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Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics

Abstract

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 with 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 (1) clinical data associating increased HIF-1 levels with patient mortality; (2) preclinical data linking HIF-1 activity with tumor growth; (3) molecular data linking specific HIF-1 target gene products to critical aspects of cancer biology and (4) pharmacological data showing anticancer effects of HIF-1 inhibitors in mouse models of human cancer.

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References

  • Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH et al. (2001). Expression of hypoxia-inducible factor-1α: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61: 2911–2916.

    CAS  PubMed  Google Scholar 

  • Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang J, Chen J et al. (2001). Constitutive expression of hypoxia-inducible factor-1α renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res 61: 6548–6554.

    CAS  PubMed  Google Scholar 

  • Bachtiary B, Schindl M, Pötter R, Dreier B, Knocke TH, Hainfellner JA et al. (2003). 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 9: 2234–2240.

    CAS  PubMed  Google Scholar 

  • Barnhart BC, Simon MC . (2007). Metastasis and stem cell pathways. Cancer Metastasis Rev 26: 261–271.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bertout JA, Patel SA, Fryer BH, Durham AC, Covello KL, Olive KP et al. (2009). Heterozygosity for hypoxia inducible factor 1α decreases the incidence of thymic lymphomas in a p53 mutant mouse model. Cancer Res 69: 3213–3220.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bindra RS, Crosby ME, Glazer PM . (2007). Regulation of DNA repair in hypoxic cancer cells. Cancer Metastasis Rev 26: 249–260.

    Article  CAS  PubMed  Google Scholar 

  • Birner P, Gatterbauer B, Oberhuber G, Schindl M, Rössler K, Prodinger A et al. (2001a). Expression of hypoxia-inducible factor-1α in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. Cancer 92: 165–171.

    CAS  PubMed  Google Scholar 

  • Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G . (2001b). Expression of hypoxia-inducible factor 1α in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res 7: 1661–1668.

    CAS  PubMed  Google Scholar 

  • Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G . (2000). Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 60: 4693–4696.

    CAS  PubMed  Google Scholar 

  • Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM et al. (2003). Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 97: 1573–1581.

    PubMed  Google Scholar 

  • Brahimi-Horn MC, Chiche J, Pouysségur J . (2007). Hypoxia and cancer. J Mol Med 85: 1301–1307.

    PubMed  Google Scholar 

  • Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin Jr WG . (2003). TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4: 147–158.

    CAS  PubMed  Google Scholar 

  • Burri P, Djonov V, Aebersold DM, Lindel K, Studer U, Altermatt HJ et al. (2003). Significant correlation of hypoxia-inducible factor-1α with treatment outcome in cervical cancer treated with radical radiotherapy. Int J Radiat Oncol Biol Phys 56: 494–501.

    CAS  PubMed  Google Scholar 

  • Cai Q, Murakami M, Si H, Robertson ES . (2007). 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 81: 10413–10423.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cai QL, Knight JS, Verma SC, Zald P, Robertson ES . (2006). EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors. PLoS Pathog 2: e116.

    PubMed  PubMed Central  Google Scholar 

  • Cavallaro U, Christofori G . (2004). Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4: 118–132.

    CAS  PubMed  Google Scholar 

  • Chan DA, Giaccia AJ . (2007). Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev 26: 333–339.

    CAS  PubMed  Google Scholar 

  • Chang Q, Qin R, Huang T, Gao J, Feng Y . (2006). Effect of antisense hypoxia-inducible factor 1α on progression, metastasis, and chemosensitivity of pancreatic cancer. Pancreas 32: 297–305.

    CAS  PubMed  Google Scholar 

  • Chen J, Zhao S, Nakada K, Kuge Y, Tamaki N, Okada F et al. (2003). Dominant-negative hypoxia-inducible factor-1α reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. Am J Pathol 162: 1283–1291.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chiche J, Ilc K, Laferrière J, Trottier E, Dayan F, Mazure NM et al. (2009). Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69: 358–368.

    CAS  PubMed  Google Scholar 

  • Cleven AH, van Engeland M, Wouters BG, de Bruine AP . (2007). Stromal expression of hypoxia regulated proteins is an adverse prognostic factor in colorectal carcinomas. Cell Oncol 29: 229–240.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dales JP, Garcia S, Meunier-Carpentier S, Andrac-Meyer L, Haddad O, Lavaut MN et al. (2005). Overexpression of hypoxia-inducible factor HIF-1α predicts early relapse in breast cancer: retrospective study in a series of 745 patients. Int J Cancer 116: 734–739.

    CAS  PubMed  Google Scholar 

  • Daponte A, Ioannou M, Mylonis I, Simos G, Minas M, Messinis IE et al. (2008). Prognostic significance of hypoxia-inducible factor 1α (HIF-1α) expression in serous ovarian cancer: an immunohistochemical study. BMC Cancer 8: 335.

    PubMed  PubMed Central  Google Scholar 

  • Dewhirst MW, Cao Y, Moeller B . (2008). Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8: 425–437.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Escuin D, Kline ER, Giannakakou P . (2005). Both microtubule-stabilizing and microtubule-destabilizing drugs inhibit hypoxia-inducible factor-1α accumulation and activity by disrupting microtubule function. Cancer Res 65: 9021–9028.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fath DM, Kong X, Liang D, Lin Z, Chou A, Jiang Y et al. (2006). Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-α. J Biol Chem 281: 13612–13619.

    CAS  PubMed  Google Scholar 

  • Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V et al. (2007). HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12: 230–238.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A et al. (2003). Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300: 1155–1159.

    CAS  PubMed  Google Scholar 

  • Gatenby RA, Gillies RJ . (2008). A microenvironmental model of carcinogenesis. Nat Rev Cancer 8: 56–61.

    CAS  PubMed  Google Scholar 

  • Generali D, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield S et al. (2006). 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 12: 4562–4568.

    CAS  PubMed  Google Scholar 

  • Giatromanolaki A, Koukourakis MI, Simopoulos C, Polychronidis A, Gatter KC, Harris AL et al. (2004). c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1α dependent. Clin Cancer Res 10: 7972–7977.

    CAS  PubMed  Google Scholar 

  • Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F et al. (2001). 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 85: 881–890.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Giatromanolaki A, Sivridis E, Kouskoukis C, Gatter KC, Harris AL, Koukourakis MI . (2003). 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 13: 493–501.

    CAS  PubMed  Google Scholar 

  • Gillies RJ, Gatenby RA . (2007). Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev 26: 311–317.

    CAS  PubMed  Google Scholar 

  • Gray LH, Conger AO, Ebert M, Hornsey S, Scott OCA . (1953). The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26: 638–648.

    CAS  PubMed  Google Scholar 

  • Griffiths EA, Pritchard SA, Valentine HR, Whitchelo N, Bishop PW, Ebert MP et al. (2007). Hypoxia-inducible factor-1α expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas. Br J Cancer 96: 95–103.

    CAS  PubMed  Google Scholar 

  • Hahnfeldt P, Folkman J, Hlatky L . (2003). Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J Theor Biol 220: 545–554.

    PubMed  Google Scholar 

  • Harris AL . (2002). Hypoxia—a key regulatory factor in tumor growth. Nat Rev Cancer 2: 38–47.

    CAS  PubMed  Google Scholar 

  • Hiraga T, Kizaka-Kondoh S, Hirota K, Hiraoka M, Yoneda T . (2007). Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer. Cancer Res 67: 4157–4163.

    CAS  PubMed  Google Scholar 

  • Imamura T, Kikuchi H, Herraiz MT, Park DY, Mizukami Y, Mino-Kenduson M et al. (2009). HIF-1α and HIF-2α have divergent roles in colon cancer. Int J Cancer 124: 763–771.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM . (2002). Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J Biol Chem 277: 29936–29944.

    CAS  PubMed  Google Scholar 

  • Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL et al. (2005). HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8: 143–153.

    CAS  PubMed  Google Scholar 

  • Jiang BH, Agani F, Passaniti A, Semenza GL . (1997). 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.

    CAS  PubMed  Google Scholar 

  • Kaelin Jr WG, Ratcliffe PJ . (2008). Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30: 393–402.

    CAS  PubMed  Google Scholar 

  • Kaluz S, Kaluzov M, Stanbridge EJ . (2006). 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 26: 5895–5907.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kaluz S, Kaluzov M, Stanbridge EJ . (2008). Comment on the role of FIH in the inhibitory effect of bortezomib on hypoxia-inducible factor-1. Blood 111: 5258–5259.

    CAS  PubMed  Google Scholar 

  • Kerbel RS, Kamen BA . (2004). The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4: 423–436.

    CAS  PubMed  Google Scholar 

  • Kondo K, Kim WY, Lechpammer M, Kaelin Jr WG . (2003). Inhibition of HIF-2α is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 1: e83.

    PubMed  PubMed Central  Google Scholar 

  • Kondo S, Seo SY, Yoshizaki T, Wakisaka N, Furukawa M, Joab I et al. (2006). 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 66: 9870–9877.

    CAS  PubMed  Google Scholar 

  • Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A et al. (2005). Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65: 9047–9055.

    CAS  PubMed  Google Scholar 

  • Kong X, Lin Z, Liang D, Fath D, Sang N, Caro J . (2006). Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1α. Mol Cell Biol 26: 2019–2028.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Korkolopoulou P, Patsouris E, Konstantinidou AE, Pavlopoulos PM, Kavantzas N, Boviatsis E et al. (2004). Hypoxia-inducible factor 1α/vascular endothelial growth factor axis in astrocytomas. Associations with microvessel morphometry, proliferation and prognosis. Neuropathol Appl Neurobiol 30: 267–278.

    CAS  PubMed  Google Scholar 

  • Koshiji M, To KK, Hammer S, Kumamoto K, Harris AL, Modrich P et al. (2005). HIF-1α induces genetic instability by transcriptionally downregulating MutSα expression. Mol Cell 17: 793–803.

    CAS  PubMed  Google Scholar 

  • Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K et al. (2002). Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 53: 1192–1202.

    CAS  PubMed  Google Scholar 

  • Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH et al. (2006). 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 66: 2725–2731.

    CAS  PubMed  Google Scholar 

  • Kronblad A, Jirstrom K, Ryden L, Nordenskjold B, Landberg G . (2006). 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 118: 2609–2616.

    CAS  PubMed  Google Scholar 

  • Kung AL, Wang S, Klco JM, Kaelin WG, Livingston DM . (2000). Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med 6: 1335–1340.

    CAS  PubMed  Google Scholar 

  • Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK . (2002). FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16: 1466–1471.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lau KW, Tian YM, Raval RR, Ratcliffe PJ, Pugh CW . (2007). Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms. Br J Cancer 96: 1284–1292.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL . (2001). 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 21: 3995–4004.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL . (2009). Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci USA 106: 2353–2358.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li F, Sonveaux P, Rabbani ZN, Liu S, Yan B, Huang Q et al. (2007). Regulation of HIF-1α stability through S-nitrosylation. Mol Cell 26: 63–74.

    PubMed  PubMed Central  Google Scholar 

  • Li L, Lin X, Staver M, Shoemaker A, Semizarov D, Fesik SW et al. (2005). Evaluating hypoxia-inducible factor-1α as a cancer therapeutic target via inducible RNA interference in vivo. Cancer Res 65: 7249–7258.

    CAS  PubMed  Google Scholar 

  • Liao D, Corle C, Seagroves TN, Johnson RS . (2007). Hypoxia-inducible factor-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res 67: 563–572.

    CAS  PubMed  Google Scholar 

  • Liao D, Johnson RS . (2007). Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26: 281–290.

    CAS  PubMed  Google Scholar 

  • Liu Y, Tao J, Li Y, Yang J, Yu Y, Wang M et al. (2009). Targeting hypoxia-inducible factor-1α with Tf–PEI–shRNA complex via transferrin receptor-mediated endocytosis inhibits melanoma growth. Mol Ther 17: 269–277.

    CAS  PubMed  Google Scholar 

  • Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL . (2007). 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 25: 207–217.

    PubMed  PubMed Central  Google Scholar 

  • Lukashev D, Ohta A, Sitkovsky M . (2007). Hypoxia-dependent anti-inflammatory pathways in protection of cancerous tissues. Cancer Metastasis Rev 26: 273–279.

    CAS  PubMed  Google Scholar 

  • Luwor RB, Lu Y, Li X, Mendelsohn J, Fan Z . (2005). 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 24: 4433–4441.

    CAS  PubMed  Google Scholar 

  • Majumder PK, Yeh JJ, George DJ, Febbo PG, Kum J, Xue Q et al. (2004). mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10: 594–601.

    CAS  PubMed  Google Scholar 

  • Makino Y, Uenishi R, Okamoto K, Isoe T, Hosono O, Tanaka H et al. (2007). 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 282: 14073–14082.

    CAS  PubMed  Google Scholar 

  • Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ et al. (2005). Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105: 659–669.

    CAS  PubMed  Google Scholar 

  • Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ et al. (1997). Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 94: 8104–8109.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME et al. (1999). The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399: 271–275.

    CAS  PubMed  Google Scholar 

  • Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C . (2002). 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.

    CAS  PubMed  Google Scholar 

  • Melillo G . (2007). Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26: 341–352.

    CAS  PubMed  Google Scholar 

  • Moeller BJ, Cao Y, Li CY, Dewhirst MW . (2004). Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5: 429–441.

    CAS  PubMed  Google Scholar 

  • Moeller BJ, Richardson RA, Dewhirst MW . (2007). Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev 26: 241–248.

    CAS  PubMed  Google Scholar 

  • Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J et al. (2009). Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem 284: 16767–16775.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura M, Bodily JM, Beglin M, Kyo S, Inoue M, Laimins LA . (2009). Hypoxia-specific stabilization of HIF-1α by human papillomaviruses. Virology 387: 442–448.

    CAS  PubMed  Google Scholar 

  • Nanni S, Benvenuti V, Grasselli A, Priolo C, Aiello A, Mattiussi S et al. (2009). Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer. J Clin Invest 119: 1093–1108.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pagès G, Pouyssègur J . (2005). Transcriptional regulation of the vascular endothelial growth factor gene—a concert of activating factors. Cardiovasc Res 65: 564–573.

    PubMed  Google Scholar 

  • Pore N, Jiang Z, Gupta A, Cerniglia G, Kao GD, Maity A . (2006). EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Cancer Res 66: 3197–3204.

    CAS  PubMed  Google Scholar 

  • Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P et al. (2006). Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1α. Cancer Res 66: 8814–8821.

    CAS  PubMed  Google Scholar 

  • Quintero M, Brennan PA, Thomas GJ, Moncada S . (2006). Nitric oxide is a factor in the stabilization of hypoxia-inducible factor-1α in cancer: role of free radical formation. Cancer Res 66: 770–774.

    CAS  PubMed  Google Scholar 

  • Rajaganeshan R, Prasad R, Guillou PJ, Poston G, Scott N, Jayne DG . (2008). The role of hypoxia in recurrence following resection of Dukes’ B colorectal cancer. Int J Colorectal Dis 23: 1049–1055.

    CAS  PubMed  Google Scholar 

  • Rapisarda A, Uranchimeg B, Scudiero DA, Selby M, Sausville EA, Shoemaker RH et al. (2002). Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res 62: 4316–4324.

    CAS  PubMed  Google Scholar 

  • Rasheed S, Harris AL, Tekkis PP, Turley H, Silver A, McDonald PJ et al. (2009). 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 100: 1666–1673.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, LI J-L et al. (2005). Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel–Lindau-associated renal cell carcinoma. Mol Cell Biol 25: 5675–5686.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q et al. (2000). Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev 14: 34–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M et al. (2002). Overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 8: 1831–1837.

    CAS  PubMed  Google Scholar 

  • Schmitz KJ, Müller CI, Reis H, Alakus H, Winde G, Baba HA et al. (2009). Combined analysis of hypoxia-inducible factor 1α and metallothionein indicates an aggressive subtype of colorectal carcinoma. Int J Colorectal Dis 24: 1287–1296.

    PubMed  Google Scholar 

  • Schrijvers ML, van der Laan BF, de Bock GH, Pattje WJ, Mastik MF, Menkema L et al. (2008). 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 72: 161–169.

    CAS  PubMed  Google Scholar 

  • Schwartz DL, Powis G, Thitai-Kumar A, He Y, Bankson J, Williams R et al. (2009). The selective hypoxia inducible factor-1 inhibitor PX-478 provides in vivo radiosensitization through tumor stromal effects. Mol Cancer Ther 8: 947–958.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD et al. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7: 77–85.

    CAS  PubMed  Google Scholar 

  • Semenza GL . (2000). Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 35: 71–103.

    CAS  PubMed  Google Scholar 

  • Semenza GL . (2009a). Oxygen homeostasis. Systems Biol Med (doi:10.1002/wsbm.69).

    CAS  PubMed  Google Scholar 

  • Semenza GL . (2009b). Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol 19: 12–16.

    CAS  PubMed  Google Scholar 

  • Shackelford DB, Vasquez DS, Corbeil J, Wu S, Leblanc M, Wu CL et al. (2009). mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz–Jeghers syndrome. Proc Natl Acad Sci USA 106: 11137–11142.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shin DH, Chun YS, Lee DS, Huang LE, Park JW . (2008). Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1. Blood 111: 3131–3136.

    CAS  PubMed  Google Scholar 

  • Shin YC, Joo CH, Gack MU, Lee HR, Jung JU . (2008). Kaposi's sarcoma-associated herpesvirus viral IFN regulatory factor 3 stabilizes hypoxia-inducible factor-1α to induce vascular endothelial growth factor expression. Cancer Res 68: 1751–1759.

    CAS  PubMed  Google Scholar 

  • Sivridis E, Giatromanolaki A, Gatter KC, Harris AL, Koukourakis MI . (2002). Association of hypoxia-inducible factors 1α and 2α with activated angiogenic pathways and prognosis in patients with endometrial carcinoma. Cancer 95: 1055–1063.

    CAS  PubMed  Google Scholar 

  • Sodhi A, Montaner S, Patel V, Zohar M, Bais C, Mesri EA et al. (2000). 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 60: 4873–4880.

    CAS  PubMed  Google Scholar 

  • Stoeltzing O, McCarty MF, Wey JS, Fan F, Liu W, Belcheva A et al. (2004). Role of hypoxia-inducible factor 1α in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst 96: 946–956.

    CAS  PubMed  Google Scholar 

  • Sullivan R, Graham CH . (2007). Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev 26: 319–331.

    CAS  PubMed  Google Scholar 

  • Sun HC, Qiu ZJ, Liu J, Sun J, Jiang T, Huang KJ et al. (2007). Expression of hypoxia-inducible factor-1α and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int J Oncol 30: 1359–1367.

    CAS  PubMed  Google Scholar 

  • Swietach P, Vaughan-Jones RD, Harris AL . (2007). Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 26: 299–310.

    CAS  PubMed  Google Scholar 

  • Swinson DE, Jones JL, Cox G, Richardson D, Harris AL, O'Byrne KJ . (2004). Hypoxia-inducible factor-1α in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer 111: 43–50.

    CAS  PubMed  Google Scholar 

  • Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ et al. (2000). The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157: 411–421.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tang N, Wang L, Esko J, Giordano FJ, Huang Y, Gerber HP et al. (2004). Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6: 485–495.

    CAS  PubMed  Google Scholar 

  • Takahashi R, Tanaka S, Hiyama T, Ito M, Kitadai Y, Sumii M et al. (2003). Hypoxia-inducible factor-1α expression and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncol Rep 10: 797–802.

    CAS  PubMed  Google Scholar 

  • Theodoropoulos VE, Lazaris AC, Kastriotis I, Spiliadi C, Theodoropoulos GE, Tsoukala V et al. (2005). Evaluation of hypoxia-inducible factor 1α overexpression as a predictor of tumor recurrence and progression in superficial urothelial bladder carcinoma. BJU Int 95: 425–431.

    CAS  PubMed  Google Scholar 

  • Theodoropoulos VE, Lazaris AC, Sofras F, Gerzelis I, Tsoukala V, Ghikonti I et al. (2004). Hypoxia-inducible factor 1α expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol 46: 200–208.

    CAS  PubMed  Google Scholar 

  • Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B et al. (2006). Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12: 122–127.

    CAS  PubMed  Google Scholar 

  • Tomita M, Semenza GL, Michiels C, Matsuda T, Uchihara JN, Okudaira T et al. (2007). 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 406: 317–323.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Trastour C, Benizri E, Ettore F, Ramaioli A, Chamorey E, Pouyssegur J et al. (2007). HIF-1α and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer 120: 1443–1450.

    Google Scholar 

  • Tzao C, Lee SC, Tung HJ, Hsu HS, Hsu WH, Sun GH et al. (2008). 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 25: 141–148.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vaupel P, Mayer A, Hockel M . (2004). Tumor hypoxia and malignant progression. Methods Enzymol 381: 335–354.

    CAS  PubMed  Google Scholar 

  • Vleugel MM, Greijer AE, Shvarts A, van der Groep P, van Berkel M, Aarbodem Y et al. (2005). Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer. J Clin Pathol 58: 172–177.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vogelstein B, Kinzler KW . (2004). Cancer genes and the pathways they control. Nat Med 10: 789–799.

    CAS  PubMed  Google Scholar 

  • Wang GL, Jiang BH, Rue EA, Semenza GL . (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92: 5510–5514.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang GL, Semenza GL . (1995). Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270: 1230–1237.

    CAS  PubMed  Google Scholar 

  • Wang XL, Xu R, Wu X, Gillespie D, Jensen R, Lu ZR . (2009). Targeted systemic delivery of a therapeutic siRNA with a multifunctional carrier controls tumor proliferation in mice. Mol Pharm 6: 738–746.

    CAS  PubMed  Google Scholar 

  • Yamamoto Y, Ibusuki M, Okumura Y, Kawasoe T, Kai K, Iyama K et al. (2008). Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res Treat 110: 465–475.

    CAS  PubMed  Google Scholar 

  • Yoo YG, Cho S, Park S, Lee MO . (2004). The carboxy-terminus of the hepatitis B virus X protein is necessary and sufficient for the activation of hypoxia-inducible factor-1α. FEBS Lett 577: 121–126.

    CAS  PubMed  Google Scholar 

  • Yu J, Zhang L, Hwang PM, Rago C, Kinzler KW, Vogelstein B . (1999). Identification and classification of p53-regulated genes. Proc Natl Acad Sci USA 96: 14517–14522.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR et al. (2008). Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proc Natl Acad Sci USA 105: 19579–19586.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P et al. (2009). Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324: 261–265.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM et al. (2000). 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 60: 1541–1545.

    CAS  PubMed  Google Scholar 

  • Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D et al. (1999). Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 59: 5830–5835.

    CAS  PubMed  Google Scholar 

  • Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E et al. (2000). Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14: 391–396.

    CAS  PubMed  PubMed Central  Google Scholar 

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Semenza, G. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2010). https://doi.org/10.1038/onc.2009.441

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