VHL protein expression in renal cell carcinoma
Keywords:
VHL gene, VHL Protein, Renal cell carcinoma, immunohistochemistry, clinical relevance
Abstract
Introduction: Various studies have been performed to detect VHL gene mutation in renal cell carcinoma (RCCs) but there is paucity of literature analyzing VHL expression at the protein level. Present study was carried out to analyze VHL protein (pVHL) expression in the tissue of RCCs and its correlation with tumor grade & stage.
Material and methods: Immunohistochemical detection of pVHL was done by using a mouse monoclonal antibody raised against amino acids 54-213 of VHL of human. Statistical analysis was done by using chi-square test and Kruskall Wallis H Test.
Results: 32 patients of renal cell carcinoma were included in the study. pVHL expression was positive in 84.40% cases . Among all pVHL positive cases, combined cytoplasmic and nuclear expression of pVHL was most common (59.0%). Exclusive nuclear expression alone was rare and was noted in only one case. Chromophobe RCC (1 case) was negative for p VHL. Exclusive cytoplasmic pVHL expression was more frequently noticed in low grade tumors.
Conclusion: VHL protein expression and its cytoplasmic and nuclear distribution is of potential relevance for the diagnosis and biological behavior of RCCs. Combined nuclear and cytoplasmic expression of VHL protein is more frequently seen in low grade and early stage of renal cell carcinomas.
Downloads
Download data is not yet available.
References
1. Belldegrum A, deKernion JB. 1998. Renal tumors. In: Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ, editors. Campbell’s urology Seventh Ed. Philadelphia: W.B. Saunders. p 2283–326. [PubMed]
2. Iliopoulos O, Eng C. Genetic and clinical aspects of familial renal neoplasms. Semin Oncol. 2000 Apr; 27(2):138-49. [PubMed]
3. Rohan SM, Xiao Y, Liang Y, Dudas ME, Al-Ahmadie HA, Fine SW, Gopalan A, Reuter VE, Rosenblum MK, Russo P, Tickoo SK. Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins. Mod Pathol. 2011 Sep; 24(9):1207-20. doi: 10.1038/modpathol.2011.80. Epub 2011 May 20.
4. Giménez-Bachs JM, Salinas-Sánchez AS, Sánchez-Sánchez F, Lorenzo-Romero JG, Donate-Moreno MJ, Pastor-Navarro H, García-Olmo DC, Escribano-Martínez J, Virseda-Rodríguez JA. Determination of vhl gene mutations in sporadic renal cell carcinoma. Eur Urol. 2006 Jun; 49(6):1051-7. Epub 2005 Dec 20.
5. Duan DR1, Humphrey JS, Chen DY, Weng Y, Sukegawa J, Lee S, Gnarra JR, Linehan WM, Klausner RD. Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations. Proc Natl Acad Sci U S A. 1995 Jul 3; 92(14):6459-63.
6. Turner KJ, Moore JW, Jones A, Taylor CF, Cuthbert-Heavens D, Han C, Leek RD, Gatter KC, Maxwell PH, Ratcliffe PJ, Cranston D, Harris AL. Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. Cancer Res. 2002 May 15; 62(10):2957-61.
7. Linehan WM, Rubin JS, Bottaro DP. VHL loss of function and its impact on oncogenic signaling networks in clear cell renal cell carcinoma. Int J Biochem Cell Biol. 2009 Apr; 41(4):753-6. doi: 10.1016/j.biocel.2008.09.024. Epub 2008 Oct 2. [PubMed]
8. Kenck C, Wilhelm M, Bugert P, Staehler G, Kovacs G. Mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinomas. J Pathol. 1996 Jun; 179(2):157-61.
9. Corless CL, Kibel AS, Iliopoulos O, Kaelin WG Jr. Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic human tissues. Hum Pathol. 1997 Apr; 28(4):459-64. [PubMed]
10. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982 Oct; 6(7):655-63. [PubMed]
11. Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89.
12. Lin F, Shi J, Liu H, Zhang J, Zhang PL, Wang HL, Yang XJ, Schuerch C. Immunohistochemical detection of the von Hippel-Lindau gene product (pVHL) in human tissues and tumors: auseful marker for metastatic renal cell carcinoma and clear cell carcinoma of the ovary and uterus. Am J Clin Pathol. 2008 Apr; 129(4):592-605. doi: 10.1309/Q0FLUXFJ4FTTW1X.
13. Kessler PM, Vasavada SP, Rackley RR, Stackhouse T, Duh FM, Latif F, Lerman MI, Zbar B, Williams BR. Expression of the Von Hippel-Lindau tumor suppressor gene, VHL, in human fetal kidney and during mouse embryogenesis. Mol Med. 1995 May; 1(4):457-66.
14. Blankenship C, Naglich JG, Whaley JM, Seizinger B, Kley N. Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene. 1999 Feb 25; 18(8):1529-35.
15. Schoenfeld A, Davidowitz EJ, Burk RD. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A. 1998 Jul 21; 95(15):8817-22.
16. Schraml P, Struckmann K, Hatz F, Sonnet S, Kully C, Gasser T, Sauter G, Mihatsch MJ, Moch H. VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis inclear cell renal cell carcinoma. J Pathol. 2002 Feb; 196(2):186-93. [PubMed]
17. Schraml P, Hergovich A, Hatz F, Amin MB, Lim SD, Krek W, Mihatsch MJ, Moch H. Relevance of nuclear and cytoplasmic von hippel lindau protein expression for renal carcinoma progression. Am J Pathol. 2003 Sep; 163(3):1013-20. [PubMed]
18. Shmueli MD, Schnaider L, Rosenblum D, Herzog G, Gazit E, Segal D. Structural insights into the folding defects of oncogenic pVHL lead to correction of its function in vitro. PLoS One. 2013 Jun 20; 8(6):e66333. doi: 10.1371/journal.pone.0066333. Print 2013. [PubMed]
10. Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996 Oct 1; 93(20):10595-9. [PubMed]
20. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000 Jul; 2(7):423-7.
21. Ye Y, Vasavada S, Kuzmin I, Stackhouse T, Zbar B, Williams BR. Subcellular localization of the von Hippel-Lindau disease gene product is cell cycle-dependent. Int J Cancer. 1998 Sep 25; 78(1):62-9. [PubMed]
22. Lee S, Chen DY, Humphrey JS, Gnarra JR, Linehan WM, Klausner RD. Nuclear/cytoplasmic localization of the von Hippel-Lindau tumor suppressor gene product is determined by cell density. Proc Natl Acad Sci U S A. 1996 Mar 5; 93(5):1770-5.
2. Iliopoulos O, Eng C. Genetic and clinical aspects of familial renal neoplasms. Semin Oncol. 2000 Apr; 27(2):138-49. [PubMed]
3. Rohan SM, Xiao Y, Liang Y, Dudas ME, Al-Ahmadie HA, Fine SW, Gopalan A, Reuter VE, Rosenblum MK, Russo P, Tickoo SK. Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins. Mod Pathol. 2011 Sep; 24(9):1207-20. doi: 10.1038/modpathol.2011.80. Epub 2011 May 20.
4. Giménez-Bachs JM, Salinas-Sánchez AS, Sánchez-Sánchez F, Lorenzo-Romero JG, Donate-Moreno MJ, Pastor-Navarro H, García-Olmo DC, Escribano-Martínez J, Virseda-Rodríguez JA. Determination of vhl gene mutations in sporadic renal cell carcinoma. Eur Urol. 2006 Jun; 49(6):1051-7. Epub 2005 Dec 20.
5. Duan DR1, Humphrey JS, Chen DY, Weng Y, Sukegawa J, Lee S, Gnarra JR, Linehan WM, Klausner RD. Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations. Proc Natl Acad Sci U S A. 1995 Jul 3; 92(14):6459-63.
6. Turner KJ, Moore JW, Jones A, Taylor CF, Cuthbert-Heavens D, Han C, Leek RD, Gatter KC, Maxwell PH, Ratcliffe PJ, Cranston D, Harris AL. Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. Cancer Res. 2002 May 15; 62(10):2957-61.
7. Linehan WM, Rubin JS, Bottaro DP. VHL loss of function and its impact on oncogenic signaling networks in clear cell renal cell carcinoma. Int J Biochem Cell Biol. 2009 Apr; 41(4):753-6. doi: 10.1016/j.biocel.2008.09.024. Epub 2008 Oct 2. [PubMed]
8. Kenck C, Wilhelm M, Bugert P, Staehler G, Kovacs G. Mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinomas. J Pathol. 1996 Jun; 179(2):157-61.
9. Corless CL, Kibel AS, Iliopoulos O, Kaelin WG Jr. Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic human tissues. Hum Pathol. 1997 Apr; 28(4):459-64. [PubMed]
10. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982 Oct; 6(7):655-63. [PubMed]
11. Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89.
12. Lin F, Shi J, Liu H, Zhang J, Zhang PL, Wang HL, Yang XJ, Schuerch C. Immunohistochemical detection of the von Hippel-Lindau gene product (pVHL) in human tissues and tumors: auseful marker for metastatic renal cell carcinoma and clear cell carcinoma of the ovary and uterus. Am J Clin Pathol. 2008 Apr; 129(4):592-605. doi: 10.1309/Q0FLUXFJ4FTTW1X.
13. Kessler PM, Vasavada SP, Rackley RR, Stackhouse T, Duh FM, Latif F, Lerman MI, Zbar B, Williams BR. Expression of the Von Hippel-Lindau tumor suppressor gene, VHL, in human fetal kidney and during mouse embryogenesis. Mol Med. 1995 May; 1(4):457-66.
14. Blankenship C, Naglich JG, Whaley JM, Seizinger B, Kley N. Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene. 1999 Feb 25; 18(8):1529-35.
15. Schoenfeld A, Davidowitz EJ, Burk RD. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A. 1998 Jul 21; 95(15):8817-22.
16. Schraml P, Struckmann K, Hatz F, Sonnet S, Kully C, Gasser T, Sauter G, Mihatsch MJ, Moch H. VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis inclear cell renal cell carcinoma. J Pathol. 2002 Feb; 196(2):186-93. [PubMed]
17. Schraml P, Hergovich A, Hatz F, Amin MB, Lim SD, Krek W, Mihatsch MJ, Moch H. Relevance of nuclear and cytoplasmic von hippel lindau protein expression for renal carcinoma progression. Am J Pathol. 2003 Sep; 163(3):1013-20. [PubMed]
18. Shmueli MD, Schnaider L, Rosenblum D, Herzog G, Gazit E, Segal D. Structural insights into the folding defects of oncogenic pVHL lead to correction of its function in vitro. PLoS One. 2013 Jun 20; 8(6):e66333. doi: 10.1371/journal.pone.0066333. Print 2013. [PubMed]
10. Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996 Oct 1; 93(20):10595-9. [PubMed]
20. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000 Jul; 2(7):423-7.
21. Ye Y, Vasavada S, Kuzmin I, Stackhouse T, Zbar B, Williams BR. Subcellular localization of the von Hippel-Lindau disease gene product is cell cycle-dependent. Int J Cancer. 1998 Sep 25; 78(1):62-9. [PubMed]
22. Lee S, Chen DY, Humphrey JS, Gnarra JR, Linehan WM, Klausner RD. Nuclear/cytoplasmic localization of the von Hippel-Lindau tumor suppressor gene product is determined by cell density. Proc Natl Acad Sci U S A. 1996 Mar 5; 93(5):1770-5.
CITATION
DOI: 10.17511/ijmrr.2016.i01.013
Published: 2016-01-31
How to Cite
1.
Yadav R, Sagar M, Kumari M, Singhai A, Babu S, Kumar A. VHL protein expression in renal cell carcinoma. Int J Med Res Rev [Internet]. 2016Jan.31 [cited 2024Dec.23];4(1):83-9. Available from: https://ijmrr.medresearch.in/index.php/ijmrr/article/view/437
Section
Original Article
OAI - Open Archives Initiative
