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Tumor Biology

, Volume 33, Issue 1, pp 9–16 | Cite as

Role of VHL gene mutation in human renal cell carcinoma

  • Wani Arjumand
  • Sarwat Sultana
Review

Abstract

The Von Hippel–Lindau (VHL) is an inherited neoplasia syndrome caused by the inactivation of VHL tumor suppressor gene, and somatic mutation of this gene has been related to the development of sporadic clear cell renal carcinoma. The affected individuals are at higher risk for the development of tumor in other organs, which include pheochromocytomas, retinal angioma, pancreatic cysts, and CNS hemangioblastomas. The VHL mRNA encodes a protein (pVHL) that contains 213 amino acid residues which migrate with an apparent molecular weight of 24 to 30 kDa. The VHL gene protein has multiple functions that are linked to tumor suppression, but the best recognized and evidently linked to the development of renal cell carcinoma (RCC) is inhibition of hypoxia-inducible factor (HIF), as well as plays a role in targeting HIF for ubiquitin-mediated degradation. Aberrations in VHL's function, either through mutation or promoter hypermethylation, lead to the accumulation of HIF, which will transcriptionally upregulate a sequence of hypoxia responsive genes, including epidermal growth factor, vascular endothelial growth factor, platelet-derived growth factor, and other proangiogenic factors, resulting in upregulated blood vessel growth, one of the prerequisites of a tumor. HIF plays a critical role in pVHL-defective tumor formation, raising the possibility that drugs directed against HIF or its downstream targets (such as vascular endothelial growth factor) may one day play a role in the treatment of RCC. Moreover, a number of drugs have been developed that target HIF-responsive gene products, many of these targeted therapies have demonstrated significant activity in kidney cancer clinical trials and signify substantive advances in the treatment of this disease.

Keywords

Von Hippel–Lindau Hypoxia-inducible factor Renal cell carcinoma Hypoxia response elements Vascular endothelial growth factor 

Notes

Acknowledgment

The authors are thankful to the Indian Council of Medical Research, New Delhi, India, for providing funds.

Conflicts of interest

None.

References

  1. 1.
    Kashyap MK, Kumar A, Emelianenko N, Kashyap A, Kaushik R, Huang R, et al. Biochemical and molecular markers in renal cell carcinoma: an update and future prospects. Biomarkers. 2005;10:258–94.PubMedCrossRefGoogle Scholar
  2. 2.
    Mancuso A, Sternberg CN. New treatments for metastatic kidney cancer. Can J Urol. 2005;12:66.PubMedGoogle Scholar
  3. 3.
    Ljungberg B, Campbell SC, Cho HY, Jacqmin D, Lee JE, Weikert S, et al. The epidemiology of renal cell carcinoma. Eur Urol. 2011;60(4):e29–36.CrossRefGoogle Scholar
  4. 4.
    Lawrence TS, Ten Haken RK, Giaccia A. Principles of radiation oncology. Cancer: principles and practice of oncology. 8th ed. Philadelphia: Williams and Wilkins; 2008.Google Scholar
  5. 5.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.PubMedCrossRefGoogle Scholar
  6. 6.
    Lipworth L, Tarone RE, McLaughlin JK. The epidemiology of renal cell carcinoma. J Urol. 2006;176:2353–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Malvezzi M, Arfé A, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2011. Ann Oncol. 2011;22:947.PubMedCrossRefGoogle Scholar
  8. 8.
    Ferlay J, Shin HR, Bray F, Parkin DM. Globocan 2008 v1. 2, cancer incidence and mortality worldwide: IARC CancerBase no. 10 (internet). International Agency for Research on Cancer, Lyon, France, 2010.Google Scholar
  9. 9.
    Hollenbeak CS, Nikkel LE, Schaefer EW, Alemao E, Ghahramani N, Raman JD. Determinants of medicare all-cause costs among elderly patients with renal cell carcinoma. J Manag Care Pharm. 2011;17:610.PubMedGoogle Scholar
  10. 10.
    Humphreys BD. Genetic tracing of the epithelial lineage during mammalian kidney repair. Kidney Int Suppl. 2011;1:83–6.CrossRefGoogle Scholar
  11. 11.
    Bodmer D, Van Den Hurk W, van Groningen JJM, Eleveld MJ, Martens GJM, Weterman MAJ, et al. Understanding familial and non-familial renal cell cancer. Hum Mol Genet. 2002;11:2489.PubMedCrossRefGoogle Scholar
  12. 12.
    Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010;7:245.PubMedCrossRefGoogle Scholar
  13. 13.
    Nagaprashantha LD, Vatsyayan R, Singhal J, Lelsani P, Prokai L, Awasthi S, et al. 2-Hydroxyflavanone inhibits proliferation, tumor vascularization and promotes normal differentiation in VHL-mutant renal cell carcinoma. Carcinogenesis. 2011;32:568.PubMedCrossRefGoogle Scholar
  14. 14.
    Cowey CL, Rathmell WK. Using molecular biology to develop drugs renal cell carcinoma. Expert Opin Drug Discov. 2008;3:311–27.PubMedCrossRefGoogle Scholar
  15. 15.
    Kaelin WG. The Von Hippel–Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 2007;13:680s.PubMedCrossRefGoogle Scholar
  16. 16.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Eng J Med. 2007;356:115.CrossRefGoogle Scholar
  17. 17.
    Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Eng J Med. 2007;356:125.CrossRefGoogle Scholar
  18. 18.
    Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81.PubMedCrossRefGoogle Scholar
  19. 19.
    Maher ER, Neumann HPH, Richard S. Von Hippel–Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19:617–23.PubMedCrossRefGoogle Scholar
  20. 20.
    Maynard MA, Ohh M. Von Hippel–Lindau tumor suppressor protein and hypoxia-inducible factor in kidney cancer. Am J Nephrol. 2000;24:1–13.CrossRefGoogle Scholar
  21. 21.
    Collins ET. Intra-ocular growths (two cases, brother and sister, with peculiar vascular new growth, probably retinal, affecting both eyes). Trans Ophthal Soc UK. 1894;14:141–9.Google Scholar
  22. 22.
    Ev H. Ueber eine sehr seltene erkrankung der nethaut. Albrecht von Graef Arch Ophthalmol. 1904;59:83–106.CrossRefGoogle Scholar
  23. 23.
    Couch V, Lindor NM, Karnes PS, Michels VV. Von Hippel–Lindau disease. Mayo Clin. 2000;75:265.CrossRefGoogle Scholar
  24. 24.
    Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004;22:4991.PubMedCrossRefGoogle Scholar
  25. 25.
    Cowey CL, Rathmell WK. VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy. Curr Oncol Rep. 2009;11:94–101.PubMedCrossRefGoogle Scholar
  26. 26.
    McNeill A, Rattenberry E, Barber R, Killick P, MacDonald F, Maher ER. Genotype–phenotype correlations in vhl exon deletions. Am J Med Genet A. 2009;149:2147–51.Google Scholar
  27. 27.
    Stolle C, Glenn G, Zbar B, Humphrey JS, Choyke P, Walther MC, et al. Improved detection of germline mutations in the Von Hippel–Lindau disease tumor suppressor gene. Hum Mutat. 1998;12:417–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Linehan WM, Bratslavsky G, Pinto PA, Schmidt LS, Neckers L, Bottaro D, et al. Molecular diagnosis and therapy of kidney cancer. Annu Rev Med. 2010;61:329.PubMedCrossRefGoogle Scholar
  29. 29.
    Wind JJ, Lonser RR. Management of Von Hippel–Lindau disease-associated CNS lesions. Expert Rev Neurother. 2011;11:1433–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Bhattacharjee H, Deka H, Deka S, Barman MJ, Mazumdar M, Medhi J. Verteporfin photodynamic therapy of retinal capillary hemangioblastoma in Von Hippel–Lindau disease. Indian J Ophthalmol. 2010;58:73.PubMedCrossRefGoogle Scholar
  31. 31.
    Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas JM, et al. Pancreatic involvement in Von Hippel–Lindau disease. Gastroenterology. 2000;119:1087–95.PubMedCrossRefGoogle Scholar
  32. 32.
    Schimke RN, Collins DL, Rothberg PG. Functioning carotid paraganglioma in the Von Hippel–Lindau syndrome. Am J Med Genet. 1998;80:533–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Matin SF, Ahrar K, Wood CG, Daniels M, Jonasch E. Patterns of intervention for renal lesions in Von Hippel–Lindau disease. BJU Int. 2008;102:940–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Young AC, Craven RA, Cohen D, Taylor C, Booth C, Harnden P, et al. Analysis of vhl gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma. Clin Cancer Res. 2009;15:7582.PubMedCrossRefGoogle Scholar
  35. 35.
    Kondo K, Yao M, Yoshida M, Kishida T, Shuin T, Miura T, et al. Comprehensive mutational analysis of the vhl gene in sporadic renal cell carcinoma: relationship to clinicopathological parameters. Genes Chromosome Canc. 2002;34:58–68.CrossRefGoogle Scholar
  36. 36.
    Yuen JSP. Molecular targeted therapy in advanced renal cell carcinoma: a review of its recent past and a glimpse into the near future. Indian J Urol. 2009;25:427.PubMedCrossRefGoogle Scholar
  37. 37.
    Ivan M, KaelinJr WG. The Von Hippel–Lindau tumor suppressor protein. Curr Opin Genet Dev. 2001;11:27–34.PubMedCrossRefGoogle Scholar
  38. 38.
    Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W. Regulation of microtubule stability by the Von Hippel–Lindau tumour suppressor protein pvhl. Nat Cell Biol. 2003;5:64–70.PubMedCrossRefGoogle Scholar
  39. 39.
    Okuda H, Hirai S, Takaki Y, Kamada M, Baba M, Sakai N, et al. Direct interaction of the [beta]-domain of VHL tumor suppressor protein with the regulatory domain of atypical pkc isotypes. Biochem Biophys Res Commun. 1999;263:491–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Kamura T, Conrad MN, Yan Q, Conaway RC, Conaway JW. The rbx1 subunit of scf and VHL e3 ubiquitin ligase activates rub1 modification of cullins cdc53 and cul2. Genes Dev. 1999;13:2928.PubMedCrossRefGoogle Scholar
  41. 41.
    Sumara I, Maerki S, Peter M. E3 ubiquitin ligases and mitosis: embracing the complexity. Trends Cell Biol. 2008;18:84–94.PubMedCrossRefGoogle Scholar
  42. 42.
    Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, et al. Hypoxia inducible factor- binding and ubiquitylation by the Von Hippel–Lindau tumor suppressor protein. J Biol Chem. 2000;275:25733.PubMedCrossRefGoogle Scholar
  43. 43.
    Zbar B: VHL family alliance. Basic facts about VHL Accessed 25 Feb 2011.Google Scholar
  44. 44.
    Pause A, Lee S, Lonergan KM, Klausner RD. The Von Hippel–Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci. 1998;95:993.PubMedCrossRefGoogle Scholar
  45. 45.
    Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN, et al. The Von Hippel–Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell. 1998;1:959–68.PubMedCrossRefGoogle Scholar
  46. 46.
    Frew IJ, Krek W. Multitasking by pVHL in tumour suppression. Curr Opin Cell Biol. 2007;19:685–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Roe JS, Youn HD. Extra view the positive regulation of p53 by the tumor suppressor VHL. Cell Cycle. 2006;5:2054–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, et al. Contrasting effects on hif-1 regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in Von Hippel–Lindau disease. Hum Mol Genet. 2001;10:1029.PubMedCrossRefGoogle Scholar
  49. 49.
    Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M, Kaelin Jr WG. Von Hippel–Lindau protein mutants linked to type 2c VHL disease preserve the ability to downregulate hif. Hum Mol Genet. 2001;10:1019.PubMedCrossRefGoogle Scholar
  50. 50.
    Lieubeau-Teillet B, Rak J, Jothy S, Iliopoulos O, Kaelin W, Kerbel RS. Von Hippel–Lindau gene-mediated growth suppression and induction of differentiation in renal cell carcinoma cells grown as multicellular tumor spheroids. Cancer Res. 1998;58:4957.PubMedGoogle Scholar
  51. 51.
    Davidowitz EJ, Schoenfeld AR, Burk RD. VHL induces renal cell differentiation and growth arrest through integration of cell–cell and cell–extracellular matrix signaling. Mol Cell Biol. 2001;21:865.PubMedCrossRefGoogle Scholar
  52. 52.
    Stickle NH, Chung J, Klco JM, Hill RP, Kaelin Jr WG, Ohh M. PVHL modification by nedd8 is required for fibronectin matrix assembly and suppression of tumor development. Mol Cell Biol. 2004;24:3251.PubMedCrossRefGoogle Scholar
  53. 53.
    Kaelin Jr WG. Von Hippel–Lindau disease. Annu Rev Pathol Mech Dis. 2007;2:145–73.CrossRefGoogle Scholar
  54. 54.
    To KKW, Huang LE. Suppression of hypoxia-inducible factor 1 (HIF-1) transcriptional activity by the HIF prolyl hydroxylase EGLN1. J Biol Chem. 2005;280:38102.PubMedCrossRefGoogle Scholar
  55. 55.
    Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1 in normoxia. EMBO J. 2003;22:4082–90.PubMedCrossRefGoogle Scholar
  56. 56.
    Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279:38458.PubMedCrossRefGoogle Scholar
  57. 57.
    Marxsen JH, Stengel P, Doege K, Heikkinen P, Jokilehto T, Wagner T, et al. Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-alpha-prolyl-4-hydroxylases. Biochem J. 2004;381:761.PubMedCrossRefGoogle Scholar
  58. 58.
    Aprelikova O, Chandramouli GVR, Wood M, Vasselli JR, Riss J, Maranchie JK, et al. Regulation of HIF prolyl hydroxylases by hypoxia inducible factors. J Cell Biochem. 2004;92:491–501.PubMedCrossRefGoogle Scholar
  59. 59.
    Haase VH. Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol. 2006;291:F271.PubMedCrossRefGoogle Scholar
  60. 60.
    Kleymenova E, Everitt JI, Pluta L, Portis M, Gnarra JR, Walker CL. Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in VHL knockout mice. Carcinogenesis. 2004;25:309.PubMedCrossRefGoogle Scholar
  61. 61.
    Haase VH, Glickman JN, Socolovsky M, Jaenisch R. Vascular tumors in livers with targeted inactivation of the Von Hippel–Lindau tumor suppressor. Proc Natl Acad Sci. 2001;98:1583.PubMedCrossRefGoogle Scholar
  62. 62.
    Chen L, Uchida K, Endler A, Shibasaki F. Mammalian tumor suppressor int6 specifically targets hypoxia inducible factor 2 for degradation by hypoxia-and pVHL-independent regulation. J Biol Chem. 2007;282:12707.PubMedCrossRefGoogle Scholar
  63. 63.
    Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin Jr WG. Inhibition of HIF is necessary for tumor suppression by the Von Hippel–Lindau protein. Cancer Cell. 2002;1:237–46.PubMedCrossRefGoogle Scholar
  64. 64.
    Li L, Lin X, Shoemaker AR, Albert DH, Fesik SW, Shen Y. Hypoxia-inducible factor-1 inhibition in combination with temozolomide treatment exhibits robust antitumor efficacy in vivo. Clin Cancer Res. 2006;12:4747.PubMedCrossRefGoogle Scholar
  65. 65.
    Wang R, Zhou S, Li S. Cancer therapeutic agents targeting hypoxia-inducible factor-1. Curr Med Chem. 2011;18:3168–89.PubMedCrossRefGoogle Scholar
  66. 66.
    Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin Jr WG. TSC2 regulates VEGF through mTOR-dependent and-independent pathways. Cancer Cell. 2003;4:147–58.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2011

Authors and Affiliations

  1. 1.Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Faculty of ScienceJamia Hamdard (Hamdard University)New DelhiIndia

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