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The role of HIF1α in renal cell carcinoma tumorigenesis

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Abstract

The transcription factor HIF1α is implicated in the development of clear cell renal cell carcinoma (ccRCC). Although HIF1α was initially believed to be essential for ccRCC development, recent studies hypothesize an oncogenic role for HIF2α in ccRCC, but a tumor suppressor role for HIF1α [1], leading to uncertainty as to the precise roles of the different HIF transcription factors in this disease. Using evidence available from studies with human ccRCC cell lines, mouse xenografts, murine models of ccRCC, and human ccRCC specimens, we evaluate the roles of HIF1α and HIF2α in the pathogenesis of ccRCC. We present a convergence of clinical and mechanistic data supporting an important role for HIF1α in promoting tumorigenesis in a clinically important and large subset of ccRCC. This indicates that current understanding of the exact roles of HIF1α and HIF2α is incomplete and that further research is required to determine the diverse roles of HIF1α and HIF2α in ccRCC.

Key messages

  • The TRACK mouse ccRCC model with constitutively active HIF1α but not HIF2α expressed in proximal tubules develops RCC.

  • HIF1α protein is expressed in the majority of human ccRCC specimens.

  • Elevated HIF1α in ccRCC correlates with a worse prognosis.

  • Many publications do not support a tumor suppressor role for HIF1α in ccRCC.

  • HIF1α, but not HIF2α, is expressed in some types of cancer stem cells.

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References

  1. Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M, Signoretti S, Kaelin WG (2011) Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov 1:222–235

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Kaelin WG (2007) Von Hippel-Lindau disease. Annu Rev Pathol 2:145–173

    CAS  PubMed  Google Scholar 

  3. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275

    CAS  PubMed  Google Scholar 

  4. Miller F, Kentsis A, Osman R, Pan ZQ (2005) Inactivation of VHL by tumorigenic mutations that disrupt dynamic coupling of the pVHL.hypoxia-inducible transcription factor-1alpha complex. J Biol Chem 280:7985–7996

    CAS  PubMed  Google Scholar 

  5. Rosenberger C, Mandriota S, Jürgensen JS, Wiesener MS, Hörstrup JH, Frei U, Ratcliffe PJ, Maxwell PH, Bachmann S, Eckardt KU (2002) Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol 13:1721–1732

    CAS  PubMed  Google Scholar 

  6. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472

    CAS  PubMed  Google Scholar 

  7. Krieg M, Haas R, Brauch H, Acker T, Flamme I, Plate KH (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 19:5435–5443

    CAS  PubMed  Google Scholar 

  8. Prabhakar NR, Semenza GL (2012) Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev 92:967–1003

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Hsu T (2012) Complex cellular functions of the von Hippel-Lindau tumor suppressor gene: insights from model organisms. Oncogene 31:2247–2257

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Coppin C, Kollmannsberger C, Le L, Porzsolt F, Wilt TJ (2011) Targeted therapy for advanced renal cell cancer (RCC): a Cochrane systematic review of published randomised trials. BJU Int 108:1556–1563

    CAS  PubMed  Google Scholar 

  11. Oladipupo S, Hu S, Kovalski J, Yao J, Santeford A, Sohn RE, Shohet R, Maslov K, Wang LV, Arbeit JM (2011) VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. Proc Natl Acad Sci USA 108:13264–13269

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Hayes DF (2011) Bevacizumab treatment for solid tumors: boon or bust? JAMA 305:506–508

    CAS  PubMed  Google Scholar 

  13. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456

    CAS  PubMed  Google Scholar 

  14. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10:307–318

    PubMed  Google Scholar 

  15. Verheul HM, Salumbides B, Van Erp K, Hammers H, Qian DZ, Sanni T, Atadja P, Pili R (2008) Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 14:3589–3597

    CAS  PubMed  Google Scholar 

  16. Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP, Varela I, Fisher R, McGranahan N, Matthews N, Santos CR et al (2014) Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet 46:225–233

    CAS  PubMed  Google Scholar 

  17. Keith B, Johnson RS, Simon MC (2012) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22

    CAS  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Fu L, Wang G, Shevchuk MM, Nanus DM, Gudas LJ (2013) Activation of HIF2α in kidney proximal tubule cells causes abnormal glycogen deposition but not tumorigenesis. Cancer Res 73:2916–2925

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Fu L, Wang G, Shevchuk MM, Nanus DM, Gudas LJ (2011) Generation of a mouse model of Von Hippel-Lindau kidney disease leading to renal cancers by expression of a constitutively active mutant of HIF1alpha. Cancer Res 71:6848–6856

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Xu K, Ding Q, Fang Z, Zheng J, Gao P, Lu Y, Zhang Y (2010) Silencing of HIF-1alpha suppresses tumorigenicity of renal cell carcinoma through induction of apoptosis. Cancer Gene Ther 17:212–222

    CAS  PubMed  Google Scholar 

  22. Razorenova OV, Castellini L, Colavitti R, Edgington LE, Nicolau M, Huang X, Bedogni B, Mills EM, Bogyo M, Giaccia AJ (2013) The apoptosis repressor with a CARD domain (ARC) is a direct HIF1 target gene and promotes survival and proliferation of VHL deficient renal cancer cells. Mol Cell Biol. doi:10.1128/MCB.00644-12

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  25. Zimmer M, Doucette D, Siddiqui N, Iliopoulos O (2004) Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL-/- tumors. Mol Cancer Res 2:89–95

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ (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 Central  PubMed  Google Scholar 

  28. Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, Greenberg RA, Flaherty KT, Rathmell WK, Keith B et al (2008) HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14:435–446

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Biswas S, Troy H, Leek R, Chung YL, Li JL, Raval RR, Turley H, Gatter K, Pezzella F, Griffiths JR et al (2010) Effects of HIF-1alpha and HIF2alpha on growth and metabolism of clear-cell renal cell carcinoma 786-0 xenografts. J Oncol 2010:757908

    PubMed Central  PubMed  Google Scholar 

  30. Cook JD, Walker CL (2004) The Eker rat: establishing a genetic paradigm linking renal cell carcinoma and uterine leiomyoma. Curr Mol Med 4:813–824

    CAS  PubMed  Google Scholar 

  31. Nanus DM, Walker CL (1997) Experimental models of renal cancer. In: Raghavan D, Scher HI, Leibel SA, Lange P (eds) Principles and practice of genitourinary oncology. Lippincott-Raven, Philadelphia, pp 779–785

    Google Scholar 

  32. Kaelin WG Jr (2009) Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein. Cancer 115:2262–2272

    CAS  PubMed  Google Scholar 

  33. Frew IJ, Thoma CR, Georgiev S, Minola A, Hitz M, Montani M, Moch H, Krek W (2008) pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J 27:1747–1757

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Haase VH, Glickman JN, Socolovsky M, Jaenisch R (2001) Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci USA 98:1583–1588

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Kleymenova E, Everitt JI, Pluta L, Portis M, Gnarra JR, Walker CL (2004) Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice. Carcinogenesis 25:309–315

    CAS  PubMed  Google Scholar 

  36. Rankin EB, Tomaszewski JE, Haase VH (2006) Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res 66:2576–2583

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Thoma CR, Toso A, Gutbrodt KL, Reggi SP, Frew IJ, Schraml P, Hergovich A, Moch H, Meraldi P, Krek W (2009) VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol 11:994–1001

    CAS  PubMed  Google Scholar 

  38. Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C (2013) Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf) 207:565–576

    CAS  Google Scholar 

  39. Kobayashi T, Minowa O, Kuno J, Mitani H, Hino O, Noda T (1999) Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res 59:1206–1211

    CAS  PubMed  Google Scholar 

  40. Onda H, Lueck A, Marks PW, Warren HB, Kwiatkowski DJ (1999) Tsc2(+/−) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J Clin Invest 104:687–695

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Cole AM, Ridgway RA, Derkits SE, Parry L, Barker N, Clevers H, Clarke AR, Sansom OJ (2010) p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium. EMBO Mol Med 2:472–486

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Hammers HJ, Verheul HM, Salumbides B, Sharma R, Rudek M, Jaspers J, Shah P, Ellis L, Shen L, Paesante S et al (2010) Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther 9:1525–1535

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Kedar D, Baker CH, Killion JJ, Dinney CP, Fidler IJ (2002) Blockade of the epidermal growth factor receptor signaling inhibits angiogenesis leading to regression of human renal cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 8:3592–3600

    CAS  PubMed  Google Scholar 

  44. Morais C, Healy H, Johnson DW, Gobe G (2010) Inhibition of nuclear factor kappa B attenuates tumour progression in an animal model of renal cell carcinoma. Nephrol Dial Transplant 25:1462–1474

    CAS  PubMed  Google Scholar 

  45. Touma SE, Goldberg JS, Moench P, Guo X, Tickoo SK, Gudas LJ, Nanus DM (2005) Retinoic acid and the histone deacetylase inhibitor trichostatin a inhibit the proliferation of human renal cell carcinoma in a xenograft tumor model. Clin Cancer Res 11:3558–3566

    CAS  PubMed  Google Scholar 

  46. Yi Y, Mikhaylova O, Mamedova A, Bastola P, Biesiada J, Alshaikh E, Levin L, Sheridan RM, Meller J, Czyzyk-Krzeska MF (2010) von Hippel-Lindau-dependent patterns of RNA polymerase II hydroxylation in human renal clear cell carcinomas. Clin Cancer Res 16:5142–5152

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Semenza GL (2013) Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene 32:4057–4063

    CAS  PubMed  Google Scholar 

  49. Schietke RE, Hackenbeck T, Tran M, Günther R, Klanke B, Warnecke CL, Knaup KX, Shukla D, Rosenberger C, Koesters R et al (2012) Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts. PLoS One 7:e31034

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6:1–6

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Biswas S, Charlesworth PJ, Turner GD, Leek R, Thamboo PT, Campo L, Turley H, Dildey P, Protheroe A, Cranston D et al (2012) CD31 angiogenesis and combined expression of HIF-1α and HIF-2α are prognostic in primary clear-cell renal cell carcinoma (CC-RCC), but HIFα transcriptional products are not: implications for antiangiogenic trials and HIFα biomarker studies in primary CC-RCC. Carcinogenesis 33:1717–1725

    CAS  PubMed  Google Scholar 

  52. Chintala S, Najrana T, Toth K, Cao S, Durrani FA, Pili R, Rustum YM (2012) Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of Hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition. BMC Cancer 12:293

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Nyhan MJ, El Mashad SM, O’Donovan TR, Ahmad S, Collins C, Sweeney P, Rogers E, O’Sullivan GC, McKenna SL (2011) VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin. Cell Oncol (Dordr) 34:225–234

    CAS  Google Scholar 

  54. Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, Shimamura T, Sato-Otsubo A, Nagae G, Suzuki H et al (2013) Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 45:860–867

    CAS  PubMed  Google Scholar 

  55. Di Cristofano C, Minervini A, Menicagli M, Salinitri G, Bertacca G, Pefanis G, Masieri L, Lessi F, Collecchi P, Minervini R et al (2007) Nuclear expression of hypoxia-inducible factor-1alpha in clear cell renal cell carcinoma is involved in tumor progression. Am J Surg Pathol 31:1875–1881

    PubMed  Google Scholar 

  56. Dorević G, Matusan-Ilijas K, Babarović E, Hadzisejdić I, Grahovac M, Grahovac B, Jonjić N (2009) Hypoxia inducible factor-1alpha correlates with vascular endothelial growth factor A and C indicating worse prognosis in clear cell renal cell carcinoma. J Exp Clin Cancer Res 28:40

    PubMed  Google Scholar 

  57. Klatte T, Seligson DB, Riggs SB, Leppert JT, Berkman MK, Kleid MD, Yu H, Kabbinavar FF, Pantuck AJ, Belldegrun AS (2007) Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma. Clin Cancer Res 13:7388–7393

    CAS  PubMed  Google Scholar 

  58. Lidgren A, Hedberg Y, Grankvist K, Rasmuson T, Vasko J, Ljungberg B (2005) The expression of hypoxia-inducible factor 1alpha is a favorable independent prognostic factor in renal cell carcinoma. Clin Cancer Res 11:1129–1135

    CAS  PubMed  Google Scholar 

  59. Lidgren A, Hedberg Y, Grankvist K, Rasmuson T, Bergh A, Ljungberg B (2006) Hypoxia-inducible factor 1alpha expression in renal cell carcinoma analyzed by tissue microarray. Eur Urol 50:1272–1277

    CAS  PubMed  Google Scholar 

  60. Medina Villaamil V, Aparicio Gallego G, Santamarina Caínzos I, Valladares-Ayerbes M, Antón Aparicio LM (2012) Searching for Hif1-α interacting proteins in renal cell carcinoma. Clin Transl Oncol 14:698–708

    CAS  PubMed  Google Scholar 

  61. Schultz L, Chaux A, Albadine R, Hicks J, Kim JJ, De Marzo AM, Allaf ME, Carducci MA, Rodriguez R, Hammers HJ et al (2011) Immunoexpression status and prognostic value of mTOR and hypoxia-induced pathway members in primary and metastatic clear cell renal cell carcinomas. Am J Surg Pathol 35:1549–1556

    PubMed Central  PubMed  Google Scholar 

  62. Kroeger N, Seligson DB, Signoretti S, Yu H, Magyar CE, Huang J, Belldegrun AS, Pantuck AJ (2014) Poor prognosis and advanced clinicopathological features of clear cell renal cell carcinoma (ccRCC) are associated with cytoplasmic subcellular localisation of hypoxia inducible factor-2α. Eur J Cancer. doi:10.1016/j.ejca.2014.01.031

    PubMed  Google Scholar 

  63. Minardi D, Lucarini G, Filosa A, Milanese G, Zizzi A, Di Primio R, Montironi R, Muzzonigro G (2008) Prognostic role of tumor necrosis, microvessel density, vascular endothelial growth factor and hypoxia inducible factor-1alpha in patients with clear cell renal carcinoma after radical nephrectomy in a long term follow-up. Int J Immunopathol Pharmacol 21:447–455

    CAS  PubMed  Google Scholar 

  64. Mylonis I, Sembongi H, Befani C, Liakos P, Siniossoglou S, Simos G (2012) Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression. J Cell Sci 125:3485–3493

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Sun RC, Denko NC (2014) Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 19:285–292

    CAS  PubMed  Google Scholar 

  66. Schödel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR (2011) High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood 117:e207–e217

    PubMed Central  PubMed  Google Scholar 

  67. Network CGAR (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499:43–49

    Google Scholar 

  68. Chen R, Xu M, Hogg RT, Li J, Little B, Gerard RD, Garcia JA (2012) The acetylase/deacetylase couple CREB-binding protein/Sirtuin 1 controls hypoxia-inducible factor 2 signaling. J Biol Chem 287:30800–30811

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Beroukhim R, Brunet JP, Di Napoli A, Mertz KD, Seeley A, Pires MM, Linhart D, Worrell RA, Moch H, Rubin MA et al (2009) Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res 69:4674–4681

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Kim HO, Jo YH, Lee J, Lee SS, Yoon KS (2008) The C1772T genetic polymorphism in human HIF-1alpha gene associates with expression of HIF-1alpha protein in breast cancer. Oncol Rep 20:1181–1187

    CAS  PubMed  Google Scholar 

  71. Lessi F, Mazzanti CM, Tomei S, Di Cristofano C, Minervini A, Menicagli M, Apollo A, Masieri L, Collecchi P, Minervini R et al (2014) VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma. Med Oncol 31:840

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  73. Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN, Schneider JW, Zhang CC, Sadek HA (2010) The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7:380–390

    CAS  PubMed  Google Scholar 

  74. Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, Shima H, Johnson RS, Hirao A, Suematsu M et al (2010) Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7:391–402

    CAS  PubMed  Google Scholar 

  75. Rouault-Pierre K, Lopez-Onieva L, Foster K, Anjos-Afonso F, Lamrissi-Garcia I, Serrano-Sanchez M, Mitter R, Ivanovic Z, de Verneuil H, Gribben J et al (2013) HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell 13:549–563

    CAS  PubMed  Google Scholar 

  76. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY et al (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12:149–162

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Kozak KR, Abbott B, Hankinson O (1997) ARNT-deficient mice and placental differentiation. Dev Biol 191:297–305

    CAS  PubMed  Google Scholar 

  79. Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, Teng SC, Wu KJ (2011) Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell 43:811–822

    CAS  PubMed  Google Scholar 

  80. Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T et al (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140:280–293

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Sebastián C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, Ram O, Truelove J, Guimaraes AR, Toiber D et al (2012) The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151:1185–1199

    PubMed Central  PubMed  Google Scholar 

  82. Wu S, Kasim V, Kano MR, Tanaka S, Ohba S, Miura Y, Miyata K, Liu X, Matsuhashi A, Chung UI et al (2013) Transcription factor YY1 contributes to tumor growth by stabilizing hypoxia factor HIF-1α in a p53-independent manner. Cancer Res 73:1787–1799

    CAS  PubMed  Google Scholar 

  83. Carbonaro M, Escuin D, O’Brate A, Thadani-Mulero M, Giannakakou P (2012) Microtubules regulate hypoxia-inducible factor-1α protein trafficking and activity: implications for taxane therapy. J Biol Chem 287:11859–11869

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Xiang L, Gilkes DM, Chaturvedi P, Luo W, Hu H, Takano N, Liang H, Semenza GL (2013) Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer. J Mol Med (Berl). doi:10.1007/s00109-013-1102-5

    Google Scholar 

  85. Network CGA (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70

    Google Scholar 

  86. Dunkel J, Vaittinen S, Grénman R, Kinnunen I, Irjala H (2013) Prognostic markers in stage I oral cavity squamous cell carcinoma. Laryngoscope 123:2435–2441

    CAS  PubMed  Google Scholar 

  87. Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, Wicha MS (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA 109:2784–2789

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Mazumdar J, O’Brien WT, Johnson RS, LaManna JC, Chavez JC, Klein PS, Simon MC (2010) O2 regulates stem cells through Wnt/β-catenin signalling. Nat Cell Biol 12:1007–1013

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Méndez O, Zavadil J, Esencay M, Lukyanov Y, Santovasi D, Wang SC, Newcomb EW, Zagzag D (2010) Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer 9:133

    PubMed Central  PubMed  Google Scholar 

  90. Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, Engh J, Iwama T, Kunisada T, Kassam AB et al (2009) Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 28:3949–3959

    CAS  PubMed  Google Scholar 

  91. Seidel S, Garvalov BK, Wirta V, von Stechow L, Schänzer A, Meletis K, Wolter M, Sommerlad D, Henze AT, Nistér M et al (2010) A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha. Brain 133:983–995

    PubMed  Google Scholar 

  92. Philip B, Ito K, Moreno-Sánchez R, Ralph SJ (2013) HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis 34:1699–1707

    CAS  PubMed  Google Scholar 

  93. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122:3589–3594

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Onnis B, Fer N, Rapisarda A, Perez VS, Melillo G (2013) Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells. J Clin Invest 123:1615–1629

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Matoba K, Kawanami D, Okada R, Tsukamoto M, Kinoshita J, Ito T, Ishizawa S, Kanazawa Y, Yokota T, Murai N et al (2013) Rho-kinase inhibition prevents the progression of diabetic nephropathy by downregulating hypoxia-inducible factor 1α. Kidney Int 84:545–554

    CAS  PubMed  Google Scholar 

  96. Turcotte S, Desrosiers RR, Béliveau R (2003) HIF-1alpha mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma. J Cell Sci 116:2247–2260

    CAS  PubMed  Google Scholar 

  97. Whelan KA, Schwab LP, Karakashev SV, Franchetti L, Johannes GJ, Seagroves TN, Reginato MJ (2013) The oncogene HER2/neu (ERBB2) requires the hypoxia-inducible factor HIF-1 for mammary tumor growth and anoikis resistance. J Biol Chem 288:15865–15877

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Thomasson M, Hedman H, Ljungberg B, Henriksson R (2012) Gene expression pattern of the epidermal growth factor receptor family and LRIG1 in renal cell carcinoma. BMC Res Notes 5:216

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt MB, Hatziapostolou M, Lim E, Tam WL, Ni M, Chen Y et al (2014) XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature 508:103–107

    CAS  PubMed  Google Scholar 

  100. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283:10892–10903

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Turcotte S, Chan DA, Sutphin PD, Hay MP, Denny WA, Giaccia AJ (2008) A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14:90–102

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Mikhaylova O, Stratton Y, Hall D, Kellner E, Ehmer B, Drew AF, Gallo CA, Plas DR, Biesiada J, Meller J et al (2012) VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma. Cancer Cell 21:532–546

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This was supported by the University of Nottingham (NPM) and by Weill Cornell funds. DM and LF are supported by NCI T32-CA062948. We thank Dr. Paraskevi Giannakakou for critically reading this manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Weill Cornell Medical College (WCMC) of Cornell University, New York, NY, 10065, USA

    Lorraine J. Gudas, Leiping Fu & Denise R. Minton

  2. Division of Hematology and Medical Oncology of the Department of Medicine, Weill Cornell Medical College (WCMC) of Cornell University, New York, NY, 10065, USA

    David M. Nanus

  3. Weill Cornell Meyer Cancer Center, Weill Cornell Medical College (WCMC) of Cornell University, E409, 1300 York Ave, New York, NY, 10065, USA

    Lorraine J. Gudas & David M. Nanus

  4. Weill Cornell Graduate School of Medical Sciences–Pharmacology Program, Weill Cornell Medical College (WCMC) of Cornell University, New York, NY, 10065, USA

    Denise R. Minton

  5. Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, The University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK

    Nigel P. Mongan

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  1. Lorraine J. Gudas
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  2. Leiping Fu
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Correspondence to Lorraine J. Gudas.

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Gudas, L.J., Fu, L., Minton, D.R. et al. The role of HIF1α in renal cell carcinoma tumorigenesis. J Mol Med 92, 825–836 (2014). https://doi.org/10.1007/s00109-014-1180-z

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  • DOI: https://doi.org/10.1007/s00109-014-1180-z

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