Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Oncogene. Author manuscript; available in PMC 2010 November 2.
Published in final edited form as:
PMCID: PMC2969168

Defining the Role of Hypoxia-Inducible Factor 1 in Cancer Biology and Therapeutics

Gregg L. Semenza, M.D., Ph.D.


Adaptation of cancer cells to their microenvironment is an important driving force in the clonal selection that leads to invasive and metastatic disease. O2 concentrations are markedly reduced in many human cancers compared to normal tissue and a major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1). This review summarizes the current state of knowledge regarding the molecular mechanisms by which HIF-1 contributes to cancer progression, focusing on (i) clinical data associating increased HIF-1 levels with patient mortality; (ii) preclinical data linking HIF-1 activity with tumor growth; (iii) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology; and (iv) pharmacological data demonstrating anti-cancer effects of HIF-1 inhibitors in mouse models of human cancer.

Keywords: angiogenesis, chemotherapy, metabolism, oxygen, radiation therapy, transcription


Human cancers frequently contain areas of necrosis in which cancer cells have died due to inadequate oxygenation (Harris, 2002; Brahimi-Horn et al., 2007). Cells closest to a perfused blood vessel are exposed to relatively high O2 concentrations, which decline as distance from the vessel increases. Although such gradients exist in normal tissues, in cancers the gradients are much steeper and O2 concentrations drop to near zero in areas of necrosis. In addition to physical gradients, temporal fluctuations in oxygenation also commonly occur within tumors (Dewhirst et al., 2008). Most physiological functions of cells are modulated according to the cellular O2 concentration. A major mechanism mediating adaptive responses to reduced O2 availability (hypoxia) is the regulation of transcription by hypoxia-inducible factor 1 (HIF-1) (Semenza, 2009a). These adaptive responses are co-opted by cancer cells, in which normal feedback mechanisms have been disrupted by somatic mutation and epigenetic changes. As a result, the adaptation to hypoxia promotes many key aspects of cancer progression that ultimately lead to patient mortality (Harris, 2002).

HIF-1α and HIF-2α levels are increased in many human cancers

HIF-1 is a heterodimeric protein that is composed of a constitutively expressed HIF-1β subunit and an O2-regulated HIF-1α subunit (Wang and Semenza, 1995; Wang et al., 1995). HIF-1α is subjected to O2-dependent hydroxylation on proline residue 402 and/or 564 by prolyl hydroxylase domain protein 2 (PHD2) and this modification creates an interface for interaction with the von Hippel-Lindau tumor suppressor protein (VHL), which recruits an E3 ubiquitin-protein ligase that catalyzes polyubiquitination of HIF-1α, thereby targeting it for proteasomal degradation (Kaelin and Ratcliffe, 2008). Under hypoxic conditions, hydroxylation is inhibited and HIF-1α rapidly accumulates, dimerizes with HIF-1β, binds to the core DNA binding sequence 5′-RCGTG-3′ (R, purine [A or G]) in target genes, recruits coactivators, and activates transcription. O2-dependent hydroxylation of asparagine-803 by factor inhibiting HIF-1 (FIH-1) blocks interaction of HIF-1α with the coactivators P300 and CBP under normoxic conditions (Lando et al., 2002). Both PHD2 and FIH-1 utilize O2 and α-ketoglutarate as substrates and generate CO2 and succinate as by-products of the hydroxylation reaction. HIF-2α is a protein with extensive sequence similarity to HIF-1α that is also regulated by proline and asparagine hydroxylation, dimerizes with HIF-1β, and activates transcription of a group of target genes that overlaps with, but is distinct from, those regulated by HIF-1α (Lau et al., 2007). HIF-3α is an inhibitor of HIF-1 that may be involved in feedback regulation because its expression is transcriptionally regulated by HIF-1 (Makino et al., 2007).

Immunohistochemical analysis of human cancer biopsies revealed increased levels (relative to surrounding normal tissue) of HIF-1α or HIF-2α protein (or both) in the majority of primary human cancers and their metastases (Zhong et al., 1999; Talks et al., 2000). Intratumoral hypoxia is a major mechanism underlying the increased levels of HIF-1α and HIF-2α in cancer and stromal cells. For example, the median PO2 level measured in breast cancers was 10 mm Hg, as compared to 65 mm Hg in normal breast tissue (Vaupel et al., 2004). Other inducers of HIF-1α in the tumor microenvironment include reactive oxygen and nitrogen species, which also inhibit proteasomal degradation of HIF-1α (Quintero et al., 2006; Gao et al., 2007; Li et al., 2007; Dewhirst et al., 2008). Complementing these mechanisms for blocking HIF-1α degradation, activation of the phosphatidylinositol-3-kinase and MAP kinase pathways (either as a result of oncogenic mutation or increased signaling from receptor tyrosine kinases and G-protein coupled receptors) increases HIF-1α synthesis, primarily through the action of mTOR (Laughner et al., 2001).

HIF-1α and HIF-2α protein levels can also be increased in cancer cells due to loss of function of many different tumor suppressors, which results in either increased HIF-1α synthesis or decreased HIF-1α degradation (Table 1). Remarkably, a large number of proteins encoded by transforming viruses that cause tumors in humans also induce HIF-1 activity (Table 2). Most remarkable is the case of Kaposi sarcoma, a highly vascularized tumor that is caused by a infection with a herpesvirus, the genome of which encodes three different proteins that together increase HIF-1α protein half-life, nuclear localization, and transactivation under non-hypoxic coinditions, thereby mimicking the effect of hypoxia. The finding that, in addition to intratumor hypoxia, major genetic and epigenetic alterations resulting in oncogene gain of function or tumor suppressor gene loss of function lead to increased HIF-1 activity suggests that increased HIF-1 activity represents a final common pathway in cancer pathogenesis, i.e. clonal selection favors those cancer cells in which HIF-1 activity is increased (Semenza, 2000; Vogelstein and Kinzler, 2004; Gillies and Gatenby, 2007; Gatenby and Gillies, 2008).

Table 1
Tumor suppressor gene (TSG) loss of function contributes to increased levels of HIF-1α in human cancers.
Table 2
Proteins of oncogenic viruses increase HIF-1 activity.

Clinical data linking HIF-1α and HIF-2α levels to cancer mortality

Taken together, the observed effects of tumor suppressor loss of function and transforming virus protein expression provide compelling evidence that HIF-1 activation promotes oncogenesis and/or cancer progression. In support of this hypothesis, a large body of clinical data demonstrates an association between increased levels of HIF-1α or HIF-2α protein, as determined by immunohistochemistry of standard formalin-fixed, paraffin-imbedded, tumor biopsy sections, with increased patient mortality in many different human cancers (Table 3). The data from studies of early-stage breast, cervical, and endometrial cancers are particularly striking. Early stage disease is usually associated with a good prognosis, but the subset of patients whose tumors contained high levels of HIF-1α had a significantly increased mortality rate. Thus, HIF-1α immunohistochemistry has the potential to identify patients for whom more aggressive therapy may be indicated. Testing this hypothesis by clinical trials is warranted, especially now that anti-cancer drugs that target HIF-1 are available, as described below.

Table 3
Immunohistochemical studies in which increased levels of HIF-1α (or HIF-2α) protein in diagnostic tumor biopsies were associated with decreased patient survival.

Experimental data linking HIF-1α and HIF-2α levels to cancer progression

Complementing the clinical data is a large body of experimental data demonstrating that HIF-1α loss of function (LOF) results in decreased tumor growth, vascularization, and metastasis, whereas HIF-1α gain of function (GOF) has the opposite effects (Table 4). Whereas the clinical data are by their nature correlative, the experimental data demonstrate causation, using many different cancer cell types and many different techniques to modulate the levels of HIF-1α or HIF-2α. Whereas the overall conclusion of these experiments is that HIF-1α and HIF-2α promote cancer progression, the association is not absolute. For example, whereas HIF-1α LOF decreased the growth of SW480 colorectal carcinoma xenografts, HIF-2α LOF increased xenograft growth and, remarkably, immunohistochemical analysis of human colon cancer biopsies revealed a significant association between loss of HIF-2α protein expression and advanced tumor stage (Imamura et al., 2009). In contrast, HIF-2α GOF increased the growth of 786-O renal cell carcinoma xenografts whereas HIF-1α GOF decreased xenograft growth (Raval et al., 2005).

Table 4
Selected experimental studies linking HIF-1 activity with cancer progression

The xenograft studies have many limitations, not the least of which is that LOF is achieved in the tumor cells but not in the host stromal cells, in which hypoxia-induced HIF-1 activity contributes to tumor progression. For example, tumor growth is impaired in mice with mutant p53 and germline heterozygosity for a HIF-1α knockout allele as compared to mutant p53 mice that are wild type for HIF-1α (Bertout et al., 2009) and in mice with conditional knockout of HIF-1α in vascular endothelial cells (Tang et al., 2004). There are no published examples of combined HIF-1α + HIF-2α inhibition in tumor + stroma resulting in increased tumor growth. Thus, inhibitors that target HIF-1α and HIF-2α will have the highest probability of therapeutic efficacy across a broad range of human cancers.

HIF-1-regulates the expression of genes encoding proteins with key roles in cancer biology

HIF-1α and HIF-2α exert their effects on cancer progression by binding to and activating the transcription of target genes with cis-acting hypoxia response elements containing the consensus binding site 5′-RCGTG-3′. The hundreds of genes that are induced by hypoxia in a HIF-1-dependent manner encode proteins from A to Z that play key roles in every critical aspect of cancer biology (Table 5), including angiogenesis (Liao and Johnson, 2007), cell survival, chemotherapy and radiation resistance (Moeller et al., 2007), genetic instability (Bindra et al., 2007), immortalization, immune evasion (Lukashev et al., 2007), invasion and metastasis (Chan and Giaccia, 2007; Sullivan and Graham, 2007), proliferation, metabolism and pH regulation (Swietach et al., 2007; Chiche et al., 2009; Semenza, 2009b), and stem cell maintenance (Barnhart and Simon, 2007). Among these functions, the most fundamental may be angiogenesis and glucose/energy metabolism, which control oxygen delivery and utilization, respectively. Angiogenesis has been a major focus of cancer biology and therapy over the last decade, while tumor metabolism is likely to attract similar attention over the next decade.

Table 5
Selected HIF-1 target genes whose products contribute to cancer progression.1

When a given cell type is exposed to hypoxia, increased expression of several hundred mRNAs is induced and expression of a roughly equal number are repressed in a HIF-1-dependent manner (Manalo et al., 2008). The hypoxia-induced binding of HIF-1 to many target genes that are activated by hypoxia has been demonstrated by chromatin immunoprecipitation assays, whereas binding of HIF-1 to hypoxia-repressed genes is not observed, suggesting an indirect, but HIF-1-dependent, mechanism for repression (Mole et al., 2009). For example, loss of E-cadherin expression is essential for cancer cell invasion and metastasis (Cavallaro and Christofori, 2004). In the renal cell carcinoma line RCC4, HIF-1 activates transcription of the genes encoding TCF3 (also known as E12/E47), ZFHX1A (also known as δEF1 or ZEB1), and ZFHX1B (also known as SIP1 or ZEB2), which are known to bind to the promoter of the gene encoding E-cadherin to repress its transcription (Krishnamachary et al., 2006). HIF-1 may also promote genetic instability by repressing transcription of the MSH2 and MSH6 genes, which encode subunits of the DNA mismatch repair protein MutSα, by blocking the interaction of MYC with SP1, an effect that does not require direct DNA binding or even the presence of HIF-1β (Koshiji et al., 2005).

Within any given cancer, only a subset of these genes will be activated by HIF-1, which increases the transcription of genes that are already active within a cell type. In addition, subsets of these genes are differentially regulated by HIF-1α and HIF-2α. Thus, the biological consequences of HIF-1 activation in a cancer will vary depending upon the battery of target genes that respond. This heterogeneity is in no way unique to HIF-1 (Yu et al., 1999) and represents one of the greatest obstacles to improving cancer therapy. The major conclusion to be drawn from these data is that HIF-1 plays an incredibly broad and important role in cancer biology and that the delineation of the HIF-1 transcriptome has provided a molecular basis for the association between intratumoral hypoxia and invasion, metastasis, and patient mortality (Vaupel et al., 2004).

Anti-cancer Drugs Inhibit HIF-1

Many of the novel anti-cancer drugs that target specific pathways have been shown to have anti-angiogenic effects that appear to be due in large part to their inhibition of HIF-1 activity (Table 6), including the BCR-ABL inhibitor imatinib/Gleevec (Mayerhofer et al., 2002); epidermal growth factor receptor inhibitors gefitinib/Iressa, erlotinib/Tarceva, and cetuximab/C225 (Luwor et al., 2005; Pore et al., 2006); HER2neu inhibitor trastuzumab/Herceptin (Laughner et al., 2001); and the mTOR inhibitors rapamycin, temsirolimus/CCI-779, and everolimus/RAD-001 (Laughner et al., 2001; Majumder et al., 2004; Thomas et al., 2006), which all act by inhibiting mTOR-dependent translation of HIF-1α mRNA into protein (Laughner et al., 2001). Inhibition of HIF-1 activity leads to decreased VEGF expression. Drugs that inhibit phosphatidylinositol-3-kinase and ERK signal transduction inhibit HIF-1 and SP1, both of which bind to the VEGF gene promoter (Pagès and Pouysségur, 2005).

Table 6
Selected classes of drugs that inhibit HIF-1 activity and tumor xenograft growth

Another novel class of molecularly targeted anti-cancer agents consists of inhibitors of heat shock protein 90 (HSP90) such as geldanamycin, 17-allylaminogeldanamycin (17-AAG), and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), which target HIF-1a for proteasomal degradation (Isaacs et al., 2002). In the absence of inhibitors, HSP90 binds to HIF-1α and promotes its stability by preventing the binding of RACK1, whereas the inhibitors block HSP90 binding, thereby promoting the binding of RACK1, which triggers ubiquitination and proteasomal degradation of HIF-1α (Liu et al., 2007). Histone deacetylase inhibitors are another novel class of anti-cancer drugs that promote HIF-1α degradation (Kong et al., 2006; Qian et al., 2006) and inhibit HIF-1α transactivation domain function (Fath et al., 2006) at clinically relevant concentrations. Finally, the proteasome inhibitor bortezomib inhibits HIF-1 by blocking its transcriptional activity (Kaluz et al., 2006). Bortezomib may promote binding of the asparagine hydroxylase FIH-1 to HIF-1α (Shin et al., 2008) although this finding has been disputed (Kaluz et al., 2008). In addition to these drugs, many other chemical compounds have been shown to inhibit HIF-1 activity and are in preclinical development (Melillo, 2007).

HIF-1 Inhibitors Block Tumor Growth and Vascularization

Cell-based screening assays have been performed to identify inhibitors of HIF-1 transcriptional activity. These assays have revealed that several traditional chemotherapeutic agents are potent HIF-1 inhibitors, including topoisomerase I inhibitors, such as topotecan (Rapisarda et al., 2002) and microtubule targeting drugs, such as taxotere (Escuin et al., 2005). DNA intercalating drugs, including echinomycin (Kong et al., 2005) and anthracyclines, such as doxorubicin (Adriamycin) and daunorubicin (Lee et al., 2009) inhibit HIF-1 transcriptional activity by blocking its binding to DNA. Since extensive clinical experience has already defined the use and limitations of these drugs, one might wonder why this is at all noteworthy. The key point is the use of these drugs as HIF-1 inhibitors engenders an entirely new treatment paradigm. Traditional chemotherapies have been administered to patients at maximum tolerated doses as cytotoxic agents intended to kill as many dividing cancer cells as possible. Unfortunately, these drugs also kill dividing hematopoietic cells and, as a result, they are administered episodically followed by drug-free intervals of 2–3 weeks during which bone marrow recovery occurs. Unfortunately, tumor recovery often occurs as well and eventually leads to the selection of a resistant clone of cancer cells that metastasizes and kills the patient. (Note also that cell proliferation is inhibited under conditions of reduced O2 availability, thereby protecting hypoxic cancer cells from chemotherapy.)

The laboratory of the late Judah Folkman discovered that administering the chemotherapy agent cyclophosphamide at reduced doses on a more frequent and regular dosing interval prevents bone marrow toxicity and blocks tumor growth by interfering with angiogenesis (Hahnfeldt et al., 2003), which was thought to result either from inducing apoptosis or decreasing proliferation of endothelial cells (Kerbel and Kamen, 2004). Treatment with doxorubicin for 5 days inhibited HIF-1-dependent transcription and significantly reduced the levels of mRNAs encoding the angiogenic cytokines stem cell factor (also known as Kit ligand), stromal-derived factor 1 (SDF-1), and vascular endothelial growth factor (VEGF) in human prostate cancer xenografts (Lee et al., 2009). These secreted proteins activate resident endothelial cells and also increase the numbers of circulating angiogenic cells, which home to the tumor and promote vascularization. Treatment of tumor bearing mice with doxorubicin for 5 days reduced blood SDF-1 levels and the number of circulating angiogenic cells to levels similar to those observed in non-tumor-bearing mice and significantly reduced tumor vascularization, leading to growth arrest (Lee et al., 2009).

HIF-1 Inhibitors Sensitize Tumors to Radiation Therapy

It has long been known that the hypoxic fraction of human cancers is resistant to radiation therapy due to reduced generation of oxygen radicals (Gray et al., 1953; Moeller et al., 2007). A major paradigm shift occurred with the discovery that the tumor vasculature represents an important target of radiation therapy and a major determinant of the clinical response (Garcia-Barros et al., 2003). Radiation was shown to induce HIF-1 activity, leading to the production of VEGF and other angiogenic cytokines that protect the endothelial cells of the tumor vasculature from radiation-induced death (Moeller et al., 2004). Treatment of tumor-bearing mice with the HIF-1 inhibitor YC-1 (3-(5′-hydroxymethyl-2′furyl)-1-benzyl indazole) dramatically increased radiation-induced vessel destruction and tumor control (Moeller et al., 2004). The HIF-1 inhibitor PX-478 (S-2-amino-3-[4′-N, N,-bis (chloroethyl) amino] phenyl propionic acid N-oxide dihydrochloride) also blocked radiation-induced VEGF expression and thereby sensitized tumor xenografts to radiation therapy (Schwartz et al., 2009). Among patients with oropharyngeal cancer, those whose tumor biopsies showed the highest HIF-1α protein levels by immunohistochemistry had a significantly increased incidence of failure to achieve complete remission after radiation therapy (Aebersold et al., 2001). Taken together, these experimental and clinical data delineate an important role for HIF-1 in mediating radiation resistance and provide a compelling rationale for clinical trials that combine radiation therapy with HIF-1 inhibitors.


It has only been ten years since the first report of HIF-1α overexpression in primary human cancers and their metastases (Zhong et al., 1999), but during that time a large body of scientific data has been amassed delineating the mechanisms and consequences of increased HIF-1 activity during human cancer progression. Most recently, a growing number of drugs that inhibit HIF-1 have been identified and validated as anti-cancer agents. The challenge now is to identify on a patient-by-patient basis: (i) those cancers in which HIF-1 is playing a critical role in disease pathogenesis; (ii) those combinations of drugs or other treatment modalities to which addition of a HIF-1 inhibitor will have additive or even synergistic effects; and (iii) clinical assays that will demonstrate an effect of HIF-1 inhibitors (or lack thereof) on critical aspects of cancer biology such as tumor metabolism and vascularization. Close collaborations between basic scientists and clinical oncologists will be needed to devise, evaluate, and refine strategies for translating research knowledge into safe and effective cancer therapies.


Conflict of Interest

The author declares no conflict of interest.


  • Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, et al. Expression of hypoxia-inducible factor-1α: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 2001;61:2911–2916. [PubMed]
  • Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang J, Chen J, et al. Constitutive expression of hypoxia-inducible factor-1α renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 2001;61:6548–6554. [PubMed]
  • Bachtiary B, Schindl M, Pötter R, Dreier B, Knocke TH, Hainfellner JA, et al. Overexpression of hypoxia-inducible factor 1α indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer. Clin Cancer Res. 2003;9:2234–2240. [PubMed]
  • Barnhart BC, Simon MC. Metastasis and stem cell pathways. Cancer Metastasis Rev. 2007;26:261–271. [PMC free article] [PubMed]
  • Bertout JA, Patel SA, Fryer BH, Durham AC, Covello KL, Olive KP, et al. Heterozygosity for hypoxia inducible factor 1α decreases the incidence of thymic lymphomas in a p53 mutant mouse model. Cancer Res. 2009;69:3213–3220. [PMC free article] [PubMed]
  • Bindra RS, Crosby ME, Glazer PM. Regulation of DNA repair in hypoxic cancer cells. Cancer Metastasis Rev. 2007;26:249–260. [PubMed]
  • Birner P, Gatterbauer B, Oberhuber G, Schindl M, Rössler K, Prodinger A, et al. Expression of hypoxia-inducible factor-1α in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. Cancer. 2001a;92:165–171. [PubMed]
  • Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G. Expression of hypoxia-inducible factor 1α in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res. 2001b;7:1661–1668. [PubMed]
  • Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G. Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 2000;60:4693–4696. [PubMed]
  • Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, et al. Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer. 2003;97:1573–1581. [PubMed]
  • Brahimi-Horn MC, Chiche J, Pouysségur J. Hypoxia and cancer. J Mol Med. 2007;85:1301–1307. [PubMed]
  • Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG., Jr TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell. 2003;4:147–158. [PubMed]
  • Burri P, Djonov V, Aebersold DM, Lindel K, Studer U, Altermatt HJ, et al. Significant correlation of hypoxia-inducible factor-1α with treatment outcome in cervical cancer treated with radical radiotherapy. Int J Radiat Oncol Biol Phys. 2003;56:494–501. [PubMed]
  • Cai Q, Murakami M, Si H, Robertson ES. A potential α-helix motif in the amino terminus of LANA encoded by Kaposi’s sarcoma-associated herpesvirus is critical for nuclear accumulation of HIF-1α in normoxia. J Virol. 2007;81:10413–10423. [PMC free article] [PubMed]
  • Cai QL, Knight JS, Verma SC, Zald P, Robertson ES. EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors. PLoS Pathog. 2006;2:e116. [PMC free article] [PubMed]
  • Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 2004;4:118–132. [PubMed]
  • Chan DA, Giaccia AJ. Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev. 2007;26:333–339. [PubMed]
  • Chang Q, Qin R, Huang T, Gao J, Feng Y. Effect of antisense hypoxia-inducible factor 1α on progression, metastasis, and chemosensitivity of pancreatic cancer. Pancreas. 2006;32:297–305. [PubMed]
  • Chen J, Zhao S, Nakada K, Kuge Y, Tamaki N, Okada F, et al. Dominant-negative hypoxia-inducible factor-1α reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. Am J Pathol. 2003;162:1283–1291. [PubMed]
  • Chiche J, Ilc K, Laferrière J, Trottier E, Dayan F, Mazure NM, et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res. 2009;69:358–368. [PubMed]
  • Cleven AH, van Engeland M, Wouters BG, de Bruine AP. Stromal expression of hypoxia regulated proteins is an adverse prognostic factor in colorectal carcinomas. Cell Oncol. 2007;29:229–240. [PubMed]
  • Dales JP, Garcia S, Meunier-Carpentier S, Andrac-Meyer L, Haddad O, Lavaut MN, et al. Overexpression of hypoxia-inducible factor HIF-1α predicts early relapse in breast cancer: retrospective study in a series of 745 patients. Int J Cancer. 2005;116:734–739. [PubMed]
  • Daponte A, Ioannou M, Mylonis I, Simos G, Minas M, Messinis IE, et al. Prognostic significance of hypoxia-inducible factor 1α (HIF-1α) expression in serous ovarian cancer: an immunohistochemical study. BMC Cancer. 2008;8:335. [PMC free article] [PubMed]
  • Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8:425–437. [PubMed]
  • Escuin D, Kline ER, Giannakakou P. Both microtubule-stabilizing and microtubule-destabilizing drugs inhibit hypoxia-inducible factor-1α accumulation and activity by disrupting microtubule function. Cancer Res. 2005;65:9021–9028. [PubMed]
  • Fath DM, Kong X, Liang D, Lin Z, Chou A, Jiang Y, et al. Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-α J Biol Chem. 2006;281:13612–13619. [PMC free article] [PubMed]
  • Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V, et al. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell. 2007;12:230–238. [PMC free article] [PubMed]
  • Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155–1159. [PubMed]
  • Gatenby RA, Gillies RJ. A microenvironmental model of carcinogenesis. Nat Rev Cancer. 2008;8:56–61. [PubMed]
  • Generali D, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield S, et al. Hypoxia-inducible factor-1α expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res. 2006;12:4562–4568. [PubMed]
  • Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, et al. Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumors and survival. Br J Cancer. 2001;85:881–890. [PMC free article] [PubMed]
  • Giatromanolaki A, Koukourakis MI, Simopoulos C, Polychronidis A, Gatter KC, Harris AL, et al. c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1α dependent. Clin Cancer Res. 2004;10:7972–7977. [PubMed]
  • Giatromanolaki A, Sivridis E, Kouskoukis C, Gatter KC, Harris AL, Koukourakis MI. Hypoxia-inducible factors 1α and 2α are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin. Melanoma Res. 2003;13:493–501. [PubMed]
  • Gillies RJ, Gatenby RA. Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev. 2007;26:311–317. [PubMed]
  • Gray LH, Conger AO, Ebert M, Hornsey S, Scott OCA. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953;26:638–648. [PubMed]
  • Griffiths EA, Pritchard SA, Valentine HR, Whitchelo N, Bishop PW, Ebert MP, et al. Hypoxia-inducible factor-1α expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas. Br J Cancer. 2007;96:95–103. [PMC free article] [PubMed]
  • Hahnfeldt P, Folkman J, Hlatky L. Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J Theor Biol. 2003;220:545–554. [PubMed]
  • Harris AL. Hypoxia — a key regulatory factor in tumor growth. Nat Rev Cancer. 2002;2:38–47. [PubMed]
  • Imamura T, Kikuchi H, Herraiz MT, Park DY, Mizukami Y, Mino-Kenduson M, et al. HIF-1α and HIF-2α have divergent roles in colon cancer. Int J Cancer. 2009;124:763–771. [PMC free article] [PubMed]
  • Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J Biol Chem. 2002;277:29936–29944. [PubMed]
  • Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005;8:143–153. [PubMed]
  • Jiang BH, Agani F, Passaniti A, Semenza GL. 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. 1997;57:5328–5335. [PubMed]
  • Kaelin WG, Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402. [PubMed]
  • Kaluz S, Kaluzová M, Stanbridge EJ. Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1α C-terminal activation domain. Mol Cell Biol. 2006;26:5895–5907. [PMC free article] [PubMed]
  • Kaluz S, Kaluzová M, Stanbridge EJ. Comment on the role of FIH in the inhibitory effect of bortezomib on hypoxia-inducible factor-1. Blood. 2008;111:5258–5259. [PubMed]
  • Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423–436. [PubMed]
  • Kondo K, Kim WY, Lechpammer M, Kaelin WG., Jr Inhibition of HIF-2α is sufficient to suppress pVHL-defective tumor growth. PLoS Biol. 2003;1:e83. [PMC free article] [PubMed]
  • Kondo S, Seo SY, Yoshizaki T, Wakisaka N, Furukawa M, Joab I, et al. EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1α through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells. Cancer Res. 2006;66:9870–9877. [PubMed]
  • Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 2005;65:9047–9055. [PubMed]
  • Kong X, Lin Z, Liang D, Fath D, Sang N, Caro J. Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1α Mol Cell Biol. 2006;26:2019–2028. [PMC free article] [PubMed]
  • Korkolopoulou P, Patsouris E, Konstantinidou AE, Pavlopoulos PM, Kavantzas N, Boviatsis E, et al. Hypoxia-inducible factor 1α/vascular endothelial growth factor axis in astrocytomas. Associations with microvessel morphometry, proliferation and prognosis. Neuropathol Appl Neurobiol. 2004;30:267–278. [PubMed]
  • Koshiji M, To KK, Hammer S, Kumamoto K, Harris AL, Modrich P, et al. HIF-1α induces genetic instability by transcriptionally downregulating MutSα expression. Mol Cell. 2005;17:793–803. [PubMed]
  • Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K, et al. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2002;53:1192–1202. [PubMed]
  • Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, et al. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res. 2006;66:2725–2731. [PubMed]
  • Kronblad A, Jirstrom K, Ryden L, Nordenskjold B, Landberg G. Hypoxia inducible factor-1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response. Int J Cancer. 2006;118:2609–2616. [PubMed]
  • Kung AL, Wang S, Klco JM, Kaelin WG, Livingston DM. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med. 2000;6:1335–1340. [PubMed]
  • Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002;16:1466–1471. [PubMed]
  • Lau KW, Tian YM, Raval RR, Ratcliffe PJ, Pugh CW. Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms. Br J Cancer. 2007;96:1284–1292. [PMC free article] [PubMed]
  • Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol. 2001;21:3995–4004. [PMC free article] [PubMed]
  • Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci U S A. 2009;106:2353–2358. [PubMed]
  • Li F, Sonveaux P, Rabbani ZN, Liu S, Yan B, Huang Q, et al. Regulation of HIF-1α stability through S-nitrosylation. Mol Cell. 2007;26:63–74. [PMC free article] [PubMed]
  • Li L, Lin X, Staver M, Shoemaker A, Semizarov D, Fesik SW, et al. Evaluating hypoxia-inducible factor-1α as a cancer therapeutic target via inducible RNA interference in vivo. Cancer Res. 2005;65:7249–7258. [PubMed]
  • Liao D, Corle C, Seagroves TN, Johnson RS. Hypoxia-inducible factor-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res. 2007;67:563–572. [PubMed]
  • Liao D, Johnson RS. Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 2007;26:281–290. [PubMed]
  • Liu Y, Tao J, Li Y, Yang J, Yu Y, Wang M, et al. Targeting hypoxia-inducible factor-1α with Tf-PEI-shRNA complex via transferrin receptor-mediated endocytosis inhibits melanoma growth. Mol Ther. 2009;17:269–277. [PubMed]
  • Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL. RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α Mol Cell. 2007;25:207–217. [PMC free article] [PubMed]
  • Lukashev D, Ohta A, Sitkovsky M. Hypoxia-dependent anti-inflammatory pathways in protection of cancerous tissues. Cancer Metastasis Rev. 2007;26:273–279. [PubMed]
  • Luwor RB, Lu Y, Li X, Mendelsohn J, Fan Z. The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1α, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene. 2005;24:4433–4441. [PubMed]
  • Makino Y, Uenishi R, Okamoto K, Isoe T, Hosono O, Tanaka H, et al. Transcriptional up-regulation of inhibitory PAS domain protein gene expression by hypoxia-inducible factor 1 (HIF-1): a negative feedback regulatory circuit in HIF-1-mediated signaling in hypoxic cells. J Biol Chem. 2007;282:14073–14082. [PubMed]
  • Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood. 2005;105:659–669. [PubMed]
  • Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 1997;94:8104–8109. [PubMed]
  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271–275. [PubMed]
  • Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1α, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood. 100:3767–3775. [PubMed]
  • Melillo G. Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev. 2007;26:341–352. [PubMed]
  • Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell. 2004;5:429–441. [PubMed]
  • Moeller BJ, Richardson RA, Dewhirst MW. Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev. 2007;26:241–248. [PubMed]
  • Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, et al. Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem. 2009;284:16767–16775. [PMC free article] [PubMed]
  • Nakamura M, Bodily JM, Beglin M, Kyo S, Inoue M, Laimins LA. Hypoxia-specific stabilization of HIF-1α by human papillomaviruses. Virology. 2009;387:442–448. [PMC free article] [PubMed]
  • Nanni S, Benvenuti V, Grasselli A, Priolo C, Aiello A, Mattiussi S, et al. Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer. J Clin Invest. 2009;119:1093–1108. [PMC free article] [PubMed]
  • Pagès G, Pouysségur J. ranscriptional regulation of the vascular endothelial growth factor gene--a concert of activating factors. Cardiovasc Res. 2005;65:564–573. [PubMed]
  • Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res. 2006;66:3197–3204. [PubMed]
  • Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P, et al. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1α Cancer Res. 2006;66:8814–8821. [PubMed]
  • Quintero M, Brennan PA, Thomas GJ, Moncada S. Nitric oxide is a factor in the stabilization of hypoxia-inducible factor-1α in cancer: role of free radical formation. Cancer Res. 2006;66:770–774. [PubMed]
  • Rajaganeshan R, Prasad R, Guillou PJ, Poston G, Scott N, Jayne DG. The role of hypoxia in recurrence following resection of Dukes’ B colorectal cancer. Int J Colorectal Dis. 2008;23:1049–1055. [PubMed]
  • Rapisarda A, Uranchimeg B, Scudiero DA, Selby M, Sausville EA, et al. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res. 2002;62:4316–4324. [PubMed]
  • Rasheed S, Harris AL, Tekkis PP, Turley H, Silver A, McDonald PJ, et al. Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis. Br J Cancer. 2009;100:1666–1673. [PMC free article] [PubMed]
  • Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol. 2005;25:5675–5686. [PMC free article] [PubMed]
  • Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α Genes Dev. 2000;14:34–44. [PubMed]
  • Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M, et al. Overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res. 2002;8:1831–1837. [PubMed]
  • Schmitz KJ, Müller CI, Reis H, Alakus H, Winde G, Baba HA, et al. Combined analysis of hypoxia-inducible factor 1α and metallothionein indicates an aggressive subtype of colorectal carcinoma. Int J Colorectal Dis. 2009 Jun 16; [Epub ahead of print] [PubMed]
  • Schrijvers ML, van der Laan BF, de Bock GH, Pattje WJ, Mastik MF, Menkema L, et al. Overexpression of intrinsic hypoxia markers HIF-1α and CA-IX predict for local recurrence in stage T1–T2 glottic laryngeal carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2008;72:161–169. [PubMed]
  • Schwartz DL, Powis G, Thitai-Kumar A, He Y, Bankson J, Williams R, et al. The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects. Mol Cancer Ther. 2009;8:947–958. [PMC free article] [PubMed]
  • Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell. 2005;7:77–85. [PubMed]
  • Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol. 2000;35:71–103. [PubMed]
  • Semenza GL. Oxygen homeostasis. Systems Biol Med. 2009a in press.
  • Semenza GL. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol. 2009b;19:12–16. [PubMed]
  • Shackelford DB, Vasquez DS, Corbeil J, Wu S, Leblanc M, Wu CL, et al. mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc Natl Acad Sci U S A. 2009;106:11137–11142. [PubMed]
  • Shin DH, Chun YS, Lee DS, Huang LE, Park JW. Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1. Blood. 2008;111:3131–3136. [PubMed]
  • Shin YC, Joo CH, Gack MU, Lee HR, Jung JU. Kaposi’s sarcoma-associated herpesvirus viral IFN regulatory factor 3 stabilizes hypoxia-inducible factor-1α to induce vascular endothelial growth factor expression. Cancer Res. 2008;68:1751–1759. [PubMed]
  • Sivridis E, Giatromanolaki A, Gatter KC, Harris AL, Koukourakis MI. Association of hypoxia-inducible factors 1α and 2α with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. Cancer. 2002;95:1055–1063. [PubMed]
  • Sodhi A, Montaner S, Patel V, Zohar M, Bais C, Mesri EA, et al. The Kaposi’s sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1α Cancer Res. 2000;60:4873–4880. [PubMed]
  • Stoeltzing O, McCarty MF, Wey JS, Fan F, Liu W, Belcheva A, et al. Role of hypoxia-inducible factor 1α in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst. 2004;96:946–956. [PubMed]
  • Sullivan R, Graham CH. Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev. 2007;26:319–331. [PubMed]
  • Sun HC, Qiu ZJ, Liu J, Sun J, Jiang T, Huang KJ, et al. Expression of hypoxia-inducible factor-1α and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int J Oncol. 2007;30:1359–1367. [PubMed]
  • Swietach P, Vaughan-Jones RD, Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev. 2007;26:299–310. [PubMed]
  • Swinson DE, Jones JL, Cox G, Richardson D, Harris AL, O’Byrne KJ. Hypoxia-inducible factor-1α in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer. 2004;111:43–50. [PubMed]
  • Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, et al. The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α i n normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 2000;157:411–421. [PubMed]
  • Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP, et al. Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell. 2004;6:485–495. [PubMed]
  • Takahashi R, Tanaka S, Hiyama T, Ito M, Kitadai Y, Sumii M, et al. Hypoxia-inducible factor-1α expression and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncol Rep. 2003;10:797–802. [PubMed]
  • Theodoropoulos VE, Lazaris AC, Kastriotis I, Spiliadi C, Theodoropoulos GE, Tsoukala V, et al. Evaluation of hypoxia-inducible factor 1α overexpression as a predictor of tumor recurrence and progression in superficial urothelial bladder carcinoma. BJU Int. 2005;95:425–431. [PubMed]
  • Theodoropoulos VE, Lazaris AC, Sofras F, Gerzelis I, Tsoukala V, Ghikonti I, et al. Hypoxia-inducible factor 1α expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol. 2004;46:200–208. [PubMed]
  • Tomita M, Semenza GL, Michiels C, Matsuda T, Uchihara JN, Okudaira T, et al. Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells. Biochem J. 2007;406:317–323. [PubMed]
  • Trastour C, Benizri E, Ettore F, Ramaioli A, Chamorey E, Pouyssegur J, et al. HIF-1α and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer. 2007;120:1443–1450. [PubMed]
  • Tzao C, Lee SC, Tung HJ, Hsu HS, Hsu WH, Sun GH, et al. Expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF)-D as outcome predictors in resected esophageal squamous cell carcinoma. Dis Markers. 2008;25:141–148. [PubMed]
  • Vaupel P, Mayer A, Hockel M. Tumor hypoxia and malignant progression. Methods Enzymol. 2004;381:335–354. [PubMed]
  • Vleugel MM, Greijer AE, Shvarts A, van der Groep P, van Berkel M, Aarbodem Y, et al. Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer. J Clin Pathol. 2005;58:172–177. [PMC free article] [PubMed]
  • Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789–799. [PubMed]
  • Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92:5510–5514. [PubMed]
  • Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995;270:1230–1237. [PubMed]
  • Wang XL, Xu R, Wu X, Gillespie D, Jensen R, Lu ZR. Targeted systemic delivery of a therapeutic siRNA with a multifunctional carrier controls tumor proliferation in mice. Mol Pharm. 2009;6:738–746. [PubMed]
  • Yamamoto Y, Ibusuki M, Okumura Y, Kawasoe T, Kai K, Iyama K, et al. Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res Treat. 2008;110:465–475. [PubMed]
  • Yoo YG, Cho S, Park S, Lee MO. The carboxy-terminus of the hepatitis B virus X protein is necessary and sufficient for the activation of hypoxia-inducible factor-1α FEBS Lett. 2004;577:121–126. [PubMed]
  • Yu J, Zhang L, Hwang PM, Rago C, Kinzler KW, Vogelstein B. Identification and classification of p53-regulated genes. Proc Natl Acad Sci U S A. 1999;96:14517–14522. [PubMed]
  • Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α Science. 2009;324:261–265. [PMC free article] [PubMed]
  • Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, et al. Modulation of hypoxia-inducible factor 1α 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. 2000;60:1541–1545. [PubMed]
  • Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res. 1999;59:5830–5835. [PubMed]
  • Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 2000;14:391–396. [PubMed]