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Published in: BMC Cancer 1/2009

Open Access 01-12-2009 | Research article

High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression

Authors: Frederikke Lihme Egerod, Annette Bartels, Niels Fristrup, Michael Borre, Torben F Ørntoft, Martin B Oleksiewicz, Nils Brünner, Lars Dyrskjøt

Published in: BMC Cancer | Issue 1/2009

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Abstract

Background

Egr-1 (early growth response-1 transcription factor) has been proposed to be involved in invasion and metastasis processes of human bladder cancer, but Egr-1 protein expression levels in human bladder cancer have not been investigated. In the present study we investigated the expression levels of Egr-1 protein in early stages of human bladder cancer and correlated it to later progression.

Methods

Expression of Egr-1 protein in human bladder cancer was examined by immunohistochemistry, on a tissue microarray constructed from tumors from 289 patients with non-muscle invasive urothelial bladder cancer.

Results

The frequency of tumor cells with nuclear Egr-1 immunolabelling correlated to bladder cancer stage, grade and to later progression to muscle-invasive bladder cancer (T2-4). Stage T1 tumors exhibited significantly higher frequencies of tumor cells with nuclear Egr-1 immunolabelling than Ta tumors (P = 0.001). Furthermore, Kaplan-Meier survival analysis showed that a high frequency of tumor cells with nuclear Egr-1 immunolabelling was significantly associated with a higher risk of progression to stage T2-4 (log-rank test, P = 0.035). Tumor cells with nuclear Egr-1 immunolabelling were found to localize at the tumor front in some of the tumor biopsies.

Conclusion

The results from this study support a potential involvement of Egr-1 in the progression from non-muscle invasive bladder cancers to muscle invasive bladder cancer.
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Literature
1.
go back to reference Ferlay J: Estimates of the worldwide mortality from 25 cancers in 1990. International Journal of Cancer. 1999, 83: 18-29.CrossRefPubMed Ferlay J: Estimates of the worldwide mortality from 25 cancers in 1990. International Journal of Cancer. 1999, 83: 18-29.CrossRefPubMed
2.
go back to reference Dyrskjøt L, Zieger K, Kruhøffer M, Thykjaer T, Jensen JL, Primdahl H, et al: A molecular signature in superficial bladder carcinoma predicts clinical outcome. Clin Cancer Res. 2005, 11: 4029-4036. 10.1158/1078-0432.CCR-04-2095.CrossRefPubMed Dyrskjøt L, Zieger K, Kruhøffer M, Thykjaer T, Jensen JL, Primdahl H, et al: A molecular signature in superficial bladder carcinoma predicts clinical outcome. Clin Cancer Res. 2005, 11: 4029-4036. 10.1158/1078-0432.CCR-04-2095.CrossRefPubMed
3.
go back to reference Barboro P, Rubagotti A, Orecchia P, Spina B, Truini M, Repaci E, et al: Differential proteomic analysis of nuclear matrix in muscle-invasive bladder cancer: potential to improve diagnosis and prognosis. Cell Oncol. 2008, 30: 13-26.PubMedPubMedCentral Barboro P, Rubagotti A, Orecchia P, Spina B, Truini M, Repaci E, et al: Differential proteomic analysis of nuclear matrix in muscle-invasive bladder cancer: potential to improve diagnosis and prognosis. Cell Oncol. 2008, 30: 13-26.PubMedPubMedCentral
4.
go back to reference Mohammed A, Khan Z, Zamora I, Bhatti A: Biological markers in the diagnosis of recurrent bladder cancer: an overview. Expert Rev Mol Diagn. 2008, 8: 63-72. 10.1586/14737159.8.1.63.CrossRefPubMed Mohammed A, Khan Z, Zamora I, Bhatti A: Biological markers in the diagnosis of recurrent bladder cancer: an overview. Expert Rev Mol Diagn. 2008, 8: 63-72. 10.1586/14737159.8.1.63.CrossRefPubMed
5.
go back to reference Pitts WR: Predicting outcome in minimally invasive (T1a and T1b) urothelial bladder cancer using a panel of biomarkers: a high-throughput tissue microarray analysis. BJU Int. 2008, 101: 1595-10.1111/j.1464-410X.2008.07728_1.x.CrossRefPubMed Pitts WR: Predicting outcome in minimally invasive (T1a and T1b) urothelial bladder cancer using a panel of biomarkers: a high-throughput tissue microarray analysis. BJU Int. 2008, 101: 1595-10.1111/j.1464-410X.2008.07728_1.x.CrossRefPubMed
6.
go back to reference Vrooman OP, Witjes JA: Molecular markers for detection, surveillance and prognostication of bladder cancer. Int J Urol. 2009, 16: 234-243. 10.1111/j.1442-2042.2008.02225.x.CrossRefPubMed Vrooman OP, Witjes JA: Molecular markers for detection, surveillance and prognostication of bladder cancer. Int J Urol. 2009, 16: 234-243. 10.1111/j.1442-2042.2008.02225.x.CrossRefPubMed
7.
go back to reference Nutt JE, Foster PA, Mellon JK, Lunec J: hEGR1 is induced by EGF, inhibited by gefitinib in bladder cell lines and related to EGF receptor levels in bladder tumours. Br J Cancer. 2007, 96: 762-768. 10.1038/sj.bjc.6603620.CrossRefPubMedPubMedCentral Nutt JE, Foster PA, Mellon JK, Lunec J: hEGR1 is induced by EGF, inhibited by gefitinib in bladder cell lines and related to EGF receptor levels in bladder tumours. Br J Cancer. 2007, 96: 762-768. 10.1038/sj.bjc.6603620.CrossRefPubMedPubMedCentral
8.
go back to reference Ogishima T, Shiina H, Breault JE, Terashima M, Honda S, Enokida H, et al: Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer. Oncogene. 2005, 24: 6765-6772. 10.1038/sj.onc.1208811.CrossRefPubMed Ogishima T, Shiina H, Breault JE, Terashima M, Honda S, Enokida H, et al: Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer. Oncogene. 2005, 24: 6765-6772. 10.1038/sj.onc.1208811.CrossRefPubMed
9.
go back to reference Lokeshwar VB, Gomez P, Kramer M, Knapp J, McCornack MA, Lopez LE, et al: Epigenetic regulation of HYAL-1 hyaluronidase expression. identification of HYAL-1 promoter. J Biol Chem. 2008, 283: 29215-29227. 10.1074/jbc.M801101200.CrossRefPubMedPubMedCentral Lokeshwar VB, Gomez P, Kramer M, Knapp J, McCornack MA, Lopez LE, et al: Epigenetic regulation of HYAL-1 hyaluronidase expression. identification of HYAL-1 promoter. J Biol Chem. 2008, 283: 29215-29227. 10.1074/jbc.M801101200.CrossRefPubMedPubMedCentral
10.
go back to reference Ogishima T, Shiina H, Breault JE, Tabatabai L, Bassett WW, Enokida H, et al: Increased heparanase expression is caused by promoter hypomethylation and up-regulation of transcriptional factor early growth response-1 in human prostate cancer. Clin Cancer Res. 2005, 11: 1028-1036.PubMed Ogishima T, Shiina H, Breault JE, Tabatabai L, Bassett WW, Enokida H, et al: Increased heparanase expression is caused by promoter hypomethylation and up-regulation of transcriptional factor early growth response-1 in human prostate cancer. Clin Cancer Res. 2005, 11: 1028-1036.PubMed
11.
go back to reference Egerod FL, Nielsen HS, Iversen L, Thorup I, Storgaard T, Oleksiewicz MB: Biomarkers for early effects of carcinogenic dual-acting PPAR agonists in rat urinary bladder urothelium in vivo. Biomarkers. 2005, 10: 295-309. 10.1080/13547500500218682.CrossRefPubMed Egerod FL, Nielsen HS, Iversen L, Thorup I, Storgaard T, Oleksiewicz MB: Biomarkers for early effects of carcinogenic dual-acting PPAR agonists in rat urinary bladder urothelium in vivo. Biomarkers. 2005, 10: 295-309. 10.1080/13547500500218682.CrossRefPubMed
12.
go back to reference Popov Z, Gil-Diez-de-Medina S, Ravery V, Hoznek A, Bastuji-Garin S, Lefrere-Belda M, et al: Prognostic value of EGF receptor and tumor cell proliferation in bladder cancer: therapeutic implications. Urologic oncology. 2004, 22: 93-101.CrossRefPubMed Popov Z, Gil-Diez-de-Medina S, Ravery V, Hoznek A, Bastuji-Garin S, Lefrere-Belda M, et al: Prognostic value of EGF receptor and tumor cell proliferation in bladder cancer: therapeutic implications. Urologic oncology. 2004, 22: 93-101.CrossRefPubMed
13.
go back to reference McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, et al: REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer. 2005, 93: 387-391. 10.1038/sj.bjc.6602678.CrossRefPubMedPubMedCentral McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, et al: REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer. 2005, 93: 387-391. 10.1038/sj.bjc.6602678.CrossRefPubMedPubMedCentral
14.
go back to reference Abdulkadir SA, Qu Z, Garabedian E, Song SK, Peters TJ, Svaren J, et al: Impaired prostate tumorigenesis in Egr1-deficient mice. Nat Med. 2001, 7: 101-107. 10.1038/83231.CrossRefPubMed Abdulkadir SA, Qu Z, Garabedian E, Song SK, Peters TJ, Svaren J, et al: Impaired prostate tumorigenesis in Egr1-deficient mice. Nat Med. 2001, 7: 101-107. 10.1038/83231.CrossRefPubMed
15.
go back to reference Virolle T, Krones-Herzig A, Baron V, De GG, Adamson ED, Mercola D: Egr1 promotes growth and survival of prostate cancer cells. Identification of novel Egr1 target genes. J Biol Chem. 2003, 278: 11802-11810. 10.1074/jbc.M210279200.CrossRefPubMed Virolle T, Krones-Herzig A, Baron V, De GG, Adamson ED, Mercola D: Egr1 promotes growth and survival of prostate cancer cells. Identification of novel Egr1 target genes. J Biol Chem. 2003, 278: 11802-11810. 10.1074/jbc.M210279200.CrossRefPubMed
16.
go back to reference Adamson ED, Mercola D: Egr1 transcription factor: multiple roles in prostate tumor cell growth and survival. Tumour Biol. 2002, 23: 93-102. 10.1159/000059711.CrossRefPubMed Adamson ED, Mercola D: Egr1 transcription factor: multiple roles in prostate tumor cell growth and survival. Tumour Biol. 2002, 23: 93-102. 10.1159/000059711.CrossRefPubMed
17.
go back to reference Eid MA, Kumar MV, Iczkowski KA, Bostwick DG, Tindall DJ: Expression of early growth response genes in human prostate cancer. Cancer Res. 1998, 58: 2461-2468.PubMed Eid MA, Kumar MV, Iczkowski KA, Bostwick DG, Tindall DJ: Expression of early growth response genes in human prostate cancer. Cancer Res. 1998, 58: 2461-2468.PubMed
18.
go back to reference Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S, et al: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998, 4: 844-847. 10.1038/nm0798-844.CrossRefPubMed Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S, et al: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998, 4: 844-847. 10.1038/nm0798-844.CrossRefPubMed
19.
go back to reference Egerod FL, Brünner N, Svendsen JE, Oleksiewicz MB: PPARalpha and PPARgamma are co-expressed, functional and show positive interactions in the rat urinary bladder urothelium. Journal of Applied Toxicology. 2009, Egerod FL, Brünner N, Svendsen JE, Oleksiewicz MB: PPARalpha and PPARgamma are co-expressed, functional and show positive interactions in the rat urinary bladder urothelium. Journal of Applied Toxicology. 2009,
20.
go back to reference Knight C, Slade JP, Carter D: The nuclear, 75 kDa form of early growth response protein-1/nerve growth factor-induced A protein is primarily restricted to LH beta-subunit-expressing cells in rat anterior pituitary. Eur J Endocrinol. 2000, 143: 817-821. 10.1530/eje.0.1430817.CrossRefPubMed Knight C, Slade JP, Carter D: The nuclear, 75 kDa form of early growth response protein-1/nerve growth factor-induced A protein is primarily restricted to LH beta-subunit-expressing cells in rat anterior pituitary. Eur J Endocrinol. 2000, 143: 817-821. 10.1530/eje.0.1430817.CrossRefPubMed
21.
go back to reference Gohji K, Hirano H, Okamoto M, Kitazawa S, Toyoshima M, Dong J, et al: Expression of three extracellular matrix degradative enzymes in bladder cancer. Int J Cancer. 2001, 295-301. 10.1002/1097-0215(20010920)95:5<295::AID-IJC1051>3.0.CO;2-A. Gohji K, Hirano H, Okamoto M, Kitazawa S, Toyoshima M, Dong J, et al: Expression of three extracellular matrix degradative enzymes in bladder cancer. Int J Cancer. 2001, 295-301. 10.1002/1097-0215(20010920)95:5<295::AID-IJC1051>3.0.CO;2-A.
22.
go back to reference Takaoka M, Naomoto Y, Ohkawa T, Uetsuka H, Shirakawa Y, Uno F, et al: Heparanase expression correlates with invasion and poor prognosis in gastric cancers. Lab Invest. 2003, 83: 613-622.CrossRefPubMed Takaoka M, Naomoto Y, Ohkawa T, Uetsuka H, Shirakawa Y, Uno F, et al: Heparanase expression correlates with invasion and poor prognosis in gastric cancers. Lab Invest. 2003, 83: 613-622.CrossRefPubMed
23.
go back to reference Koliopanos A, Friess H, Kleeff J, Shi X, Liao Q, Pecker I, et al: Heparanase expression in primary and metastatic pancreatic cancer. Cancer Res. 2001, 61: 4655-4659.PubMed Koliopanos A, Friess H, Kleeff J, Shi X, Liao Q, Pecker I, et al: Heparanase expression in primary and metastatic pancreatic cancer. Cancer Res. 2001, 61: 4655-4659.PubMed
24.
go back to reference Marchetti D, McQuillan DJ, Spohn WC, Carson DD, Nicolson GL: Neurotrophin stimulation of human melanoma cell invasion: selected enhancement of heparanase activity and heparanase degradation of specific heparan sulfate subpopulations. Cancer Res. 1996, 56: 2856-2863.PubMed Marchetti D, McQuillan DJ, Spohn WC, Carson DD, Nicolson GL: Neurotrophin stimulation of human melanoma cell invasion: selected enhancement of heparanase activity and heparanase degradation of specific heparan sulfate subpopulations. Cancer Res. 1996, 56: 2856-2863.PubMed
25.
go back to reference Kosir MA, Quinn CC, Zukowski KL, Grignon DJ, Ledbetter S: Human prostate carcinoma cells produce extracellular heparanase. J Surg Res. 1997, 67: 98-105. 10.1006/jsre.1996.4976.CrossRefPubMed Kosir MA, Quinn CC, Zukowski KL, Grignon DJ, Ledbetter S: Human prostate carcinoma cells produce extracellular heparanase. J Surg Res. 1997, 67: 98-105. 10.1006/jsre.1996.4976.CrossRefPubMed
26.
go back to reference Kramer MW, Golshani R, Merseburger AS, Knapp J, Garcia A, Hennenlotter J, et al: HYAL-1 Hyaluronidase: A Potential Prognostic Indicator for Progression to Muscle Invasion and Recurrence in Bladder Cancer. European Urology. 2009, Kramer MW, Golshani R, Merseburger AS, Knapp J, Garcia A, Hennenlotter J, et al: HYAL-1 Hyaluronidase: A Potential Prognostic Indicator for Progression to Muscle Invasion and Recurrence in Bladder Cancer. European Urology. 2009,
27.
go back to reference Lokeshwar VB, Cerwinka WH, Isoyama T, Lokeshwar BL: HYAL1 hyaluronidase in prostate cancer: a tumor promoter and suppressor. Cancer Res. 2005, 65: 7782-7789. 10.1158/0008-5472.CAN-04-2805.CrossRefPubMed Lokeshwar VB, Cerwinka WH, Isoyama T, Lokeshwar BL: HYAL1 hyaluronidase in prostate cancer: a tumor promoter and suppressor. Cancer Res. 2005, 65: 7782-7789. 10.1158/0008-5472.CAN-04-2805.CrossRefPubMed
28.
go back to reference Lokeshwar VB, Cerwinka WH, Lokeshwar BL: HYAL1 hyaluronidase: a molecular determinant of bladder tumor growth and invasion. Cancer Res. 2005, 65: 2243-2250. 10.1158/0008-5472.CAN-04-2805.CrossRefPubMed Lokeshwar VB, Cerwinka WH, Lokeshwar BL: HYAL1 hyaluronidase: a molecular determinant of bladder tumor growth and invasion. Cancer Res. 2005, 65: 2243-2250. 10.1158/0008-5472.CAN-04-2805.CrossRefPubMed
29.
go back to reference Lokeshwar VB, Selzer MG: Hyalurondiase: both a tumor promoter and suppressor. Seminars in Cancer Biology. 2008, 18: 281-287. 10.1016/j.semcancer.2008.03.008.CrossRefPubMedPubMedCentral Lokeshwar VB, Selzer MG: Hyalurondiase: both a tumor promoter and suppressor. Seminars in Cancer Biology. 2008, 18: 281-287. 10.1016/j.semcancer.2008.03.008.CrossRefPubMedPubMedCentral
30.
go back to reference Lam T, Nabi G: Potential of urinary biomarkers in early bladder cancer diagnosis. Expert Rev Anticancer Ther. 2007, 7: 1105-1115. 10.1586/14737140.7.8.1105.CrossRefPubMed Lam T, Nabi G: Potential of urinary biomarkers in early bladder cancer diagnosis. Expert Rev Anticancer Ther. 2007, 7: 1105-1115. 10.1586/14737140.7.8.1105.CrossRefPubMed
31.
go back to reference Baron V, De GG, Krones-Herzig A, Virolle T, Calogero A, Urcis R, et al: Inhibition of Egr-1 expression reverses transformation of prostate cancer cells in vitro and in vivo. Oncogene. 2003, 22: 4194-4204. 10.1038/sj.onc.1206560.CrossRefPubMed Baron V, De GG, Krones-Herzig A, Virolle T, Calogero A, Urcis R, et al: Inhibition of Egr-1 expression reverses transformation of prostate cancer cells in vitro and in vivo. Oncogene. 2003, 22: 4194-4204. 10.1038/sj.onc.1206560.CrossRefPubMed
32.
go back to reference Singh A, Kinoshita Y, Rovito PMJ, Landas S, Silberstein J, Nsouli I, et al: Higher than expected association of clinical prostate and bladder cancers. J Urol. 2005, 173: 1526-1529. 10.1097/01.ju.0000154700.80042.c6.CrossRefPubMed Singh A, Kinoshita Y, Rovito PMJ, Landas S, Silberstein J, Nsouli I, et al: Higher than expected association of clinical prostate and bladder cancers. J Urol. 2005, 173: 1526-1529. 10.1097/01.ju.0000154700.80042.c6.CrossRefPubMed
Metadata
Title
High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression
Authors
Frederikke Lihme Egerod
Annette Bartels
Niels Fristrup
Michael Borre
Torben F Ørntoft
Martin B Oleksiewicz
Nils Brünner
Lars Dyrskjøt
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2009
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-9-385

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