The role of hypoxia-inducible factor-2 in digestive system cancers

Tian H, McKnight SL, Russell DW . Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 1997; 11: 72–82.

Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y . A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 1997; 94: 4273–4278.

Flamme I, Fröhlich T, von Reutern M, Kappel A, Damert A, Risau W . HRF a putative basic helixloop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mech Dev 1997; 63: 51–60.

Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M et al. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem 1997; 272: 8581–8593.

Gordan JD, Simon MC . Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev 2007; 17: 71–77.

Mahon PC, Semenza GL . FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediaterepression of HIF-1 transcriptional activity. Genes Dev 2001; 15: 2675–2686.

Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292: 468–472.

Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000; 2: 423–427.

Maxwell PH, Pugh CW, Ratcliffe PJ . Activation of the HIF pathway in cancer. Curr Opin Genet Dev 2001; 11: 293–299.

Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL . The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 1998; 12: 3320–3324.

Wiesener MS, Jurgensen JS, Rosenberger C, Scholze CK, Horstrup JH, Warnecke C et al. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB J 2003; 17: 271–273.

Holmquist-Mengelbier L, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell 2006; 10: 413–423.

Wiesener MS, Turley H, Allen WE, Willam C, Eckardt KU, Talks KL et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha. Blood 1998; 92: 2260–2268.

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

Bangoura G, Liu ZS, Qian Q, Jiang CQ, Yang GF, Jing S . Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol 2007; 13: 3176–3182.

Shi CY, Fan Y, Liu B, Lou WH . HIF1 contributes to hypoxia-induced pancreatic cancer cells invasion via promoting QSOX1 expression. Cell Physiol Biochem 2013; 32: 561–568.

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

Yoon H, Shin SH, Shin DH, Chun YS, Park JW . Differential roles of Sirt1 in HIF-1α and HIF-2α mediated hypoxic responses. Biochem Biophys Res Commun 2014; 444: 36–43.

Eubank TD, Roda JM, Liu H, O’Neil T, Marsh CB . Opposing roles for HIF-1α and HIF-2α in the regulation of angiogenesis by mononuclear phagocytes. Blood 2011; 117: 323–332.

Koh MY, Lemos R Jr, Liu X, Powis G . The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res 2011; 71: 4015–4027.

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

Fraisl P, Mazzone M, Schmidt T, Carmeliet P . Regulation of angiogenesis by oxygen and metabolism. Dev Cell 2009; 16: 167–179.

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

Florczyk U, Czauderna S, Stachurska A, Tertil M, Nowak W, Kozakowska M . Opposite effects of HIF-1α and HIF-2α on the regulation of IL-8 expression in endothelial cells. Free Radic Biol Med 2011; 51: 1882–1892.

Xia G, Kageyama Y, Hayashi T, Kawakami S, Yoshida M, Kihara K . Regulation of vascular endothelial growth factor transcription by endothelial PAS domain protein 1 (EPAS1) and possible involvement of EPAS1 in the angiogenesis of renal cell carcinoma. Cancer 2001; 91: 1429–1436.

Akeno N, Czyzyk-Krzeska MF, Gross TS, Clemens TL . Hypoxia induces vascular endothelial growth factor gene transcription in human osteoblast-like cells through the hypoxia-inducible factor 2alpha. Endocrinology 2001; 142: 959–962.

Rankin EB, Rha J, Unger TL, Wu CH, Shutt HP, Johnson RS et al. Hypoxia- inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene 2008; 27: 5354–5358.

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.

Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD . The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 2002; 1: 247–255.

Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL 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.

Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr . Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002; 1: 237–246.

Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr . Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003; 1: E83.

Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 2002; 1: 459–468.

Yang SL, Liu LP, Jiang JX, Xiong ZF, He QJ, Wu C . The correlation of expression levels of HIF-1α and HIF-2α in hepatocellular carcinoma with capsular invasion, portal vein tumor thrombi and patients' clinical outcome. Jpn J Clin Oncol 2014; 44: 159–167.

Covello KL, Simon MC, Keith B . Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Cancer Res 2005; 65: 2277–2286.

Branco-Price C, Zhang N, Schnelle M, Evans C, Katschinski DM, Liao D et al. Endothelial cell HIF-1α and HIF-2α differentially regulate metastatic success. Cancer Cell 2012; 21: 52–65.

Mazumdar J, Hickey MM, Pant DK, Durham AC, Sweet-Cordero A, Vachani A et al. HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc Natl Acad Sci USA 2010; 107: 14182–14187.

Chae KS, Kang MJ, Lee JH, Ryu BK, Lee MG, Her NG et al. Opposite functions of HIF-α isoforms in VEGF induction by TGF-β1 under non-hypoxic conditions. Oncogene 2011; 30: 1213–1328.

Mazumdar J, Dondeti V, Simon MC . Hypoxia-inducible factors in stem cells and cancer. J Cell Mol Med 2009; 13: 4319–4328.

Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 2009; 15: 501–513.

Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE . HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J 2004; 23: 1949–1956.

Koshiji M, To KK, Hammer S, Kumamoto K, Harris AL, Modrich P et al. HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol Cell 2005; 77: 793–803.

Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC . HIF-2alpha promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity. Cancer Cell 2007; 11: 335–347.

Cummins EP . HIF-2α-a mediator of stem cell altruism? Stem Cell Res Ther 2012; 3: 52.

Das B, Bayat-Mokhtari R, Tsui M, Lotfi S, Tsuchida R, Felsher DW . HIF-2α suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells. Stem Cells 2012; 30: 1685–1695.

Gan B, Melkoumian ZK, Wu X, Guan KL, Guan JL . Identification of FIP200 interaction with the SC1-TSC2 complex and its role in regulation of cell size control. J Cell Biol 2005; 170: 379–389.

Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1rrSC2 tumor suppressor complex. Genes Dev 2004; 18: 2893–2904.

De Young MP, Horak P, Sofer A, Sgroi D, Ellisen LW . Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008; 22: 239–251.

Choi H, Chun YS, Kim TY, Park JW . HIF-2alpha enhances beta-catenin/TCF- driven transcription by interacting with beta-catenin. Cancer Res 2010; 70: 10101–10111.

Liu YL, Yu JM, Song XR, Wang XW, Xing LG, Gao BB . Regulation of the chemokine receptor CXCR4 and metastasis by hypoxia-inducible factor in non small cell lung cancer cell lines. Cancer Biol Ther 2006; 5: 1320–1326.

Winter SC, Shah KA, Han C, Campo L, Turley H, Leek R et al. The relation between hypoxia inducible factor (HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer. Cancer 2006; 107: 757–766.

Hui EP, Chan AT, Pezzella F, Turley H, To KF, Poon TC et al. Coexpression of hypoxiainducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res 2002; 8: 2595–2604.

Yoshimura H, Dhar DK, Kohno H, Kubota H, Fujii T, Ueda S et al. Prognostic impact of hypoxiainducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression. Clin Cancer Res 2004; 10: 8554–8560.

Arabi A, Wu S, Ridderstråle K, Bierhoff H, Shiue C, Fatyol K et al. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. Nat Cell Biol 2005; 7: 303–310.

Li QQ, Sun YP, Ruan CP, Xu XY, Ge JH, He J et al. Cellular prion protein promotes glucose uptake through the Fyn-HIF-2α-Glut1 pathway to support colorectal cancer cell survival. Cancer Sci 2011; 102: 400–406.

Criscimanna A, Duan LJ, Rhodes JA, Fendrich V, Wickline E, Hartman DJ . PanIN-specific regulation of Wnt signaling by HIF2α during early pancreatic tumorigenesis. Cancer Res 2013; 73: 4781–4790.

Sun HX, Xu Y, Yang XR, Wang WM, Bai H, Shi RY et al. Hypoxia inducible factor 2 alpha inhibits hepatocellular carcinoma growth through the transcription factor dimerization partner 3/ E2F transcription factor 1-dependent apoptotic pathway. Hepatology 2013; 57: 1088–1097.

Mignotte B, Vayssiere JL . Mitochondria and apoptosis. Eur J Biochem 1998; 252: 1–15.

Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC . Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 1998; 95: 4997–5002.

Menrad H, Werno C, Schmid T, Copanaki E, Deller T, Dehne N et al. Roles of hypoxiainducible factor-1alpha (HIF-1alpha) versus HIF-2alpha in the survival of hepatocellular tumor spheroids. Hepatology 2010; 51: 2183–2192.

Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008; 283: 10892–108903.

Mazure NM, Pouysségur J . Atypical BH3-domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy 2009; 5: 868–869.

Xue X, Shah YM . Hypoxia-inducible factor-2α is essential in activating the COX2/mPGES-1/PGE2 signaling axis in colon cancer. Carcinogenesis 2013; 34: 163–169.

Franovic A, Holterman CE, Payette J, Lee S . Human cancers converge at the HIF-2alpha oncogenic axis. Proc Natl Acad Sci USA 2009; 106: 21306–21311.

Yang H, Li TW, Peng J, Tang X, Ko KS, Xia M et al. A mouse model of cholestasis-associated cholangiocarcinoma and transcription factors involved in progression. Gastroenterology 2011; 141: 378–388.

Jungermann K, Kietzmann T . Oxygen: modulator of metabolic zonation and disease of the liver. Hepatology 2000; 31: 255–260.

Qu A, Taylor M, Xue X, Matsubara T, Metzger D, Chambon P et al. Hypoxiainducible transcription factor 2alpha promotes steatohepatitis through augmenting lipid accumulation, inflammation, and fibrosis. Hepatology 2011; 54: 472–483.

Gordan JD, Thompson CB, Simon MC . HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 2007; 12: 108–113.

Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan LJ et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice. Nat Genet 2003; 35: 331–340.

Warburg O . On the origin of cancer cells. Science 1956; 123: 309–314.

Shaw RJ . Glucose metabolism and cancer. Curr Opin Cell Biol 2006; 18: 598–608.

Weidemann A, Johnson RS . Biology of HIF-1alpha. Cell Death Differ 2008; 15: 621–627.

Bertout JA, Majmundar AJ, Gordan JD, Lam JC, Ditsworth D, Keith B et al. HIF2 alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc Natl Acad Sci USA 2009; 106: 14391–14396.

Chun SY, Johnson C, Washburn JG, Cruz-Correa MR, Dang DT, Dang LH . Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes. Mol Cancer 2010; 9: 293.

Lum JJ, Bui T, Gruber M, Gordan JD, DeBerardinis RJ, Covello KL et al. The transcription factor HIF-1a plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev 2007; 21: 1037–1049.

Cleven AH, Wouters BG, Schutte B, Spiertz AJ, van Engeland M, de Bruïne AP . Poorer outcome in stromal HIF-2 alpha- and CA9-positive colorectal adenocarcinomas is associated with wild-type TP53 but not with BNIP3 promoter hypermethylation or apoptosis. Br J Cancer 2008; 99: 727–733.

Keith B, Johnson RS, Simon MC . HIFlα and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev 2012; 12: 9–22.

Zhao D, Zhai B, He C, Tan G, Jiang X, Pan S et al. Upregulation of HIF-2α induced by sorafenib contributes to the resistance by activating the TGF-α/EGFR pathway in hepatocellular carcinoma cells. Cell Signal 2014; 26: 1030–1039.

Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 2007; 117: 1068–1077.

Imai T, Horiuchi A, Wang C, Oka K, Ohira S, Nikaido T et al. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am J Pathol 2003; 163: 1437–1447.

Esteban MA, Tran MG, Harten SK, Hill P, Castellanos MC, Chandra A et al. Regulation of Ecadherin expression by VHL and hypoxia-inducible factor. Cancer Res 2006; 66: 3567–3575.

Arya M, Ahmed H, Silhi N, Williamson M, Patel HR . Clinical importance and therapeutic implications of the pivotal CXCL12-CXCR4 (chemokine ligand-receptor) interaction in cancer cell migration. Tumour Biol 2007; 28: 123–131.

Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10: 858–864.

Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W . Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 2003; 425: 307–311.

Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006; 440: 1222–1226.

Wang Y, Li Z, Zhang H, Jin H, Sun L, Dong H et al. HIF-1α and HIF-2α correlate with migration and invasion in gastric cancer. Cancer Biol Ther 2010; 15: 376–382.

Kourakis MI, Giatromanolaki A, Polychronidis A, Simopoulos C, Gatter KC, Harris AL et al. Endogenous markers of hypoxia/anaerobic metabolism and anemia in primary colorectal cancer. Cancer Sci 2006; 97: 582–588.

Ahn YT, Chua MS, Whitlock JP Jr, Shin YC, Song WH, Kim Y, Eom CY et al. Rodent-specific hypoxia response elements enhance PAI-1 expression through HIF-1 or HIF-2 in mouse hepatoma cells. Int J Oncol 2010; 37: 1627–1638.

Li F, Tiede B, Massague J, Kang Y . Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res 2007; 17: 3–14.

Heddleston JM, Li Z, Lathia JD, Bao S, Hjelmeland AB, Rich JN . Hypoxia inducible factors in cancer stem cells. Br J Cancer 2010; 102: 789–795.

Keith B, Simon MC . Hypoxia-inducible factors, stem cells, and cancer. Cell 2007; 129: 465–472.

Koh MY, Powis G . Passing the baton: the HIF switch. Trends Biochem Sci 2012; 37: 364–472.

Salnikov AV, Liu L, Platen M, Gladkich J, Salnikova O, Ryschich E et al. Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PLoS One 2012; 7: e46391.

Wilson WR, Hay MP . Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011; 11: 393–410.

Rankin EB, Giaccia AJ . The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 2008; 15: 678–685.

Wen YA, Stevens PD, Gasser ML, Andrei R, Gao T . Downregulation of PHLPP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells. Mol Cell Biol 2013; 33: 4594–4605.

Burkitt K, Chun SY, Dang DT, Dang LH . Targeting both HIF-1 and HIF-2 in human colon cancer cells improves tumor response to sunitinib treatment. Mol Cancer Ther 2009; 8: 1148–1156.

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

Semenza GL . Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 2010; 29: 625–634.

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 1 alpha. Mol Cell Biol 2006; 26: 2019–2028.

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 1 alpha. Cancer Res 2006; 66: 8814–8821.

Härter M, Thierauch KH, Boyer S, Bhargava A, Ellinghaus P, Beck H et al. Inhibition of hypoxia-induced gene transcription by substituted pyrazolyl oxadiazoles: initial lead generation and structure-activity relationships. ChemMedChem 2014; 9: 61–66.

Philips GK, Atkins MB . New agents and new targets for renal cell carcinoma. Am Soc Clin Oncol Educ Book 2014: e222–e227.

Grkovic T, Whitson EL, Rabe DC, Gardella RS, Bottaro DP, Linehan WM et al. Identification and evaluation of soft coral diterpenes as inhibitors of HIF-2α induced gene expression. Bioorg Med Chem Lett 2011; 21: 2113–2115.

Rabbani ZN, Spasojevic I, Zhang X, Moeller BJ, Haberle S, Vasquez-Vivar J et al. Antiangiogenic action of redox-modulating Mn(III) meso-tetrakis (Nethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidativestress in a mouse model of breast tumor. Free Radic Biol Med 2009; 47: 992–1004.

Wang J, Ma Y, Jiang H, Zhu H, Liu L, Sun B et al. Overexpression of von Hippel-Lindau protein synergizes with doxorubicin to suppress hepatocellular carcinoma in mice. J Hepatol 2011; 55: 359–368.

Bhatt RS, Landis DM, Zimmer M, Torregrossa J, Chen S, Sukhatme VP et al. Hypoxia-inducible factor-2alpha: effect on radiation sensitivity and differential regulation by an mTOR inhibitor. BJU Int 2008; 102: 358–363.

Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA . Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit HIF3alpha. Gene Expr 1998; 7: 205–213.