Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Technical advance

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

Authors: Hisashi Hasegawa, Yoshiaki Kusumi, Takeshi Asakawa, Miyoko Maeda, Toshinori Oinuma, Tohru Furusaka, Takeshi Oshima, Mariko Esumi

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

Patients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel–Lindau (VHL) tumor suppressor gene. However, expression of VHL protein (pVHL) in tongue cancer has rarely been investigated and remains largely unknown. We performed immunohistochemical staining of pVHL in tongue tissues and dysplasia, and examined the association with LOH and its clinical significance.

Methods

Immunohistochemical staining of pVHL in formalin-fixed, paraffin-embedded sections of cancerous and other tissues from 19 tongue cancer patients showed positivity for LOH of VHL in four samples, negativity in four samples, and was non-informative in 11 samples. The staining pattern of pVHL was also compared with those of cytokeratin (CK) 13 and CK17.

Results

In normal tongue tissues, pVHL staining was localized to the cytoplasm of cells in the basal layer and the area of the spinous layer adjacent to the basal layer of stratified squamous epithelium. Positive staining for pVHL was observed in the cytoplasm of cancer cells from all 19 tongue cancer patients. No differences as a result of the presence or absence of LOH were found. Notably, cytoplasm of poorly differentiated invasive cancer cells was less intensely stained than that of well and moderately differentiated invasive cancer cells. pVHL staining was also evident in epithelial dysplasia lesions with pVHL-positive cells expanding from the basal layer to the middle of the spinous layer. However, no CK13 staining was noted in regions of the epithelium, which were positive for pVHL. In contrast, regions with positive staining for CK17 closely coincided with those positive for pVHL.

Conclusions

Positive staining for pVHL was observed in cancerous areas but not in normal tissues. pVHL expression was also detected in lesions of epithelial dysplasia. These findings suggest that pVHL may be a useful marker for proliferative lesions.
Appendix
Available only for authorised users
Literature
1.
Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011;11(1):9–22.CrossRefPubMed
2.
Blot WJ, McLaughlin JK, Winn DM, Austin DF, Greenberg RS, Preston-Martin S, Bernstein L, Schoenberg JB, Stemhagen A, Fraumeni Jr JF. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988;48(11):3282–7.PubMed
3.
Vargas H, Pitman KT, Johnson JT, Galati LT. More aggressive behavior of squamous cell carcinoma of the anterior tongue in young women. Laryngoscope. 2000;110(10 Pt 1):1623–6.CrossRefPubMed
4.
Scully C, Field J, Tanzawa H. Genetic aberrations in oral or head and neck squamous cell carcinoma 3: clinico-pathological applications. Oral Oncol. 2000;36(5):404–13.CrossRefPubMed
5.
El-Naggar AK, Lai S, Clayman G, Lee J, Luna MA, Goepfert H, Batsakis JG. Methylation, a major mechanism of p16/CDKN2 gene inactivation in head and neck squamous carcinoma. Am J Pathol. 1997;151(6):1767.PubMedPubMedCentral
6.
Nagai MA, Miracca EC, Yamamoto L, Moura RP, Simpson AJ, Kowalski LP, Brentani RR. TP53 genetic alterations in head‐and‐neck carcinomas from Brazil. Int J Cancer. 1998;76(1):13–8.CrossRefPubMed
7.
Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie T-X, Zhang J, Wang J. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154–7.CrossRefPubMedPubMedCentral
8.
Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.CrossRefPubMedPubMedCentral
9.
Gross AM, Orosco RK, Shen JP, Egloff AM, Carter H, Hofree M, Choueiri M, Coffey CS, Lippman SM, Hayes DN. Multi-tiered genomic analysis of head and neck cancer ties TP53 mutation to 3p loss. Nat Genet. 2014;46(9):939–43.CrossRefPubMedPubMedCentral
10.
Asakawa T, Esumi M, Endo S, Kida A, Ikeda M. Tongue cancer patients have a high frequency of allelic loss at the von Hippel-Lindau gene and other loci on 3p. Cancer. 2008;112(3):527–34.CrossRefPubMed
11.
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260(5112):1317–20.CrossRefPubMed
12.
Crossey PA, Foster K, Richards FM, Phipps ME, Latif F, Tory K, Jones MH, Bentley E, Kumar R, Lerman MI, et al. Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours. Hum Genet. 1994;93(1):53–8.CrossRefPubMed
13.
Seizinger BR, Rouleau GA, Ozelius LJ, Lane AH, Farmer GE, Lamiell JM, Haines J, Yuen JW, Collins D, Majoor-Krakauer D, et al. Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature. 1988;332(6161):268–9.CrossRefPubMed
14.
Chino K, Esumi M, Ishida H, Okada K. Characteristic loss of heterozygosity in chromosome 3P and low frequency of replication errors in sporadic renal cell carcinoma. J Urol. 1999;162(2):614–8.CrossRefPubMed
15.
Phillips JL, Pavlovich CP, Walther M, Ried T, Linehan WM. The genetic basis of renal epithelial tumors: advances in research and its impact on prognosis and therapy. Curr Opin Urol. 2001;11(5):463–9.CrossRefPubMed
16.
Zbar B, Klausner R, Linehan WM. Studying cancer families to identify kidney cancer genes. Annu Rev Med. 2003;54:217–33.CrossRefPubMed
17.
Duan DR, Pause A, Burgess WH, Aso T, Chen D, Garrett KP, Conaway RC, Conaway JW, Linehan WM, Klausner RD. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science. 1995;269(5229):1402–6.CrossRefPubMed
18.
Kibel A, Iliopoulos O, DeCaprio JA, Kaelin W. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science. 1995;269(5229):1444–6.CrossRefPubMed
19.
Kishida T, Stackhouse TM, Chen F, Lerman MI, Zbar B. Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations. Cancer Res. 1995;55(20):4544–8.PubMed
20.
Aso T, Lane WS, Conaway JW, Conaway RC. Elongin (SIII): a multisubunit regulator of elongation by RNA polymerase II. Science. 1995;269(5229):1439–43.CrossRefPubMed
21.
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.CrossRefPubMed
22.
Kaelin Jr WG. The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 2007;13(2 Pt 2):680s–4s.CrossRefPubMed
23.
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(3):993–8.CrossRefPubMedPubMedCentral
24.
Sobin L, Wittekind C. International Union Against Cancer (UICC): TNM classification of malignant tumors. 6th ed. New York: Willey–Liss; 2002.
25.
Barnes L, Eveson J, Recichart P, Sidransky D. Pathology and genetics of head and neck tumours. vol. 9. Lyon: IARC; 2005.
26.
Corless CL, Kibel AS, Iliopoulos O, Kaelin WG. Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic human tissues. Hum Pathol. 1997;28(4):459–64.CrossRefPubMed
27.
Mikami T, Cheng J, Maruyama S, Kobayashi T, Funayama A, Yamazaki M, Adeola HA, Wu L, Shingaki S, Saito C, et al. Emergence of keratin 17 vs. loss of keratin 13: their reciprocal immunohistochemical profiles in oral carcinoma in situ. Oral Oncol. 2011;47(6):497–503.CrossRefPubMed
28.
Di Cristofano C, Minervini A, Menicagli M, Salinitri G, Bertacca G, Pefanis G, Masieri L, Lessi F, Collecchi P, Minervini R. Nuclear expression of hypoxia-inducible factor-1α in clear cell renal cell carcinoma is involved in tumor progression. Am J Surg Pathol. 2007;31(12):1875–81.CrossRefPubMed
29.
Zhang S, Zhou X, Wang B, Zhang K, Liu S, Yue K, Zhang L, Wang X. Loss of VHL expression contributes to epithelial-mesenchymal transition in oral squamous cell carcinoma. Oral Oncol. 2014;50(9):809–17.CrossRefPubMed
30.
Nobusawa A, Sano T, Negishi A, Yokoo S, Oyama T. Immunohistochemical staining patterns of cytokeratins 13, 14, and 17 in oral epithelial dysplasia including orthokeratotic dysplasia. Pathol Int. 2014;64(1):20–7.CrossRefPubMed
31.
Jonasch E, Futreal PA, Davis IJ, Bailey ST, Kim WY, Brugarolas J, Giaccia AJ, Kurban G, Pause A, Frydman J. State of the science: an update on renal cell carcinoma. Mol Cancer Res. 2012;10(7):859–80.CrossRefPubMedPubMedCentral
32.
Roland NJ, Caslin AW, Nash J, Stell PM. Value of grading squamous cell carcinoma of the head and neck. Head Neck. 1992;14(3):224–9.CrossRefPubMed
33.
Schraml P, Hergovitz 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;163(3):1013–20.CrossRefPubMedPubMedCentral
Metadata
Title
Expression of von Hippel–Lindau tumor suppressor protein (pVHL) characteristic of tongue cancer and proliferative lesions in tongue epithelium
Authors
Hisashi Hasegawa
Yoshiaki Kusumi
Takeshi Asakawa
Miyoko Maeda
Toshinori Oinuma
Tohru Furusaka
Takeshi Oshima
Mariko Esumi
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3364-8

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Research article

Nomogram prediction of individual prognosis of patients with hepatocellular carcinoma

Review

A comprehensive overview on the surgical management of secondary lymphedema of the upper and lower extremities related to prior oncologic therapies

Research article

High blood glucose levels are associated with higher risk of colon cancer in men: a cohort study

Research article

Programmed cell death ligand 1 cut-point is associated with reduced disease specific survival in resected pancreatic ductal adenocarcinoma

Research article

The correlation between poor prognosis and increased yes-associated protein 1 expression in keratin 19 expressing hepatocellular carcinomas and cholangiocarcinomas

Research article

Chromosomal instability induced by increased BIRC5/Survivin levels affects tumorigenicity of glioma cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits