDF]
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F. Wang, S. S. Li, R. Segersvard, L. Strommer, K.-G. Sundqvist, J. Holgersson, and J. Permert Hypoxia Inducible Factor-1 Mediates Effects of Insulin on Pancreatic Cancer Cells and Disturbs Host Energy Homeostasis Am. J. Pathol., February 1, 2007; 170(2): 469 - 477. [Abstract] [Full Text] [PDF]
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D. Liao, C. Corle, T. N. Seagroves, and R. S. Johnson Hypoxia-Inducible Factor-1{alpha} Is a Key Regulator of Metastasis in a Transgenic Model of Cancer Initiation and Progression Cancer Res., January 15, 2007; 67(2): 563 - 572. [Abstract] [Full Text] [PDF]
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Q. Zhou, L.-Z. Liu, B. Fu, X. Hu, X. Shi, J. Fang, and B.-H. Jiang Reactive oxygen species regulate insulin-induced VEGF and HIF-1{alpha} expression through the activation of p70S6K1 in human prostate cancer cells Carcinogenesis, January 1, 2007; 28(1): 28 - 37. [Abstract] [Full Text] [PDF]
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B. Fu, J. Xue, Z. Li, X. Shi, B.-H. Jiang, and J. Fang Chrysin inhibits expression of hypoxia-inducible factor-1{alpha} through reducing hypoxia-inducible factor-1{alpha} stability and inhibiting its protein synthesis Mol. Cancer Ther., January 1, 2007; 6(1): 220 - 226. [Abstract] [Full Text] [PDF]
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M. Lopez-Lazaro Hypoxia-Inducible Factor 1 as a Possible Target for Cancer Chemoprevention Cancer Epidemiol. Biomarkers Prev., December 1, 2006; 15(12): 2332 - 2335. [Abstract] [Full Text] [PDF]
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C. Leo, L.-C. Horn, C. Rauscher, B. Hentschel, A. Liebmann, G. Hildebrandt, and M. Hockel Expression of Erythropoietin and Erythropoietin Receptor in Cervical Cancer and Relationship to Survival, Hypoxia, and Apoptosis Clin. Cancer Res., December 1, 2006; 12(23): 6894 - 6900. [Abstract] [Full Text] [PDF]
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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]
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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]
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Q. Ke and M. Costa Hypoxia-Inducible Factor-1 (HIF-1) Mol. Pharmacol., November 1, 2006; 70(5): 1469 - 1480. [Abstract] [Full Text] [PDF]
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K S Kimbro and J W Simons Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 739 - 749. [Abstract] [Full Text] [PDF]
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R. P Singh and R. Agarwal Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr. Relat. Cancer, September 1, 2006; 13(3): 751 - 778. [Abstract] [Full Text] [PDF]
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D. T. Jones and A. L. Harris Identification of novel small-molecule inhibitors of hypoxia-inducible factor-1 transactivation and DNA binding. Mol. Cancer Ther., September 1, 2006; 5(9): 2193 - 2202. [Abstract] [Full Text] [PDF]
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G. Melillo Inhibiting Hypoxia-Inducible Factor 1 for Cancer Therapy Mol. Cancer Res., September 1, 2006; 4(9): 601 - 605. [Abstract] [Full Text] [PDF]
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Y. Sumiyoshi, Y. Kakeji, A. Egashira, K. Mizokami, H. Orita, and Y. Maehara Overexpression of Hypoxia-Inducible Factor 1{alpha} and p53 Is a Marker for an Unfavorable Prognosis in Gastric Cancer Clin. Cancer Res., September 1, 2006; 12(17): 5112 - 5117. [Abstract] [Full Text] [PDF]
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S. McMahon, M. Charbonneau, S. Grandmont, D. E. Richard, and C. M. Dubois Transforming Growth Factor beta1 Induces Hypoxia-inducible Factor-1 Stabilization through Selective Inhibition of PHD2 Expression J. Biol. Chem., August 25, 2006; 281(34): 24171 - 24181. [Abstract] [Full Text] [PDF]
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S.-B. Catrina, I. R. Botusan, A. Rantanen, A. I. Catrina, P. Pyakurel, O. Savu, M. Axelson, P. Biberfeld, L. Poellinger, and K. Brismar Hypoxia-Inducible Factor-1{alpha} and Hypoxia-Inducible Factor-2{alpha} Are Expressed in Kaposi Sarcoma and Modulated by Insulin-like Growth Factor-I Clin. Cancer Res., August 1, 2006; 12(15): 4506 - 4514. [Abstract] [Full Text] [PDF]
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D. Generali, A. Berruti, M. P. Brizzi, L. Campo, S. Bonardi, S. Wigfield, A. Bersiga, G. Allevi, M. Milani, S. Aguggini, et al. Hypoxia-Inducible Factor-1{alpha} Expression Predicts a Poor Response to Primary Chemoendocrine Therapy and Disease-Free Survival in Primary Human Breast Cancer Clin. Cancer Res., August 1, 2006; 12(15): 4562 - 4568. [Abstract] [Full Text] [PDF]
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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]
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D. Nie, S. Krishnamoorthy, R. Jin, K. Tang, Y. Chen, Y. Qiao, A. Zacharek, Y. Guo, J. Milanini, G. Pages, et al. Mechanisms Regulating Tumor Angiogenesis by 12-Lipoxygenase in Prostate Cancer Cells J. Biol. Chem., July 7, 2006; 281(27): 18601 - 18609. [Abstract] [Full Text] [PDF]
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A. Kaidi, D. Qualtrough, A. C. Williams, and C. Paraskeva Direct Transcriptional Up-regulation of Cyclooxygenase-2 by Hypoxia-Inducible Factor (HIF)-1 Promotes Colorectal Tumor Cell Survival and Enhances HIF-1 Transcriptional Activity during Hypoxia. Cancer Res., July 1, 2006; 66(13): 6683 - 6691. [Abstract] [Full Text] [PDF]
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C. Koumenis and B. G. Wouters "Translating" Tumor Hypoxia: Unfolded Protein Response (UPR)-Dependent and UPR-Independent Pathways Mol. Cancer Res., July 1, 2006; 4(7): 423 - 436. [Abstract] [Full Text] [PDF]
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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]
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Q. Zhang, S.-Y. Wang, A. C. Nottke, J. V. Rocheleau, D. W. Piston, and R. H. Goodman Redox sensor CtBP mediates hypoxia-induced tumor cell migration PNAS, June 13, 2006; 103(24): 9029 - 9033. [Abstract] [Full Text] [PDF]
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