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[Cancer Research 63, 2330-2334, May 1, 2003]
© 2003 American Association for Cancer Research

Tumor Biology

Vascular Endothelial Growth Factor Gene Expression in Colon Cancer Cells Exposed to Prostaglandin E2 Is Mediated by Hypoxia-inducible Factor 11

Ryo Fukuda, Brian Kelly and Gregg L. Semenza2

McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prostaglandin E2 (PGE2) has been implicated as an inducer of angiogenesis in human colon cancer. Here, we demonstrate that PGE2 exposure induces the expression of vascular endothelial growth factor (VEGF) mRNA in HCT116 human colon carcinoma cells that is mediated by the transcriptional activator hypoxia-inducible factor 1 (HIF-1). PGE2 exposure induces the phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Pharmacologic inhibition of ERK phosphorylation blocks the induction of VEGF mRNA and HIF-1{alpha} protein expression in response to PGE2 stimulation. Inhibition of C-SRC tyrosine kinase activity also blocks PGE2-induced HIF-1{alpha} protein and VEGF mRNA expression without blocking ERK phosphorylation. In contrast, phosphorylation of AKT is dependent on ERK and C-SRC activity. Thus, the activity of multiple signal transduction pathways is required for the HIF-1-mediated induction of VEGF expression in colon cancer cells exposed to PGE2.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Colorectal cancer is the second leading cause of mortality from neoplastic disease in the United States. Tumor microvessel density is an important determinant of colon cancer metastasis and patient mortality (1 , 2) . The level of VEGF3 expression is a major determinant of microvessel density in colon cancers, and VEGF expression is also correlated with metastasis and mortality. Recent studies of human colon cancers have demonstrated that expression of COX2 is also correlated with VEGF expression, angiogenesis, and patient mortality (3, 4, 5) . COX2 catalyzes the production of PGE2, and high levels of PGE2 have been demonstrated in colorectal adenocarcinomas in comparison with adjacent normal tissue (6 , 7) . In mice, pharmacologic or genetic inhibition of COX2 activity suppresses colon carcinogenesis (8, 9, 10) and can block the growth of established tumors (11) . In humans, the use of nonsteroidal anti-inflammatory drugs that nonselectively inhibit COX2 is associated with a reduced risk of colorectal cancer (12, 13, 14, 15) .

The mechanism by which COX2-generated PGE2 induces VEGF expression in colon cancer cells has not been determined. VEGF expression is also induced in colon cancer cells by other stimuli, including hypoxia, activation of the IGF-1R, or p53 loss-of-function, and, in these cases, transcriptional activation of the VEGF gene is mediated by HIF-1 (16 , 17) . HIF-1 is a heterodimeric protein consisting of a constitutively expressed HIF-1ß subunit and a HIF-1{alpha} subunit, the expression of which is regulated by the cellular O2 concentration and diverse signal transduction pathways leading from cell surface receptors to kinase cascades (18) . Under hypoxic conditions, the O2-dependent hydroxylation of proline residues 402 and 564, which is required for ubiquitination and proteasomal degradation of HIF-1{alpha}, is inhibited (19, 20, 21) . In contrast, activation of the PI3K and ERK pathways after ligand binding to the IGF-1R stimulates increased synthesis of HIF-1{alpha} protein (16) . HIF-1{alpha} overexpression has been demonstrated in human colon cancer biopsies (22 , 23) , and forced overexpression of HIF-1{alpha} in human colon carcinoma HCT116 cells increases tumor growth and angiogenesis in nude mice (17) .

In the present study, we investigated the mechanism by which PGE2 exposure induces VEGF gene expression in HCT116 human colon carcinoma cells. We demonstrate that PGE2 induces expression of HIF-1{alpha} protein and VEGF mRNA and that inhibition of HIF-1{alpha} expression by RNA interference blocks the induction of VEGF mRNA. We also provide evidence that the activity of multiple signal transduction pathways is required for the HIF-1-mediated induction of VEGF expression in colon cancer cells exposed to PGE2.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tissue Culture and Reagents.
HCT116 cells (wild type with respect to p53 expression) were cultured in McCoy’s 5A medium with 10% FBS, 100 units/ml penicillin, and 100 µg/ml streptomycin (Invitrogen Corp., Carlsbad, CA). PGE2, PD98059, Wortmannin, rapamycin, SB203580, cycloheximide, and cobalt chloride (CoCl2) were from Sigma (St. Louis, MO). SC-51322 and 17-pt-PGE2 were from Biomol Research Laboratories (Butler Pike, PA). PP2 and JNK inhibitor were from Calbiochem. For hypoxic exposures, cells were placed in a modulator incubator chamber (Billups-Rothenberg, Del Mar, CA) flushed with 1% O2/5% CO2/balance N2, sealed, and incubated at 37°C.

PGE2 and Inhibitor Treatments.
HCT116 cells were plated at a density of 2.5 x 106/10-cm or 8.6 x 105/6-cm dish. Subconfluent cells were serum starved (0.1% FBS) for 24 h before PGE2 or 17-pt-PGE2 was added. Kinase inhibitors PD98059, Wortmannin, rapamycin, and SB203580 were added 1 h before exposure to PGE2, 1% O2, or 100 µM CoCl2. JNK inhibitor and PP2 were added 20 min and 2 h, respectively, before the exposure to PGE2 or 1% O2. EP1 receptor antagonist SC-51322 was added 30 min before exposure to PGE2. Cycloheximide was added to the media of HCT116 cells that had been serum starved and treated with CoCl2 for 4 h or PGE2 for 24 h, and whole cell extracts were prepared at 0, 20, and 40 min.

Immunoblot Assays.
Whole cell extracts were prepared using radioimmunoprecipitation assay buffer, fractionated by SDS-PAGE, and transferred to a nitrocellulose filter. For HIF-1{alpha} and HIF-1ß, 150-µg aliquots of protein were analyzed using a monoclonal antibody against HIF-1{alpha} (H1{alpha}67; Ref. 23 ) or HIF-1ß (H1ß234; Novus Biologicals, Littleton, CO; Ref. 24 ) at 1:1000 dilution (16) . Aliquots (50 µg) were analyzed using antibodies (1:1000 dilution) specific for phosphorylated (Thr202/Tyr204) or total p44/p42 MAP kinase and phosphorylated (Ser473) or total AKT (Cell Signaling Technology, Beverly, MA, and Santa Cruz Biotechnology, Santa Cruz, CA). Horseradish peroxidase-conjugated secondary antibodies against mouse and rabbit IgG (1:2500 dilution) and enhanced chemiluminescence reagents were from Amersham Biosciences (Piscataway, NJ).

RT-PCR Assays.
Total RNA was extracted from HCT116 cells using TRIzol reagent (Invitrogen Corp.). Aliquots (5 µg) of RNA were reverse transcribed to cDNA using Superscribe First-Strand Synthesis System (Invitrogen Corp.). Aliquots (1, 2, and 4 µl) of cDNA were used as template for PCR of HIF-1{alpha}, VEGF, and 18S rRNA sequences. The following oligonucleotides were used as primers: (a) 5'-GGGAGAAAATCAAGTCGTGC-3' and 5'-AGCAAGGAGGGCCTCTGATG-3' (HIF-1{alpha}); (b) 5'-TACCTCCACCATGCCAAGTG-3' and 5'-AAGATGTCCACCAGGGTCTC-3 (VEGF); and (c) 5'-ATCCTGCCAGTAGCATATGC-3' and 5'-ACCGGGTTGGTTTTGATCTG-3' (18S rRNA). Thermocycling conditions were 30 s at 95°C, 30 s at 55°C, and 30 s at 72°C for 25 (HIF-1{alpha}), 27 (VEGF), or 13 (18S rRNA) cycles.

RNA Interference.
To generate siRNAHIF-1{alpha}, two oligonucleotides consisting of ribonucleosides, except for the presence of 2'-deoxyribonucleosides at the 3' end (5'-AGAGGUGGAUAUGUGUGGGdTdT-3' and 5'-CCCACACAUAUCCACCUCUdTdT-3'), were synthesized and annealed (Dharmacon Research, Inc., Lafayette, CO). HCT116 cells were plated at 2 x 106 cells/10-cm dish and exposed to 100 nM siRNAHIF-1{alpha} in the presence of Oligofectamine (Invitrogen Corp.) for 4 h and then cultured for 24 h in complete media (25) . Cells were serum starved for another 24 h and exposed to 100 µM PGE2 or vehicle for 24 h, and total RNA was isolated for RT-PCR analysis of HIF-1{alpha} and VEGF mRNA. As control, cells were exposed to Oligofectamine without siRNAHIF-1{alpha}. Neither mock transfection nor transfection with an siRNA targeted to an irrelevant mRNA inhibited HIF-1{alpha} mRNA or protein expression (26) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We first performed a time course experiment in which HCT116 cells were serum starved and exposed to PGE2 for 0–40 h before preparation of whole cell protein lysates or isolation of total RNA. Immunoblot assay revealed that HIF-1ß protein was constitutively expressed and HIF-1{alpha} protein expression was induced with peak levels observed 18–32 h after the addition of PGE2 to the culture media (Fig. 1A)Citation . In contrast, we have demonstrated previously that maximal induction of HIF-1{alpha} protein expression is observed 8 h after IGF-1 addition to HCT116 cells (16) . Thus, compared with IGF-1, PGE2 induces HIF-1{alpha} protein expression with delayed kinetics. HIF-1{alpha} mRNA expression was not induced by PGE2 stimulation (Fig. 1A)Citation , indicating that the increased HIF-1{alpha} protein levels resulted from either increased protein synthesis or decreased protein degradation. VEGF mRNA expression was induced by PGE2 with kinetics similar to those observed for HIF-1{alpha} protein expression (Fig. 1A)Citation . Exposure of HCT116 cells to various concentrations of PGE2 for 24 h induced HIF-1{alpha} protein and VEGF mRNA expression in a dose-dependent manner, although the responses were modest in comparison with the responses induced by hypoxia (Fig. 1B)Citation .



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  		Fig. 1. PGE2-induced responses in HCT116 cells. A, time course. Cells were serum starved for 24 h; 100 µM PGE2 was added to the media for the indicated time, and cells were harvested for immunoblot (HIF-1{alpha}, HIF-1ß, phospho-ERK [Thr202/Tyr204], and total ERK protein) and RT-PCR (VEGF and HIF-1{alpha} mRNA) assays. B, dose response. Cells were untreated (Lane 1) or exposed to 1–100 µM PGE2 (Lanes 2–4) or 1% O2 (Lane 5) for 24 h and harvested for analysis of HIF-1{alpha} protein or VEGF mRNA.

 
PGE2 binds to the G protein-coupled receptors EP1, EP2, EP3, and EP4. The EP1 receptor-selective agonist 17-pt-PGE2 was as effective as PGE2 in stimulating HIF-1{alpha} protein expression in HCT116 cells (Fig. 2A)Citation . Furthermore, the EP1 receptor-selective antagonist SC51322 inhibited PGE2-induced HIF-1{alpha} expression in a dose-dependent manner (Fig. 2B)Citation . Neither 17-pt-PGE2 nor SC51322 had any effect on HIF-1ß expression. Thus, EP1 receptor activation appears to be necessary and sufficient to induce HIF-1{alpha} expression in HCT116 cells.



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  		Fig. 2. Effect of EP1 receptor agonist and antagonist. In A, HCT116 cells were untreated (Lane 1) or exposed to the EP1 receptor agonist 17-pt-PGE2 (Lanes 2–4) or PGE2 (Lane 5) for 24 h. In B, cells were untreated (Lane 1) or exposed to PGE2 for 24 h in the presence of 0–50 µM EP1 receptor antagonist SC-51322 (Lanes 2–5).

 
In HCT116 cells subjected to hypoxia or IGF-1 treatment, increased HIF-1{alpha} protein levels result from a decreased rate of degradation and an increased rate of synthesis, respectively (16) . To determine which of these mechanisms is involved in PGE2-induced HIF-1{alpha} expression, cells were cultured for 24 h in the presence of PGE2 or CoCl2, which inhibits HIF-1{alpha} degradation, similar to the effect of hypoxia. The half-life of HIF-1{alpha} protein was >40 min in CoCl2-treated cells but <20 min in PGE2-treated cells (Fig. 3)Citation . These results indicate that, unlike CoCl2, PGE2 does not increase the half-life of HIF-1{alpha} protein and therefore must stimulate HIF-1{alpha} protein synthesis, similar to the effect of IGF-1.



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  		Fig. 3. Analysis of HIF-1{alpha} protein stability. HCT116 cells were exposed to 100 µM PGE2 for 24 h (Lanes 1–3) or 100 µM CoCl2 for 4 h (Lanes 4–6). Cycloheximide was added to a final concentration of 100 µM, and cells were harvested 0, 20, or 40 min later. The fraction of HIF-1{alpha} remaining is indicated.

 
To investigate the signal transduction pathways activated by PGE2, we first analyzed the phosphorylation status of ERK. Phosphorylation of ERK was induced with delayed kinetics in response to PGE2 stimulation (Fig. 1A)Citation . PD98059 inhibits the activity of MEK, which is responsible for the activating phosphorylation of ERK. PD98059 blocked the induction of HIF-1{alpha} protein and VEGF mRNA that was induced by PGE2 (Fig. 4A)Citation . Wortmannin and rapamycin are inhibitors of PI3K and the downstream serine-threonine kinase FKBP rapamycin-associated protein (also known as mammalian target of rapamycin), respectively. Both Wortmannin and rapamycin partially inhibited PGE2-induced HIF-1{alpha} protein and VEGF mRNA expression. Neither the inducers or inhibitors had any consistent effect on the expression of HIF-1ß protein or HIF-1{alpha} mRNA (Fig. 4A)Citation . In the presence of a submaximal concentration of PD98059, Wortmannin further decreased HIF-1{alpha} protein expression in a dose-dependent manner (Fig. 4B)Citation . Inhibitors of two other MAP kinases, p38 and JNK, had no effect on PGE2-induced HIF-1{alpha} protein expression (Fig. 4C)Citation .



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  		Fig. 4. Effect of kinase inhibitors. In A, HCT116 cells were untreated (Lane 1) or exposed to 1% O2 (Lane 2) or 100 µM PGE2 (Lanes 3–6) for 24 h after pretreatment for 1 h with 100 µM PD98059 (PD), 200 nM Wortmannin (WM), or 100 nM rapamycin (Rap). In B, cells were exposed to vehicle (Lane 1) or PGE2 (Lanes 2–5) after pretreatment with vehicle or 10 µM PD98059 plus 0–200 nM Wortmannin. In C, cells were exposed to vehicle (Lane 1) or 100 µM PGE2 (Lanes 2–4) after pretreatment with vehicle, 2.5 µM SB203580 (SB), or 100 µM JNK inhibitor (JNKI). In D, cells were pretreated with vehicle or 20 µM PP2 and exposed to vehicle (Lane 1), 100 µM PGE2 (Lanes 2–3), or 1% O2 (Lanes 4–5). In E, cells were exposed to vehicle (Lane 1) or PGE2 (Lanes 2–6) after pretreatment with vehicle or 50 µM PD98059 (PD), 200 nM Wortmannin (WM), 100 nM rapamycin (Rap), or 20 µM PP2. Immunoblot assays were performed using antibodies against phosphorylated (Thr202/Tyr204) or total ERK and phosphorylated (Ser473) or total AKT.

 
PP2, an inhibitor of C-SRC tyrosine kinase activity, completely blocked HIF-1{alpha} protein expression induced by PGE2 but not by hypoxia (Fig. 4D)Citation . Although PD98059, Wortmannin, rapamycin, and PP2 all inhibited PGE2-induced HIF-1{alpha} protein expression (Fig. 4A–D)Citation , only PD98059 blocked PGE2-induced ERK phosphorylation (Fig. 4E)Citation . These results indicate that neither C-SRC nor PI3K pathway activation was required for PGE2-induced ERK activation. PGE2 induced phosphorylation of AKT that was blocked by pretreatment with Wortmannin (Fig. 4E)Citation . Pretreatment with PD98059 or PP2 partially inhibited PGE2-induced AKT phosphorylation, suggesting that PI3K-AKT signaling was dependent on both ERK and C-SRC activity.

The data presented above (Figs. 1, A and BCitation and 4A)Citation demonstrate a remarkably consistent correlation between HIF-1{alpha} protein and VEGF mRNA expression in cells treated with various kinase inhibitors and/or PGE2. To further demonstrate that HIF-1{alpha} is required for the induction of VEGF mRNA expression in response to PGE2, HCT116 cells were mock transfected or transfected with a small interfering RNA (siRNAHIF-1{alpha}) that targets HIF-1{alpha} mRNA for degradation. After transfection, the cells were serum starved and exposed to vehicle or PGE2. As expected, HIF-1{alpha} mRNA levels were reduced in cells transfected with siRNAHIF-1{alpha} (Fig. 5)Citation . VEGF mRNA levels were slightly reduced in siRNAHIF-1{alpha}-transfected cells treated with vehicle and dramatically reduced in PGE2-treated cells. Thus, inhibition of HIF-1{alpha} expression is sufficient to block PGE2-induced VEGF mRNA expression.



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  		Fig. 5. Effect of HIF-1{alpha} RNA interference on VEGF mRNA expression. HCT116 cells were exposed to Oligofectamine in the absence (-) or presence (+) of a small interfering RNA directed against HIF-1{alpha} (siRNAHIF-1{alpha}). A day after transfection, the cells were serum starved for 24 h and then exposed to vehicle (Control) or 100 µM PGE2 for 24 h.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present studies have delineated molecular mechanisms by which PGE2 stimulates VEGF mRNA expression in human colon carcinoma cells, thus providing a link between COX2 activity and tumor angiogenesis. Although most experiments involved exposing cells to relatively high concentrations of PGE2, concentration-dependent effects were observed over the range of 1–100 µM. Induction of VEGF mRNA expression is mediated by binding of PGE2 to the EP1 G protein-coupled receptor and activation of the MEK-ERK and PI3K-AKT pathways. We have demonstrated previously that transfection of HCT116 cells with an expression vector encoding constitutively active MEK results in HIF-1{alpha} protein and VEGF mRNA expression (16) . We demonstrate that, unlike hypoxia, PGE2 treatment is not associated with an increase in the half-life of HIF-1{alpha} protein. Our data suggest that, as in the case of IGF-1, PGE2 increases the rate of HIF-1{alpha} protein synthesis. The induction of HIF-1{alpha} protein and VEGF mRNA expression in PGE2-treated cells is completely or partially blocked by inhibitors of MEK and PI3K, respectively, as was also observed in IGF-1-treated HCT116 cells (16) . Inhibition of C-SRC tyrosine kinase activity also blocks the induction of HIF-1{alpha} protein and VEGF mRNA expression in PGE2-treated cells without blocking ERK phosphorylation. Our data indicate that the signal transduction from PGE2 receptor binding to HIF-1{alpha} expression is complex, and additional studies are required to determine the mechanisms and consequences of ERK, PI3K, and C-SRC activation in PGE2-treated HCT116 cells.

Although HIF-1{alpha} protein and VEGF mRNA expression are induced in HCT116 cells exposed to either IGF-1 or PGE2, there are several notable differences in the respective signal-transduction pathways: (a) in contrast to IGF-1, PGE2 induces ERK phosphorylation and HIF-1{alpha} expression with delayed kinetics, which suggests a requirement for gene expression; and (b) AKT phosphorylation is dependent on ERK activation in PGE2-treated HCT116 cells but independent of ERK activation in IGF-1-treated cells. PGE2-induced AKT phosphorylation is also dependent on C-SRC tyrosine kinase activity. Induction of HIF-1{alpha} protein and VEGF mRNA expression in V-SRC-transfected rodent cells has been demonstrated previously (27) .

While this study was in preparation, the induction of HIF-1{alpha} expression by PGE2 treatment of PC-3ML human prostate cancer cells was reported (28) . HIF-1{alpha} expression was induced by EP2 and EP4 but not EP3 receptor-selective agonists, whereas the EP1 receptor was not expressed. PD98059 inhibited PGE2-induced HIF-1{alpha} expression. However, HIF-1{alpha} expression was induced within 4 h in PGE2-treated PC-3ML cells (28) . These results suggest that different signal transduction pathways are activated by PGE2 in prostate and colon cancer cells, although MEK-ERK activation appears to play an essential role in both cases. The effect of PGE2 in PC-3ML cells was attributed to stabilization of HIF-1{alpha} protein, but no data were presented to support this conclusion. Additional studies are required to address this issue.

VEGF expression is induced in colon and other cancer cells as a result of hypoxia and multiple genetic alterations, including p53 and PTEN loss-of-function, RAS and SRC gain-of-function, and autocrine tyrosine kinase signaling pathways involving epidermal growth factor receptor, HER2neu, and IGF-1R (29, 30, 31, 32, 33, 34, 35) . In each case, VEGF gene expression is activated by HIF-1 (16 , 17 , 27 , 36, 37, 38, 39) . Based on the analysis of prostate cancer cells recently reported (28) and colon cancer cells presented in this study, this list can now be extended to include the increased VEGF expression resulting from COX2-generated PGE2. COX2 inhibitors, either alone or in combination with traditional cancer therapies such as radiation, have antiangiogenic effects (5 , 40) . As in the case of the tyrosine kinase-signaling pathways described above, the antiangiogenic effects of COX2 inhibitors appear to be attributable in part to their inhibition of HIF-1{alpha} expression (28 , 41) . Efforts to identify small molecules that directly inhibit HIF-1 activity are under way (42) , and such compounds may represent useful additions to the armamentarium of anticancer agents that target signal transduction pathways and angiogenesis.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by NIH grants (to G. L. S.). Back

2 To whom requests for reprints should be addressed, at The Johns Hopkins University School of Medicine, CMSC-1004, 600 North Wolfe Street, Baltimore, MD 21287-3914. Fax: (410) 955-0484; E-mail: gsemenza{at}jhmi.edu Back

3 The abbreviations used are: VEGF, vascular endothelial growth factor; IGF, insulin-like growth factor; ERK, extracellular signal-regulated kinase; COX2, cyclooxygenase 2; HIF-1, hypoxia-inducible factor 1; PI3K, phosphatidylinositol-3-kinase; 17-pt-PGE2, 17-phenyl-trinor-prostaglandin E2; IGF-1R, insulin-like growth factor-1 receptor; MEK, mitogen-activated protein/extracellular signal-regulated kinase kinase; JNK, c-Jun NH2-terminal kinase; PGE2, prostaglandin E2; MAP, mitogen-activated protein; RT-PCR, reverse transcription-PCR. Back

Received 12/18/02. Accepted 3/ 4/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Takahashi Y., Kitadai Y., Bucana C. D., Cleary K. R., Ellis L. M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res., 55: 3964-3968, 1995.[Abstract/Free Full Text]
  2. Takahashi Y., Tucker S. L., Kitadai Y., Koura A. N., Bucana C. D., Cleary K. R., Ellis L. M. Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch. Surg., 132: 541-546, 1997.[Abstract/Free Full Text]
  3. Cianchi F., Cortesini C., Bechi P., Fantappie O., Messerini L., Vannacci A., Sardi I., Baroni G., Boddi V., Mazzanti R., Masini E. Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer. Gastroenterology, 121: 1339-1347, 2001.[Medline]
  4. Masunaga R., Kohno H., Dhar D. K., Ohno S., Shibakita M., Kinugasa S., Yoshimura H., Tachibana M., Kubota H., Nagasue N. Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients. Clin. Cancer Res., 6: 4064-4068, 2000.[Abstract/Free Full Text]
  5. Tsujii M., Kawano S., Tsuji S., Sawaoka H., Hori M., DuBois R. N. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell, 93: 705-716, 1998.[Medline]
  6. Eberhart C. E., Coffey R. J., Radhika A., Giardiello F. M., Ferrenbach S., DuBois R. N. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology, 107: 1183-1188, 1994.[Medline]
  7. Kargman S. L., O’Neill G. P., Vickers P. J., Evans J. F., Mancini J. A., Jothy S. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res., 55: 2556-2559, 1995.[Abstract/Free Full Text]
  8. Kawamori T., Rao C. V., Seibert K., Reddy B. S. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res., 58: 409-412, 1998.[Abstract/Free Full Text]
  9. Oshima M., Murai N., Kargman S., Arguello M., Luk P., Kwong E., Taketo M. M., Evans J. F. Chemoprevention of intestinal polyposis in the Apc{Delta}716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res., 61: 1733-1740, 2001.[Abstract/Free Full Text]
  10. Sheng H., Shao J., Kirkland S. C., Isakson P., Coffey R. J., Morrow J., Beauchamp R. D., DuBois R. N. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J. Clin. Investig., 99: 2254-2259, 1997.[Medline]
  11. Williams C. S., Sheng H., Brockman J. A., Armandla R., Shao J., Washington M. K., Elkahloun A. G., Dubois R. N. A cyclooxygenase-2 inhibitor (SC-58125) blocks growth of established human colon cancer xenografts. Neoplasia, 3: 428-436, 2001.[Medline]
  12. Giardiello F. M., Hamilton S. R., Krush A. J., Piantadosi S., Hylind L. M., Celano P., Booker S. V., Robinson C. R., Offerhaus G. J. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N. Engl. J. Med., 328: 1313-1316, 1993.[Abstract/Free Full Text]
  13. Giovannucci E., Rimm E. B., Stampfer M. J., Colditz G. A., Ascherio A., Willett W. C. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann. Intern. Med., 121: 241-246, 1994.[Abstract/Free Full Text]
  14. Rao C. V., Rivenson A., Simi B., Zang E., Kelloff G., Steele V., Reddy B. S. Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent. Cancer Res., 55: 1464-1472, 1995.[Abstract/Free Full Text]
  15. Thun M. J., Namboodiri M. M., Heath C. W., Jr. Aspirin use and reduced risk of fatal colon cancer. N. Engl. J. Med., 325: 1593-1596, 1991.[Abstract]
  16. Fukuda R., Hirota K., Fan F., Jung Y. D., Ellis L. M., Semenza G. L. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J. Biol. Chem., 277: 38205-38211, 2002.[Abstract/Free Full Text]
  17. Ravi R., Mookerjee B., Bhujwalla Z. M., Sutter C. H., Artemov D., Zeng Q., Dillehay L. E., Madan A., Semenza G. L., Bedi A. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1{alpha}. Genes Dev., 14: 34-44, 2000.[Abstract/Free Full Text]
  18. Semenza G. L. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol. Med., 8: S62-S67, 2002.[Medline]
  19. Epstein A. C., Gleadle J. M., McNeill L. A., Hewitson K. S., O’Rourke J., Mole D. R., Mukherji M., Metzen E., Wilson M. I., Dhanda A., Tian Y. M., Masson N., Hamilton D. L., Jaakkola P., Barstead R., Hodgkin J., Maxwell P. H., Pugh C. W., Schofield C. J., Ratcliffe P. J. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 107: 43-54, 2001.[Medline]
  20. Ivan M., Kondo K., Yang H., Kim W., Valiando J., Ohh M., Salic A., Asara J. M., Lane W. S., Kaelin W. G., Jr. HIF{alpha} targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science, 292: 464-468, 2001.[Abstract/Free Full Text]
  21. Jaakkola P., Mole D. R., Tian Y. M., Wilson M. I., Gielbert J., Gaskell S. J., Kriegsheim A. V., Hebestreit H. F., Mukherji M., Schofield C. J., Maxwell P. H., Pugh C. W., Ratcliffe P. J. Targeting of HIF-{alpha} to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292: 468-472, 2001.[Abstract/Free Full Text]
  22. Talks K. L., Turley H., Gatter K. C., Maxwell P. H., Pugh C. W., Ratcliffe P. J., Harris A. L. The expression and distribution of the hypoxia-inducible factors HIF-1{alpha} and HIF-2{alpha} in normal human tissues, cancers, and tumor-associated macrophages. Am. J. Pathol., 157: 411-421, 2000.[Abstract/Free Full Text]
  23. Zhong H., De Marzo A. M., Laughner E., Lim M., Hilton D. A., Zagzag D., Buechler P., Isaacs W. B., Semenza G. L., Simons J. W. Overexpression of hypoxia-inducible factor 1{alpha} in common human cancers and their metastases. Cancer Res., 59: 5830-5835, 1999.[Abstract/Free Full Text]
  24. Zagzag D., Zhong H., Scalzitti J. M., Laughner E., Simons J. W., Semenza G. L. Expression of hypoxia-inducible factor 1{alpha} in human brain tumors: association with angiogenesis, invasion, and progression. Cancer (Phila.), 88: 2606-2618, 2000.[Medline]
  25. Elbashir S. M., Harborth J., Lendeckel W., Yalcin A., Weber K., Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature (Lond.), 411: 494-498, 2001.[Medline]
  26. Krishnamachary B., Berg-Dixon S., Kelly B., Agani F., Feldser D., Ferreira G., Iyer N., LaRusch J., Pak B., Taghavi P., Semenza G. L. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res., 63: 1138-1143, 2003.[Abstract/Free Full Text]
  27. Jiang B. H., Agani F., Passaniti A., Semenza G. L. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res., 57: 5328-5335, 1997.[Abstract/Free Full Text]
  28. Liu X. H., Kirschenbaum A., Lu M., Yao S., Dosoretz A., Holland J. F., Levine A. C. Prostaglandin E2 induces hypoxia-inducible factor 1{alpha} stabilization and nuclear localization in a human prostate cancer cell line. J. Biol. Chem., 277: 50081-50086, 2002.[Abstract/Free Full Text]
  29. Akagi Y., Liu W., Zebrowski B., Xie K., Ellis L. M. Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I. Cancer Res., 58: 4008-4014, 1998.[Abstract/Free Full Text]
  30. Arbiser J. L., Moses M. A., Fernandez C. A., Ghiso N., Cao Y., Klauber N., Frank D., Brownlee M., Flynn E., Parangi S., Byers H. R., Folkman J. Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc. Natl. Acad. Sci. USA, 94: 861-866, 1997.[Abstract/Free Full Text]
  31. Ellis L. M., Staley C. A., Liu W., Fleming R. Y., Parikh N. U., Bucana C. D., Gallick G. E. Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src. J. Biol. Chem., 273: 1052-1057, 1998.[Abstract/Free Full Text]
  32. Mukhopadhyay D., Tsiokas L., Sukhatme V. P. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res., 55: 6161-6165, 1995.[Abstract/Free Full Text]
  33. Petit A. M., Rak J., Hung M. C., Rockwell P., Goldstein N., Fendly B., Kerbel R. S. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am. J. Pathol., 151: 1523-1530, 1997.[Abstract]
  34. Rak J., Mitsuhashi Y., Bayko L., Filmus J., Shirasawa S., Sasazuki T., Kerbel R. S. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res., 55: 4575-4580, 1995.[Abstract/Free Full Text]
  35. Yen L., You X. L., Al Moustafa A. E., Batist G., Hynes N. E., Mader S., Meloche S., Alaoui-Jamali M. A. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene, 19: 3460-3469, 2000.[Medline]
  36. Laughner E., Taghavi P., Chiles K., Mahon P. C., Semenza G. L. 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., 21: 3995-4004, 2001.[Abstract/Free Full Text]
  37. Mazure N. M., Chen E. Y., Laderoute K. R., Giaccia A. J. Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood, 90: 3322-3331, 1997.[Abstract/Free Full Text]
  38. Zhong H., Chiles K., Feldser D., Laughner E., Hanrahan C., Georgescu M. M., Simons J. W., Semenza G. L. Modulation of hypoxia-inducible factor 1{alpha} expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res., 60: 1541-1545, 2000.[Abstract/Free Full Text]
  39. Zundel W., Schindler C., Haas-Kogan D., Koong A., Kaper F., Chen E., Gottschalk A. R., Ryan H. E., Johnson R. S., Jefferson A. B., Stokoe D., Giaccia A. J. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev., 14: 391-396, 2000.[Abstract/Free Full Text]
  40. Dicker A. P., Williams T. L., Grant D. S. Targeting angiogenic processes by combination rofecoxib and ionizing radiation. Am. J. Clin. Oncol., 24: 438-442, 2001.[Medline]
  41. Jones M. K., Szabo I. L., Kawanaka H., Husain S. S., Tarnawski A. S. Von Hippel Lindau tumor suppressor and HIF-1{alpha}: new targets of NSAIDs inhibition of hypoxia-induced angiogenesis. FASEB J., 16: 264-266, 2002.[Abstract/Free Full Text]
  42. Rapisarda A., Uranchimeg B., Scudiero D. A., Selby M., Sausville E. A., Shoemaker R. H., Melillo G. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res., 62: 4316-4324, 2002.[Abstract/Free Full Text]



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[Abstract] [Full Text] [PDF]

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Mol. Cancer Ther., August 1, 2004; 3(8): 1031 - 1039.
[Abstract] [Full Text] [PDF]

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Mol. Cell. Biol., June 15, 2004; 24(12): 5223 - 5234.
[Abstract] [Full Text] [PDF]

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J. Biol. Chem., April 9, 2004; 279(15): 15025 - 15031.
[Abstract] [Full Text] [PDF]

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J. Biol. Chem., April 2, 2004; 279(14): 13564 - 13574.
[Abstract] [Full Text] [PDF]

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Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R608 - R623.
[Abstract] [Full Text] [PDF]

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Am. J. Pathol., March 1, 2004; 164(3): 987 - 995.
[Abstract] [Full Text] [PDF]

Home page
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Nitric Oxide Induces Hypoxia-inducible Factor 1 Activation That Is Dependent on MAPK and Phosphatidylinositol 3-Kinase Signaling
J. Biol. Chem., January 23, 2004; 279(4): 2550 - 2558.
[Abstract] [Full Text] [PDF]

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Expression of cyclooxygenase 2, microsomal prostaglandin E synthase 1, and EP receptors is increased in rat oesophageal squamous cell dysplasia and Barrett's metaplasia induced by duodenal contents reflux
Gut, January 1, 2004; 53(1): 27 - 33.
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Home page
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