Role of Hypoxia-Inducible Factor (HIF) in Liver Cancer

  • Inho Choi
  • Saipriya Lammata
  • Neha Merchant
  • Dongkyoo ParkEmail author


Liver cancer is one of the major causes of cancer-related deaths in the United States, accounting for 4.5% of the total estimated cancer deaths in 2016 and standing as the second leading cause of cancer-related deaths in men worldwide in 2012. There are two major types of primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The most common type of primary liver cancer is HCC, which begins in hepatocytes and accounts for approximately 75% of all liver cancers. Hypoxia, a condition of oxygen deprivation in the tissue, is a common feature of the cancer microenvironment due to increased cell proliferation and limited blood supply. Hypoxia-inducible factor-1 (HIF-1) was the first transcription factor discovered to regulate a wide range of target genes involved in many cellular processes in response to low oxygen levels. HIF-1 is a heterodimeric protein complex composed of two different subunits, α and β. During a condition of hypoxia, HIF-1 heterodimer activates target genes that contain a hypoxia response element (HRE) in the promoter region. The overexpression of HIF-1 is frequently observed in many human solid tumors, including liver cancer, and is associated with tumor development, poor prognosis, and resistance to chemotherapy, suggesting that HIF-1 is a new therapeutic target in liver cancer treatment. In this chapter, we define the molecular mechanism that controls HIF-1 and how it maintains a variation of biological processes in hypoxic environments.


Liver cancer Hepatocellular carcinoma Hypoxia-inducible factor Metastasis Cell cycle 


  1. 1.
    van Leeuwen MS et al (1995) Planning of liver surgery using three dimensional imaging techniques. Eur J Cancer 31A(7–8):1212–1215CrossRefPubMedGoogle Scholar
  2. 2.
    Fasel JH (2008) Portal venous territories within the human liver: an anatomical reappraisal. Anat Rec (Hoboken) 291(6):636–642CrossRefGoogle Scholar
  3. 3.
    Fasel JH, Majno PE, Peitgen HO (2010) Liver segments: an anatomical rationale for explaining inconsistencies with Couinaud’s eight-segment concept. Surg Radiol Anat 32(8):761–765CrossRefPubMedGoogle Scholar
  4. 4.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30CrossRefGoogle Scholar
  5. 5.
    Torre LA et al (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108CrossRefGoogle Scholar
  6. 6.
    Sherman M, Llovet JM (2011) Smoking, hepatitis B virus infection, and development of hepatocellular carcinoma. J Natl Cancer Inst 103(22):1642–1643CrossRefPubMedGoogle Scholar
  7. 7.
    Badvie S (2000) Hepatocellular carcinoma. Postgrad Med J 76(891):4–11CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sherman M (2005) Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis 25(2):143–154CrossRefPubMedGoogle Scholar
  9. 9.
    El-Serag HB, Tran T, Everhart JE (2004) Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126(2):460–468CrossRefPubMedGoogle Scholar
  10. 10.
    Bosch FX et al (2005) Epidemiology of hepatocellular carcinoma. Clin Liver Dis 9(2):191–211. vCrossRefPubMedGoogle Scholar
  11. 11.
    Lavanchy D (2004) Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 11(2):97–107CrossRefPubMedGoogle Scholar
  12. 12.
    Chisari FV (2005) Unscrambling hepatitis C virus-host interactions. Nature 436(7053):930–932CrossRefPubMedGoogle Scholar
  13. 13.
    Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocarcinoma. Semin Liver Dis 24(2):115–125CrossRefPubMedGoogle Scholar
  14. 14.
    Razumilava N, Gores GJ (2013) Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol 11(1):13–21. e1; quiz e3-4CrossRefPubMedGoogle Scholar
  15. 15.
    De Ioris M et al (2008) Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer 44(4):545–550CrossRefPubMedGoogle Scholar
  16. 16.
    Rankin EB, Giaccia AJ (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 15(4):678–685CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Carmeliet P et al (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394(6692):485–490CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Pennacchietti S et al (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3(4):347–361CrossRefPubMedGoogle Scholar
  19. 19.
    Jiang BH et al (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271(30):17771–17778CrossRefPubMedGoogle Scholar
  20. 20.
    Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol (1985) 88(4):1474–1480CrossRefGoogle Scholar
  21. 21.
    Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12(12):5447–5454CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ziello JE, Jovin IS, Huang Y (2007) Hypoxia-inducible factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med 80(2):51–60PubMedPubMedCentralGoogle Scholar
  23. 23.
    Mandl M, Depping R (2014) Hypoxia-inducible aryl hydrocarbon receptor nuclear translocator (ARNT) (HIF-1beta): is it a rare exception? Mol Med 20:215–220CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Koh MY, Powis G (2012) Passing the baton: the HIF switch. Trends Biochem Sci 37(9):364–372CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Salceda S, Caro J (1997) Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272(36):22642–22647CrossRefPubMedGoogle Scholar
  26. 26.
    Huang LE et al (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 95(14):7987–7992CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ohh M et al (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2(7):423–427CrossRefPubMedGoogle Scholar
  28. 28.
    Maxwell PH et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399(6733):271–275CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lando D et al (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16(12):1466–1471CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Bangoura G et al (2004) Expression of HIF-2alpha/EPAS1 in hepatocellular carcinoma. World J Gastroenterol 10(4):525–530CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Krieg M et al (2000) Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene 19(48):5435–5443CrossRefPubMedGoogle Scholar
  32. 32.
    Wu XY et al (2010) Identification of differential proteins in colon cancer SW480 cells with HIF1-alpha silence by proteome analysis. Neoplasma 57(4):299–305CrossRefPubMedGoogle Scholar
  33. 33.
    Chiavarina B et al (2010) HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: autophagy drives compartment-specific oncogenesis. Cell Cycle 9(17):3534–3551CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Talks KL et al (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157(2):411–421CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6):393–410CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Onnis B, Rapisarda A, Melillo G (2009) Development of HIF-1 inhibitors for cancer therapy. J Cell Mol Med 13(9A):2780–2786CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Xia Y, Choi HK, Lee K (2012) Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur J Med Chem 49:24–40CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Unruh A et al (2003) The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22(21):3213–3220CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Li S et al (2011) Expression characteristics of hypoxia-inducible factor-1alpha and its clinical values in diagnosis and prognosis of hepatocellular carcinoma. Hepat Mon 11(10):821–828PubMedPubMedCentralGoogle Scholar
  40. 40.
    Forsythe JA et al (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16(9):4604–4613CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Feldser D et al (1999) Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 59(16):3915–3918PubMedGoogle Scholar
  42. 42.
    Grimshaw MJ (2007) Endothelins and hypoxia-inducible factor in cancer. Endocr Relat Cancer 14(2):233–244CrossRefPubMedGoogle Scholar
  43. 43.
    Chen TM et al (2014) Overexpression of FGF9 in colon cancer cells is mediated by hypoxia-induced translational activation. Nucleic Acids Res 42(5):2932–2944CrossRefPubMedGoogle Scholar
  44. 44.
    Chen N et al (2009) BCL-xL is a target gene regulated by hypoxia-inducible factor-1{alpha}. J Biol Chem 284(15):10004–10012CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Erler JT et al (2004) Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol Cell Biol 24(7):2875–2889CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Bellot G et al (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29(10):2570–2581CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Xia LM et al (2009) Transcriptional up-regulation of FoxM1 in response to hypoxia is mediated by HIF-1. J Cell Biochem 106(2):247–256CrossRefPubMedGoogle Scholar
  48. 48.
    Xia L et al (2012) The TNF-alpha/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. Carcinogenesis 33(11):2250–2259CrossRefPubMedGoogle Scholar
  49. 49.
    Xu Z et al (2012) Role of hypoxia-inducible-1alpha in hepatocellular carcinoma cells using a Tet-on inducible system to regulate its expression in vitro. Oncol Rep 27(2):573–578PubMedGoogle Scholar
  50. 50.
    Piret JP et al (2005) Hypoxia-inducible factor-1-dependent overexpression of myeloid cell factor-1 protects hypoxic cells against tert-butyl hydroperoxide-induced apoptosis. J Biol Chem 280(10):9336–9344CrossRefPubMedGoogle Scholar
  51. 51.
    Baek JH et al (2000) Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene 19(40):4621–4631CrossRefPubMedGoogle Scholar
  52. 52.
    Abramovitch R et al (2004) A pivotal role of cyclic AMP-responsive element binding protein in tumor progression. Cancer Res 64(4):1338–1346CrossRefPubMedGoogle Scholar
  53. 53.
    Thelander L, Graslund A, Thelander M (1983) Continual presence of oxygen and iron required for mammalian ribonucleotide reduction: possible regulation mechanism. Biochem Biophys Res Commun 110(3):859–865CrossRefPubMedGoogle Scholar
  54. 54.
    Loffler M (1989) The biosynthetic pathway of pyrimidine (deoxy)nucleotides: a sensor of oxygen tension necessary for maintaining cell proliferation? Exp Cell Res 182(2):673–680CrossRefPubMedGoogle Scholar
  55. 55.
    Gardner LB et al (2001) Hypoxia inhibits G1/S transition through regulation of p27 expression. J Biol Chem 276(11):7919–7926CrossRefPubMedGoogle Scholar
  56. 56.
    Krtolica A, Krucher NA, Ludlow JW (1998) Hypoxia-induced pRB hypophosphorylation results from downregulation of CDK and upregulation of PP1 activities. Oncogene 17(18):2295–2304CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ortmann B, Druker J, Rocha S (2014) Cell cycle progression in response to oxygen levels. Cell Mol Life Sci 71(18):3569–3582CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Goda N et al (2003) Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia. Mol Cell Biol 23(1):359–369CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Uchino K et al (2011) Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors. Cancer 117(19):4475–4483CrossRefPubMedGoogle Scholar
  60. 60.
    Jiang WG et al (2015) Tissue invasion and metastasis: molecular, biological and clinical perspectives. Semin Cancer Biol 35(Suppl):S244–S275CrossRefPubMedGoogle Scholar
  61. 61.
    Bendas G, Borsig L (2012) Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. Int J Cell Biol 2012:676731CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    van Zijl F et al (2009) Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol 5(8):1169–1179CrossRefPubMedGoogle Scholar
  63. 63.
    Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26(2):225–239CrossRefPubMedGoogle Scholar
  64. 64.
    Miyoshi A et al (2006) Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-1alpha-independent manner. Int J Oncol 29(6):1533–1539PubMedGoogle Scholar
  65. 65.
    Liu K et al (2016) The changes of HIF-1alpha and VEGF expression after TACE in patients with hepatocellular carcinoma. J Clin Med Res 8(4):297–302CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Wu XZ, Xie GR, Chen D (2007) Hypoxia and hepatocellular carcinoma: the therapeutic target for hepatocellular carcinoma. J Gastroenterol Hepatol 22(8):1178–1182CrossRefPubMedGoogle Scholar
  67. 67.
    Lin D, Wu J (2015) Hypoxia inducible factor in hepatocellular carcinoma: a therapeutic target. World J Gastroenterol 21(42):12171–12178CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Corley KM, Taylor CJ, Lilly B (2005) Hypoxia-inducible factor 1alpha modulates adhesion, migration, and FAK phosphorylation in vascular smooth muscle cells. J Cell Biochem 96(5):971–985CrossRefPubMedGoogle Scholar
  69. 69.
    Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15(3):178–196CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Haase VH (2009) Oxygen regulates epithelial-to-mesenchymal transition: insights into molecular mechanisms and relevance to disease. Kidney Int 76(5):492–499CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Luo D et al (2014) The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int 2014:409272PubMedPubMedCentralGoogle Scholar
  72. 72.
    Lauffenburger DA, Horwitz AF (1996) Cell migration: a physically integrated molecular process. Cell 84(3):359–369CrossRefPubMedGoogle Scholar
  73. 73.
    Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9(6):653–660CrossRefPubMedGoogle Scholar
  74. 74.
    Yancopoulos GD et al (2000) Vascular-specific growth factors and blood vessel formation. Nature 407(6801):242–248CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29(6 Suppl 16):15–18CrossRefPubMedGoogle Scholar
  76. 76.
    Jain RK (2002) Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin Oncol 29(6 Suppl 16):3–9CrossRefPubMedGoogle Scholar
  77. 77.
    Jiang BH et al (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(23):5328–5335PubMedGoogle Scholar
  78. 78.
    Ryan HE, Lo J, Johnson RS (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 17(11):3005–3015CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Semela D, Dufour JF (2004) Angiogenesis and hepatocellular carcinoma. J Hepatol 41(5):864–880CrossRefPubMedGoogle Scholar
  80. 80.
    Zhu YJ et al (2017) New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin 38(5):614–622CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Wang W et al (2009) Expression and correlation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor and microvessel density in experimental rat hepatocarcinogenesis. J Int Med Res 37(2):417–425CrossRefPubMedGoogle Scholar
  82. 82.
    Rey S, Semenza GL (2010) Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res 86(2):236–242CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Semenza GL (2007) Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 2007(407):cm8CrossRefPubMedGoogle Scholar
  84. 84.
    Jeong JW et al (2002) Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 111(5):709–720CrossRefPubMedGoogle Scholar
  85. 85.
    Yoshioka Y et al (2012) Micromanaging iron homeostasis: hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins. J Biol Chem 287(41):34110–34119CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Nagaraju GP et al (2015) Hypoxia inducible factor-1alpha: its role in colorectal carcinogenesis and metastasis. Cancer Lett 366(1):11–18CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    el Azzouzi H et al (2013) The hypoxia-inducible microRNA cluster miR-199a approximately 214 targets myocardial PPARdelta and impairs mitochondrial fatty acid oxidation. Cell Metab 18(3):341–354CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  • Inho Choi
    • 1
  • Saipriya Lammata
    • 2
  • Neha Merchant
    • 3
  • Dongkyoo Park
    • 4
    Email author
  1. 1.Department of Pharmaceutical Engineering, College of Life and Health SciencesHoseo UniversityAsanRepublic of Korea
  2. 2.Rice UniversityHoustonUSA
  3. 3.Department of Hematology and Medical Oncology, Winship Cancer InstituteEmory UniversityAtlantaUSA
  4. 4.Department of Radiation Oncology, Winship Cancer InstituteEmory UniversityAtlantaUSA

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