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 1/2013

Open Access 01-12-2013 | Research article

High expression of wee1 is associated with malignancy in vulvar squamous cell carcinoma patients

Authors: Gry Irene Magnussen, Ellen Hellesylt, Jahn M Nesland, Claes G Trope, Vivi Ann Flørenes, Ruth Holm

Published in: BMC Cancer | Issue 1/2013

Login to get access

Abstract

Background

Vulvar squamous cell carcinoma is a cancer form with increasing incidence rate and few treatment options. Wee1 is a central regulator of the G2/M DNA-damage checkpoint, and has in previous studies been described as a prognostic biomarker and a potential target for therapy in other cancer forms.

Methods

In the present study we analyzed the expression of Wee1 in a panel of 297 vulvar tumors by immunohistochemistry. Furthermore, siRNA transfections were carried out in two vulvar cancer cell lines (SW-954 and CAL-39) in order to study the effect on cell cycle distribution (flow cytometry) and proteins (western blot) involved in DNA damage response and apoptosis.

Results

Wee1 kinase is increased in vulvar squamous cell carcinomas, as compared to expression in normal epithelium, and a high Wee1 expression is associated with markers of malignancy, such as lymph node metastasis and poor differentiation. Our in vitro results showed that siRNA mediated Wee1 silencing only led to a modest reduction in viability, when examined in vulvar cancer cell lines. Nonetheless, a marked increase in DNA damages, as assessed by augmented levels of γ-H2AX, was observed in both cell lines in the absence of Wee1.

Conclusions

Our results suggest that Wee1 may be involved in the progression of vulvar carcinomas. Based on our in vitro results, Wee1 is unlikely to function as a target for mono-treatment of these patients.
Appendix
Available only for authorised users
Literature
1.
Judson PL, Habermann EB, Baxter NN, Durham SB, Virnig BA: Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet Gynecol. 2006, 107: 1018-1022. 10.1097/01.AOG.0000210268.57527.a1.CrossRefPubMed
2.
Siegel R, Ward E, Brawley O, Jemal A: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011, 61: 212-236. 10.3322/caac.20121.CrossRefPubMed
3.
Canavan TP, Cohen D: Vulvar cancer. Am Fam Physician. 2002, 66: 1269-1274.PubMed
4.
Jones RW, Baranyai J, Stables S: Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia. Obstet Gynecol. 1997, 90: 448-452. 10.1016/S0029-7844(97)00298-6.CrossRefPubMed
5.
Coulter J, Gleeson N: Local and regional recurrence of vulval cancer: management dilemmas. Best Pract Res Clin Obstet Gynaecol. 2003, 17: 663-681. 10.1016/S1521-6934(03)00050-6.CrossRefPubMed
6.
Kuntz K, O’Connell MJ: The G(2) DNA damage checkpoint: could this ancient regulator be the Achilles heel of cancer?. Cancer Biol Ther. 2009, 8: 1433-1439.CrossRefPubMed
7.
Beck H, Nahse-Kumpf V, Larsen MS, O’Hanlon KA, Patzke S, Holmberg C, Mejlvang J, Groth A, Nielsen O, Syljuasen RG, Sorensen CS: Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption. Mol Cell Biol. 2012, 32: 4226-4236. 10.1128/MCB.00412-12.CrossRefPubMedPubMedCentral
8.
Dominguez-Kelly R, Martin Y, Koundrioukoff S, Tanenbaum ME, Smits VA, Medema RH, Debatisse M, Freire R: Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease. J Cell Biol. 2011, 194: 567-579. 10.1083/jcb.201101047.CrossRefPubMedPubMedCentral
9.
Iorns E, Lord CJ, Grigoriadis A, McDonald S, Fenwick K, Mackay A, Mein CA, Natrajan R, Savage K, Tamber N, Reis-Filho JS, Turner NC, Ashworth A: Integrated functional, gene expression and genomic analysis for the identification of cancer targets. PLoS One. 2009, 4: e5120-10.1371/journal.pone.0005120.CrossRefPubMedPubMedCentral
10.
Magnussen GI, Holm R, Emilsen E, Rosnes AK, Slipicevic A, Florenes VA: High expression of Wee1 is associated with poor disease-free survival in malignant melanoma: potential for targeted therapy. PLoS One. 2012, 7: e38254-10.1371/journal.pone.0038254.CrossRefPubMedPubMedCentral
11.
Mir SE, De Witt Hamer PC, Krawczyk PM, Balaj L, Claes A, Niers JM, Van Tilborg AA, Zwinderman AH, Geerts D, Kaspers GJ, Peter VW, Cloos J, Tannous BA, Wesseling P, Aten JA, Noske DP, Van Noorden CJ, Wurdinger T: In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell. 2010, 18: 244-257. 10.1016/j.ccr.2010.08.011.CrossRefPubMedPubMedCentral
12.
PosthumaDeBoer J, Wurdinger T, Graat HC, van Beusechem VW, Helder MN, van Royen BJ, Kaspers GJ: WEE1 inhibition sensitizes osteosarcoma to radiotherapy. BMC Cancer. 2011, 11: 156-10.1186/1471-2407-11-156.CrossRefPubMedPubMedCentral
13.
Yoshida T, Tanaka S, Mogi A, Shitara Y, Kuwano H: The clinical significance of Cyclin B1 and Wee1 expression in non-small-cell lung cancer. Ann Oncol. 2004, 15: 252-256. 10.1093/annonc/mdh073.CrossRefPubMed
14.
Pecorelli S: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 2009, 105: 103-104. 10.1016/j.ijgo.2009.02.012.CrossRefPubMed
15.
Kleihues PSL: Pathology and genetics of tumors of the breast and female genital organs. 2003, World Health Organization of Tumors: World Health Organization of Tumors, 316-321. IARC Press,
16.
Wang Z, Nesland JM, Suo Z, Trope CG, Holm R: The prognostic value of 14-3-3 isoforms in vulvar squamous cell carcinoma cases: 14-3-3beta and epsilon are independent prognostic factors for these tumors. PLoS One. 2011, 6: e24843-10.1371/journal.pone.0024843.CrossRefPubMedPubMedCentral
17.
Wang Z, Trope CG, Florenes VA, Suo Z, Nesland JM, Holm R: Overexpression of CDC25B, CDC25C and phospho-CDC25C (Ser216) in vulvar squamous cell carcinomas are associated with malignant features and aggressive cancer phenotypes. BMC Cancer. 2010, 10: 233-10.1186/1471-2407-10-233.CrossRefPubMedPubMedCentral
18.
Knopp S, Bjorge T, Nesland JM, Trope C, Holm R: Cyclins D1, D3, E, and A in vulvar carcinoma patients. Gynecol Oncol. 2005, 97: 733-739. 10.1016/j.ygyno.2005.03.025.CrossRefPubMed
19.
Knopp S, Bjorge T, Nesland JM, Trope C, Scheistroen M, Holm R: p16INK4a and p21Waf1/Cip1 expression correlates with clinical outcome in vulvar carcinomas. Gynecol Oncol. 2004, 95: 37-45. 10.1016/j.ygyno.2004.07.026.CrossRefPubMed
20.
Mah LJ, El-Osta A, Karagiannis TC: gammaH2AX: a sensitive molecular marker of DNA damage and repair. Leukemia. 2010, 24: 679-686. 10.1038/leu.2010.6.CrossRefPubMed
21.
Eom M, Han A, Lee MJ, Park KH: Expressional Difference of RHEB, HDAC1, and WEE1 Proteins in the Stromal Tumors of the Breast and Their Significance in Tumorigenesis. Korean J Pathol. 2012, 46: 324-330. 10.4132/KoreanJPathol.2012.46.4.324.CrossRefPubMedPubMedCentral
22.
Bhattacharya A, Schmitz U, Wolkenhauer O, Schonherr M, Raatz Y, Kunz M: Regulation of cell cycle checkpoint kinase WEE1 by miR-195 in malignant melanoma. 2012, Epud: Oncogene
23.
Davies KD, Cable PL, Garrus JE, Sullivan FX, von Carlowitz I, Huerou YL, Wallace E, Woessner RD, Gross S: Chk1 inhibition and Wee1 inhibition combine synergistically to impede cellular proliferation. Cancer Biol Ther. 2011, 12: 788-796. 10.4161/cbt.12.9.17673.CrossRefPubMed
24.
Hashimoto O, Shinkawa M, Torimura T, Nakamura T, Selvendiran K, Sakamoto M, Koga H, Ueno T, Sata M: Cell cycle regulation by the Wee1 inhibitor PD0166285, pyrido [2,3-d] pyimidine, in the B16 mouse melanoma cell line. BMC Cancer. 2006, 6: 292-10.1186/1471-2407-6-292.CrossRefPubMedPubMedCentral
25.
Kreahling JM, Gemmer JY, Reed D, Letson D, Bui M, Altiok S: MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. Mol Cancer Ther. 2012, 11: 174-182. 10.1158/1535-7163.MCT-11-0529.CrossRefPubMed
26.
Sorensen CS, Syljuasen RG: Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res. 2011, 40: 477-486.CrossRefPubMedPubMedCentral
27.
Hermeking H, Benzinger A: 14-3-3 proteins in cell cycle regulation. Semin Cancer Biol. 2006, 16: 183-192. 10.1016/j.semcancer.2006.03.002.CrossRefPubMed
28.
Beck H, Nahse V, Larsen MS, Groth P, Clancy T, Lees M, Jorgensen M, Helleday T, Syljuasen RG, Sorensen CS: Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase. J Cell Biol. 2010, 188: 629-638. 10.1083/jcb.200905059.CrossRefPubMedPubMedCentral
29.
Fung TK, Poon RY: A roller coaster ride with the mitotic cyclins. Semin Cell Dev Biol. 2005, 16: 335-342. 10.1016/j.semcdb.2005.02.014.CrossRefPubMed
30.
Leijen S, Beijnen JH, Schellens JH: Abrogation of the G2 checkpoint by inhibition of Wee-1 kinase results in sensitization of p53-deficient tumor cells to DNA-damaging agents. Curr Clin Pharmacol. 2010, 5: 186-191. 10.2174/157488410791498824.CrossRefPubMed
31.
Rajeshkumar NV, De OE, Ottenhof N, Watters J, Brooks D, Demuth T, Shumway SD, Mizuarai S, Hirai H, Maitra A, Hidalgo M: MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res. 2011, 17: 2799-2806. 10.1158/1078-0432.CCR-10-2580.CrossRefPubMedPubMedCentral
32.
Wang Y, Li J, Booher RN, Kraker A, Lawrence T, Leopold WR, Sun Y: Radiosensitization of p53 mutant cells by PD0166285, a novel G(2) checkpoint abrogator. Cancer Res. 2001, 61: 8211-8217.PubMed
33.
Choschzick M, Hantaredja W, Tennstedt P, Gieseking F, Wolber L, Simon R: Role of TP53 mutations in vulvar carcinomas. Int J Gynecol Pathol. 2011, 30: 497-504. 10.1097/PGP.0b013e3182184c7a.CrossRefPubMed
Metadata
Title
High expression of wee1 is associated with malignancy in vulvar squamous cell carcinoma patients
Authors
Gry Irene Magnussen
Ellen Hellesylt
Jahn M Nesland
Claes G Trope
Vivi Ann Flørenes
Ruth Holm
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-288

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue

Research article

MiR-204 down regulates SIRT1 and reverts SIRT1-induced epithelial-mesenchymal transition, anoikis resistance and invasion in gastric cancer cells

Technical advance

Detection and characterization of classical and “uncommon” exon 19 Epidermal Growth Factor Receptor mutations in lung cancer by pyrosequencing

Research article

Trends of lip, oral cavity and oropharyngeal cancers in Australia 1982–2008: overall good news but with rising rates in the oropharynx

Study protocol

Design of the SHAPE-2 study: the effect of physical activity, in addition to weight loss, on biomarkers of postmenopausal breast cancer risk

Study protocol

Radiotherapy of abdomen with precise renal assessment with SPECT/CT imaging (RAPRASI): design and methodology of a prospective trial to improve the understanding of kidney radiation dose response

Research article

Diagnostic accuracy of diffuse reflectance imaging for early detection of pre-malignant and malignant changes in the oral cavity: a feasibility study
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