Relevance of Nuclear and Cytoplasmic Von Hippel Lindau Protein Expression for Renal Carcinoma Progression

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2003 Aug 26

PMID 12937142

Citations 10

Authors

Peter Schraml

Alexander Hergovich

Florian Hatz

Mahul B Amin

So D Lim

Wilhelm Krek

Michael J Mihatsch

Holger Moch

Alexander Hergovitz

Affiliations

Soon will be listed here.

Abstract

Alterations of the von Hippel-Lindau tumor-suppressor gene (VHL) on 3p25-p26 are frequent in clear-cell renal-cell carcinoma (RCC). The VHL protein (pVHL) is implicated in cell-cycle control and gene regulation, and requires transcription-dependent nuclear-cytoplasmic trafficking for its function. There are two biologically active VHL protein isoforms: pVHL(30) and pVHL(19). To study prevalence, subcellular expression and biological significance of pVHL in renal tumors, tissue microarrays with renal-cell carcinomas were immunohistochemically examined for pVHL expression. Antibodies against both protein isoforms (anti-pVHL(30)/pVHL(19)) and against pVHL(30) (anti-pVHL(30); Ig33) were used. The anti-pVHL(30)/pVHL(19) antibody showed nuclear and cytoplasmic pVHL expression, whereas the anti-pVHL(30) antibody (Ig33) detected cytoplasmic pVHL expression, suggesting that the distribution of VHL protein isoforms varies in the nuclear and cytoplasmic compartments of renal tumors. There were 175 of 398 primary clear-cell RCCs (44%) with both nuclear and cytoplasmic pVHL expression. Seventy-seven clear-cell RCCs (19%) showed only nuclear, 22 (6%) showed only cytoplasmic, and 124 tumors (31%) showed no pVHL expression. Notably, combined nuclear and cytoplasmic pVHL expression was associated with low histological grade (P < 0.0001), early tumor stage (P < 0.01), and better prognosis (P < 0.01). These results imply that alteration of subcellular pVHL trafficking is of potential relevance for the biological behavior of clear-cell RCC.

Citing Articles

Review of Prognostic Expression Markers for Clear Cell Renal Cell Carcinoma.

Petitprez F, Ayadi M, De Reynies A, Fridman W, Sautes-Fridman C, Job S Front Oncol. 2021; 11:643065.

PMID: 33996558 PMC: 8113694. DOI: 10.3389/fonc.2021.643065.

Expression of von Hippel-Lindau tumor suppressor protein (pVHL) characteristic of tongue cancer and proliferative lesions in tongue epithelium.

Hasegawa H, Kusumi Y, Asakawa T, Maeda M, Oinuma T, Furusaka T BMC Cancer. 2017; 17(1):381.

PMID: 28549422 PMC: 5446680. DOI: 10.1186/s12885-017-3364-8.

Novel interactions of the von Hippel-Lindau (pVHL) tumor suppressor with the CDKN1 family of cell cycle inhibitors.

Minervini G, Lopreiato R, Bortolotto R, Falconieri A, Sartori G, Tosatto S Sci Rep. 2017; 7:46562.

PMID: 28425505 PMC: 5397843. DOI: 10.1038/srep46562.

Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance.

Razafinjatovo C, Bihr S, Mischo A, Vogl U, Schmidinger M, Moch H BMC Cancer. 2016; 16:638.

PMID: 27530247 PMC: 4987997. DOI: 10.1186/s12885-016-2688-0.

Analyses of potential predictive markers and survival data for a response to sunitinib in patients with metastatic renal cell carcinoma.

Dornbusch J, Zacharis A, Meinhardt M, Erdmann K, Wolff I, Froehner M PLoS One. 2013; 8(9):e76386.

PMID: 24086736 PMC: 3785463. DOI: 10.1371/journal.pone.0076386.

References

Los M, Jansen G, Kaelin W, Lips C, Blijham G, Voest E . Expression pattern of the von Hippel-Lindau protein in human tissues. Lab Invest. 1996; 75(2):231-8. View

Velickovic M, Delahunt B, Grebe S . Loss of heterozygosity at 3p14.2 in clear cell renal cell carcinoma is an early event and is highly localized to the FHIT gene locus. Cancer Res. 1999; 59(6):1323-6. View

Iliopoulos O, Ohh M, Kaelin Jr W . pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci U S A. 1998; 95(20):11661-6. PMC: 21697. DOI: 10.1073/pnas.95.20.11661. View

Latif F, Tory K, Gnarra J, Yao M, Duh F, Orcutt M . Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993; 260(5112):1317-20. DOI: 10.1126/science.8493574. View

Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S . Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998; 4(7):844-7. DOI: 10.1038/nm0798-844. View

Schraml P, Struckmann K, Bednar R, Fu W, Gasser T, Wilber K . CDKNA2A mutation analysis, protein expression, and deletion mapping of chromosome 9p in conventional clear-cell renal carcinomas: evidence for a second tumor suppressor gene proximal to CDKN2A. Am J Pathol. 2001; 158(2):593-601. PMC: 1850295. DOI: 10.1016/s0002-9440(10)64001-1. View

Ohh M, Park C, Ivan M, Hoffman M, Kim T, Huang L . Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol. 2000; 2(7):423-7. DOI: 10.1038/35017054. View

Gronwald J, Hadaczek P, Storkel S, Holtgreve-Grez H, Rabbitts P, Cremer T . Molecular evidence for derivation of metastatic cells from minor subclones of primary clear renal cell carcinomas. Cancer Detect Prev. 1999; 23(6):479-84. DOI: 10.1046/j.1525-1500.1999.99056.x. View

Sakashita N, Takeya M, Kishida T, Stackhouse T, Zbar B, Takahashi K . Expression of von Hippel-Lindau protein in normal and pathological human tissues. Histochem J. 1999; 31(2):133-44. DOI: 10.1023/a:1003554712386. View

10.

Lee S, Neumann M, Stearman R, Stauber R, Pause A, Pavlakis G . Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel-Lindau tumor suppressor protein. Mol Cell Biol. 1999; 19(2):1486-97. PMC: 116077. DOI: 10.1128/MCB.19.2.1486. View

11.

Corless C, Kibel A, Iliopoulos O, Kaelin Jr W . Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic human tissues. Hum Pathol. 1997; 28(4):459-64. DOI: 10.1016/s0046-8177(97)90035-6. View

12.

Lisztwan J, Imbert G, Wirbelauer C, Gstaiger M, Krek W . The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev. 1999; 13(14):1822-33. PMC: 316884. DOI: 10.1101/gad.13.14.1822. View

13.

Thoenes W, Storkel S, Rumpelt H . Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics. Pathol Res Pract. 1986; 181(2):125-43. DOI: 10.1016/S0344-0338(86)80001-2. View

14.

Maxwell P, Wiesener M, Chang G, Clifford S, Vaux E, Cockman M . The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999; 399(6733):271-5. DOI: 10.1038/20459. View

15.

Brauch H, Weirich G, Brieger J, Glavac D, Rodl H, Eichinger M . VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Res. 2000; 60(7):1942-8. View

16.

Velickovic M, Delahunt B, Storkel S, Grebem S . VHL and FHIT locus loss of heterozygosity is common in all renal cancer morphotypes but differs in pattern and prognostic significance. Cancer Res. 2001; 61(12):4815-9. View

17.

Tanimoto K, Makino Y, Pereira T, Poellinger L . Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 2000; 19(16):4298-309. PMC: 302039. DOI: 10.1093/emboj/19.16.4298. View

18.

Los M, Zeamari S, Foekens J, Gebbink M, Voest E . Regulation of the urokinase-type plasminogen activator system by the von Hippel-Lindau tumor suppressor gene. Cancer Res. 1999; 59(17):4440-5. View

19.

Gronwald J, Storkel S, Holtgreve-Grez H, Hadaczek P, Brinkschmidt C, Jauch A . Comparison of DNA gains and losses in primary renal clear cell carcinomas and metastatic sites: importance of 1q and 3p copy number changes in metastatic events. Cancer Res. 1997; 57(3):481-7. View

20.

Ye Y, Vasavada S, Kuzmin I, Stackhouse T, Zbar B, Williams B . Subcellular localization of the von Hippel-Lindau disease gene product is cell cycle-dependent. Int J Cancer. 1998; 78(1):62-9. DOI: 10.1002/(sici)1097-0215(19980925)78:1<62::aid-ijc11>3.0.co;2-7. View