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Open Access 01-12-2011 | Research

Decreased levels of serum glutathione peroxidase 3 are associated with papillary serous ovarian cancer and disease progression

Authors: Deep Agnani, Olga Camacho-Vanegas, Catalina Camacho, Shashi Lele, Kunle Odunsi, Samantha Cohen, Peter Dottino, John A Martignetti

Published in: Journal of Ovarian Research | Issue 1/2011

Abstract

Background

Glutathione peroxidase 3 (GPX3) is a selenocysteine-containing antioxidant enzyme that reacts with hydrogen peroxide and soluble fatty acid hydroperoxides, thereby helping to maintain redox balance within cells. Serum levels of GPX3 have been found to be reduced in various cancers including prostrate, thyroid, colorectal, breast and gastric cancers. Intriguingly, GPX3 has been reported to be upregulated in clear cell ovarian cancer tissues and thus may have implications in chemotherapeutic resistance. Since clear cell and serous subtypes of ovarian cancer represent two distinct disease entities, the aim of this study was to determine GPX3 levels in serous ovarian cancer patients and establish its potential as a biomarker for detection and/or surveillance of papillary serous ovarian cancer, the most frequent form of ovarian tumors in women.

Patients and Methods

Serum was obtained from 66 patients (median age: 62 years, range: 22-89) prior to surgery and 65 controls with a comparable age-range (median age: 53 years, range: 25-83). ELISA was used to determine the levels of serum GPX3. The Mann Whitney U test was performed to determine statistical significance between the levels of serum GPX3 in patients and controls.

Results

Serum levels of GPX3 were found to be significantly lower in patients than controls (p = 1 × 10^-2). Furthermore, this was found to be dependent on the stage of disease. While levels in early stage (I/II) patients showed no significant difference when compared to controls, there was a significant reduction in late stage (III/IV, p = 9 × 10^-4) and recurrent (p = 1 × 10^-2) patients. There was a statistically significant reduction in levels of GPX3 between early and late stage (p = 5 × 10^-4) as well as early and recurrent (p = 1 × 10^-2) patients. Comparison of women and controls stratified to include only women at or above 50 years of age shows that the same trends were maintained and the differences became more statistically significant.

Conclusions

Serum GPX3 levels are decreased in women with papillary serous ovarian cancer in a stage-dependent manner and also decreased in women with disease recurrence. Whether this decrease represents a general feature in response to the disease or a link to the progression of the cancer is unknown. Understanding this relationship may have clinical and therapeutic consequences for women with papillary serous adenocarcinoma.

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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global Cancer statistics. CA Cancer J Clin 2011, 61: 69–90. 10.3322/caac.20107PubMedCrossRef

Ovarian Cancer Home Page-National Cancer Institute [http://www.cancer.gov/cancertopics/types/ovarian]

Kim YM, Whang DH, Park J, Kim SH, Lee SW, Park HA, Ha M, Choi KH: Evaluation of the accuracy of serum human epididymis protein 4 in combination with CA125 for detecting ovarian cancer: a prospective case-control study in a Korean population. Clin Chem Lab Med 2011, 49: 527–534. 10.1515/CCLM.2011.085PubMed

Zhu CS, Pinsky PF, Cramer DW, Ransohoff DF, Hartge P, Pfeiffer RM, Urban N, Mor G, Bast RC Jr, Moore LE, Lokshin AE, McIntosh MW, Skates SJ, Vitonis A, Zhang Z, Ward DC, Symanowski JT, Lomakin A, Fung ET, Sluss PM, Scholler N, Lu KH, Marrangoni AM, Patriotis C, Srivastava S, Buys SS, Berg CD, PLCO Project Team: A Framework for evaluating biomarkers for early detection: validation of biomarker panels for ovarian cancer. Cancer Prev Res (Phila) 2011, 4: 375–383. 10.1158/1940-6207.CAPR-10-0193CrossRef

Cramer DW, Bast RC Jr, Berg CD, Diamandis EP, Godwin AK, Hartge P, Lokshin AE, Lu KH, McIntosh MW, Mor G, Patriotis C, Pinsky PF, Thornquist MD, Scholler N, Skates SJ, Sluss PM, Srivastava S, Ward DC, Zhang Z, Zhu CS, Urban N: Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens. Cancer Prev Res (Phila) 2011, 4: 365–374. 10.1158/1940-6207.CAPR-10-0195CrossRef

Mai PL, Wentzensen N, Greene MH: Challenges related to developing serum-based biomarkers for early ovarian cancer detection. Cancer Prev Res (Phila) 2011, 4: 303–306. 10.1158/1940-6207.CAPR-11-0053CrossRef

Petricoin EF, Ardekani AM, Hitt BA, et al.: Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002, 359: 572–577. 10.1016/S0140-6736(02)07746-2PubMedCrossRef

Zhang Z, Bast RC Jr, Yu Y, Li J, Sokoll LJ, Rai AJ, Rosenzweig JM, Cameron B, Wang YY, Meng XY, Berchuck A, Van Haaften-Day C, Hacker NF, de Bruijn HW, van der Zee AG, Jacobs IJ, Fung ET, Chan DW: Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 2004, 64: 5882–5890. 10.1158/0008-5472.CAN-04-0746PubMedCrossRef

Gorelik E, Landsittel DP, Marrangoni AM, Modugno F, Velikokhatnaya L, Winans MT, Bigbee WL, Herberman RB, Lokshin AE: Multiplexed immunobead-based cytokine profiling for early detection of ovarian cancer. Cancer Epidemiol Biomarkers Prev 2005, 14: 981–987. 10.1158/1055-9965.EPI-04-0404PubMedCrossRef

10.

Visintin I, Feng Z, Longton G, Ward DC, Alvero AB, Lai Y, Tenthorey J, Leiser A, Flores-Saaib R, Yu H, Azori M, Rutherford T, Schwartz PE, Mor G: Diagnostic markers for early detection of ovarian cancer. Clin Cancer Res 2008, 14: 1065–1072. 10.1158/1078-0432.CCR-07-1569PubMedCrossRef

11.

Zhang Z, Chan DW: The road from discovery to clinical diagnostics: lessons learned from the first FDA-cleared in vitro diagnostic multivariate index assay of proteomic biomarkers. Cancer Epidemiol Biomarkers Prev 2010, 19: 2995–2999. 10.1158/1055-9965.EPI-10-0580PubMedCrossRef

12.

Azad MB, Chen Y, Gibson SB: Regulation of autophagy by reactive oxygen species (ROS): Implications for cancer progression and treatment. Antioxid Redox Signal 2009, 11: 777–790. 10.1089/ars.2008.2270PubMedCrossRef

13.

Pelicano H, Carney D, Huang P: ROS stress in cancer cells and therapeutic implications. Drug Resist Updat 2004, 7: 97–110. 10.1016/j.drup.2004.01.004PubMedCrossRef

14.

Harris AL: Hypoxia-A key regulatory factor in tumor growth. Nat Rev Cancer 2002, 2: 38–47. 10.1038/nrc704PubMedCrossRef

15.

Tertil M, Jozkowicz A, Dulak J: Oxidative stress in tumor angiogenesis-therapeutic targets. Curr Pharm Des 2010, 16: 3877–3894. 10.2174/138161210794454969PubMedCrossRef

16.

Avni R, Cohen B, Neeman M: Hypoxic stress and cancer: imaging the axis of evil in tumor metastasis. NMR Biomed 2011, in press.

17.

Brigelius-Flohé R, Kipp A: Glutathione peroxidases in different stages of carcinogenesis. Biochim Biophys Acta 2009, 1790: 1555–1568.PubMedCrossRef

18.

Pawłowicz Z, Zachara BA, Trafikowska U, Maciag A, Marchaluk E, Nowicki A: Blood selenium concentrations and glutathione peroxidase activities in patients with breast cancer and with advanced gastrointestinal cancer. J Trace Elem Electrolytes Health Dis 1991, 5: 275–277.PubMed

19.

Falck E, Karlsson S, Carlsson J, Helenius G, Karlsson M, Klinga-Levan K: Loss of glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma. Cancer Cell Int 2010, 10: 46–54. 10.1186/1475-2867-10-46PubMedCentralPubMedCrossRef

20.

Sreekanthreddy P, Srinivasan H, Kumar DM, Nijaguna MB, Sridevi S, Vrinda M, Arivazhagan A, Balasubramaniam A, Hegde AS, Chandramouli BA, Santosh V, Rao MR, Kondaiah P, Somasundaram K: Identification of potential serum biomarkers of glioblastoma: serum osteopontin levels correlate with poor prognosis. Cancer Epidemiol Biomarkers Prev 2010, 19: 1409–1422. 10.1158/1055-9965.EPI-09-1077PubMedCrossRef

21.

He Y, Wang Y, Li P, Zhu S, Wang J, Zhang S: Identification of GPX3 epigenetically silenced by CpG methylation in human esophageal squamous cell carcinoma. Dig Dis Sci 2011, 56: 681–688. 10.1007/s10620-010-1369-0PubMedCrossRef

22.

Lodygin D, Epanchintsev A, Menssen A, Diebold J, Hermeking H: Functional epigenomics identifies genes frequently silenced in prostate cancer. Cancer Res 2005, 15: 4218–4227.CrossRef

23.

Yu YP, Yu G, Tseng G, Cieply K, Nelson J, Defrances M, Zarnegar R, Michalopoulos G, Luo JH: Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis. Cancer Res 2007, 67: 8043–8050. 10.1158/0008-5472.CAN-07-0648PubMedCrossRef

24.

Lee HJ, Do JH, Bae S, Yang S, Zhang X, Lee A, Choi YJ, Park DC, Ahn WS: Immunohistochemical evidence for the over-expression of glutathione peroxidase 3 in clear cell type ovarian adenocarcinoma. Med Oncol 2010, in press.

25.

Saga Y, Ohwada M, Suzuki M, Konno R, Kigawa J, Ueno S, Mano H: Glutathione peroxidase 3 is a candidate mechanism of anticancer drug resistance of ovarian clear cell adenocarcinoma. Oncol Rep 2008, 20: 1299–1303.PubMed

26.

Hough CD, Cho KR, Zonderman AB, Schwartz DR, Morin PJ: Coordinately up-regulated genes in ovarian cancer. Cancer Res 2001, 61: 3869–3876.PubMed

27.

Kuk C, Kulasingam V, Gunawardana CG, Smith CR, Batruch I, Diamandis EP: Mining the Ovarian Cancer Ascites Proteome for Potential Ovarian Cancer Biomarkers. Mol Cell Proteomics 2009, 8: 661–9. 10.1074/mcp.M800313-MCP200PubMedCentralPubMedCrossRef

28.

Sarto C, Frutiger S, Cappellano F, Sanchez JC, Doro G, Catanzaro F, Hughes GJ, Hochstrasser DF, Mocarelli P: Modified expression of plasma glutathione peroxidase and manganese superoxide dismutase in human renal cell carcinoma. Electrophoresis 1999, 20: 3458–3466. 10.1002/(SICI)1522-2683(19991101)20:17<3458::AID-ELPS3458>3.0.CO;2-5PubMedCrossRef

29.

Howie AF, Walker SW, Akesson B, Arthur JR, Beckett GJ: Thyroidal extracellular glutathione peroxidase: a potential regulator of thyroid-hormone synthesis. Biochem J 1995, 308: 713–717.PubMedCentralPubMed

30.

Manzanares W, Biestro A, Galusso F, Torre MH, Mañay N, Pittini G, Facchin G, Hardy G: Serum selenium and glutathione peroxidase-3 activity: biomarkers of systemic inflammation in the critically ill? Intensive Care Med 2009, 35: 882–889. 10.1007/s00134-008-1356-5PubMedCrossRef

31.

Ye He Y, Wang Y, Li P, Zhu S, Wang J, Zhang S: Identification of GPX3 epigenetically silenced by CpG methylation in human esophageal squamous cell carcinoma. Dig Dis Sci 2011, 56: 681–8. 10.1007/s10620-010-1369-0CrossRef

32.

Zhang X, Yang JJ, Kim YS, Kim KY, Ahn WS, Yang S: An 8-gene signature, including methylated and down-regulated glutathione peroxidase 3, of gastric cancer. Int J Oncol 2010, 36: 405–14.PubMed

33.

Schmutzler C, Mentrup B, Schomburg L, Hoang-Vu C, Herzog V, Köhrle J: Selenoproteins of the thyroid gland: expression, localization and possible function of glutathione peroxidase 3. Biol Chem 2007, 388: 1053–1059. 10.1515/BC.2007.122PubMedCrossRef

34.

Fevre-Montange M, Champier J, Durand A, Wierinckx A, Honnorat J, Guyotat J, Jouvet A: Microarray gene expression profiling in meningiomas: differential expression according to grade or histopathological subtype. Int J Oncol 2009, 35: 1395–4077.PubMedCrossRef

35.

Zachara BA, Marchaluk-Wisniewska E, Maciaq A, Peplinski J, Skokowski J, et al.: Decreased selenium concentration and glutathione peroxidase activity in blood and increase of these parameters in malignant tissue of lung cancer patients. Lung 1997, 175: 321–332. 10.1007/PL00007578PubMedCrossRef

36.

Lee OJ, Schneider-Stock R, McChesney PA, Kuester D, Roessner A, Vieth M, Moskaluk CA, El-Rifai W: Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis. Neoplasia 2005, 7: 854–61. 10.1593/neo.05328PubMedCentralPubMedCrossRef

37.

Chatterji B, Borlak J: A 2-DE MALDI-TOF study to identify disease regulated serum proteins in lung cancer of c-myc transgenic mice. Proteomics 2009, 9: 1044–1056. 10.1002/pmic.200701135PubMedCrossRef

38.

Fan Y, Murphy TB, Byrne JC, Brennan L, Fitzpatrick JM, Watson RWG: Applying Random Forests To Identify Biomarker Panels in Serum 2D-DIGE Data for the Detection and Staging of Prostate Cancer. J Proteome Res 2011, 10: 1361–1373. 10.1021/pr1011069PubMedCrossRef

Title: Decreased levels of serum glutathione peroxidase 3 are associated with papillary serous ovarian cancer and disease progression
Authors: Deep Agnani
Olga Camacho-Vanegas
Catalina Camacho
Shashi Lele
Kunle Odunsi
Samantha Cohen
Peter Dottino
John A Martignetti
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Journal of Ovarian Research / Issue 1/2011
Electronic ISSN: 1757-2215
DOI: https://doi.org/10.1186/1757-2215-4-18

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Decreased levels of serum glutathione peroxidase 3 are associated with papillary serous ovarian cancer and disease progression

Abstract

Background

Patients and Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Patients and Methods

Results

Conclusions

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