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Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2016

Open Access 01-12-2016 | Research

Targeting of topoisomerases for prognosis and drug resistance in ovarian cancer

Authors: Yang Bai, Liang-Dong Li, Jun Li, Xin Lu

Published in: Journal of Ovarian Research | Issue 1/2016

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Abstract

Backgroud

As magicians of the DNA world, topoisomerases resolve all of the topological problems in relation to DNA during a variety of genetic processes. While the prognostic value of topoisomerase isoenzymes in epithelial ovarian carcinoma (EOC) is still elusive. In current study, we investigated the prognostic value of topoisomerase isoenzymes in the EOC patients. Kaplan Meier plotter (KM plotter) database were used to assess the relevance of individual topoisomerase isoenzyme mRNA expression to EOC patients overall survival (OS), in which updated survival information and gene expression data were from a total of 1,648 EOC patients.

Results

High expression of TOP1 and TOP2A were found to be correlated to worse OS in all patients and serous patients, but not in endometrioid patients. Contrary to TOP1 and TOP2A, TOP3A and TOP3B expression were associated with better OS in all patients and serous patients, but not in endometrioid patients. While TOP2B were not found any significant prognostic value for EOC patients. From the Oncomine database, we also found widespread upregulation in the expression of TOP1 and TOP2A genes in primary tumor tissues. Albeit limited in number, all datasets exhibiting differential expression showed TOP3A and TOP3B under-regulated.

Conclusion

These results strongly supported that TOP1 and TOP2A were potential biomarkers for predicting poor survival of EOC patients, while TOP3A and TOP3B were expected to be further exploited as tumor suppressors. Comprehensive understanding of the topoisomerase isoforms may have guiding significance for the diagnosis treatment and prognosis in EOC patients.
Appendix
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Literature
1.
Raja FA, Chopra N, Ledermann JA. Optimal first-line treatment in ovarian cancer. ANN ONCOL. 2012;23 Suppl 10:x118–27.CrossRefPubMed
2.
Erriquez J, Becco P, Olivero M, Ponzone R, Maggiorotto F, Ferrero A, Scalzo MS, Canuto EM, Sapino A, Verdun Di Cantogno L, Bruna P, Aglietta M, Di Renzo MF, Valabrega G. TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin. GYNECOL ONCOL. 2015;138:627–33.CrossRefPubMed
3.
Kavanagh JJ, Kudelka AP, de Leon CG, Tresukosol D, Hord M, Finnegan MB, Kim EE, Varma D, Forman A, Cohen P, Edwards CL, Freedman RS, Verschraegen CF. Phase II study of docetaxel in patients with epithelial ovarian carcinoma refractory to platinum. CLIN CANCER RES. 1996;2:837–42.PubMed
4.
Shapiro JD, Millward MJ, Rischin D, Michael M, Walcher V, Francis PA, Toner GC. Activity of gemcitabine in patients with advanced ovarian cancer: Responses seen following platinum and paclitaxel. GYNECOL ONCOL. 1996;63:89–93.CrossRefPubMed
5.
Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. CHEM BIOL. 2010;17:421–33.CrossRefPubMed
6.
Hashimoto K, Man S, Xu P, Cruz-Munoz W, Tang T, Kumar R, Kerbel RS. Potent preclinical impact of metronomic Low-Dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer. MOL CANCER THER. 2010;9:996–1006.CrossRefPubMedPubMedCentral
7.
Chekerov R, Klaman I, Zafrakas M, Konsgen D, Mustea A, Petschke B, Lichtenegger W, Sehouli J, Dahl E. Altered expression pattern of topoisomerase IIalpha in ovarian tumor epithelial and stromal cells after platinum-based chemotherapy. NEOPLASIA. 2006;8:38–45.CrossRefPubMedPubMedCentral
8.
Larsen AK, Skladanowski A. Cellular resistance to topoisomerase-targeted drugs: From drug uptake to cell death. Biochim Biophys Acta. 1998;1400:257–74.CrossRefPubMed
9.
Valkov NI, Sullivan DM. Tumor p53 status and response to topoisomerase II inhibitors. Drug Resist Updat. 2003;6:27–39.CrossRefPubMed
10.
Wang JC. Cellular roles of DNA topoisomerases: A molecular perspective. Nat Rev Mol Cell Biol. 2002;3:430–40.CrossRefPubMed
11.
Forterre P, Gribaldo S, Gadelle D, Serre MC. Origin and evolution of DNA topoisomerases. BIOCHIMIE. 2007;89:427–46.CrossRefPubMed
12.
Norman AU, Durand DM, Prasad P, Ekwall K. DNA topoisomerase III localizes to centromeres and affects centromeric CENP-A levels in fission yeast. PLoS Genet. 2013;9:e1003371.CrossRef
13.
14.
Zhang H, Barcelo JM, Lee B, Kohlhagen G, Zimonjic DB, Popescu NC, Pommier Y. Human mitochondrial topoisomerase I. Proc Natl Acad Sci U S A. 2001;98:10608–13.CrossRefPubMedPubMedCentral
15.
Champoux JJ. DNA topoisomerases: Structure, function, and mechanism. ANNU REV BIOCHEM. 2001;70:369–413.CrossRefPubMed
16.
Nitiss JL. Investigating the biological functions of DNA topoisomerases in eukaryotic cells. Biochim Biophys Acta. 1998;1400:63–81.CrossRefPubMed
17.
Schoeffler AJ, Berger JM. DNA topoisomerases: Harnessing and constraining energy to govern chromosome topology. Q REV BIOPHYS. 2008;41:41–101.CrossRefPubMed
18.
Stone MD, Bryant Z, Crisona NJ, Smith SB, Vologodskii A, Bustamante C, Cozzarelli NR. Chirality sensing by Escherichia coli topoisomerase IV and the mechanism of type II topoisomerases. Proc Natl Acad Sci U S A. 2003;100:8654–9.CrossRefPubMedPubMedCentral
19.
Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AJ, Stewart L. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A. 2002;99:15387–92.CrossRefPubMedPubMedCentral
20.
Strick TR, Allemand JF, Bensimon D, Bensimon A, Croquette V. The elasticity of a single supercoiled DNA molecule. SCIENCE. 1996;271:1835–7.CrossRefPubMed
21.
Materna V, Pleger J, Hoffmann U, Lage H. RNA expression of MDR1/P-glycoprotein, DNA-topoisomerase I, and MRP2 in ovarian carcinoma patients: Correlation with chemotherapeutic response. GYNECOL ONCOL. 2004;94:152–60.CrossRefPubMed
22.
Mihaly Z, Kormos M, Lanczky A, Dank M, Budczies J, Szasz MA, Gyorffy B. A meta-analysis of gene expression-based biomarkers predicting outcome after tamoxifen treatment in breast cancer. Breast Cancer Res Treat. 2013;140:219–32.CrossRefPubMed
23.
Gyorffy B, Lánczky A, Szállási Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 2012;19:197–208.CrossRefPubMed
24.
Gyorffy B, Surowiak P, Budczies J, Lanczky A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One. 2013;8:e82241.CrossRefPubMedPubMedCentral
25.
Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123:725–31.CrossRefPubMed
26.
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM. ONCOMINE: A cancer microarray database and integrated data-mining platform. NEOPLASIA. 2004;6:1–6.CrossRefPubMedPubMedCentral
27.
Brustmann H. Vascular endothelial growth factor expression in serous ovarian carcinoma: Relationship with topoisomerase II alpha and prognosis. GYNECOL ONCOL. 2004;95:16–22.CrossRefPubMed
28.
Jiang HL, Sun HF, Gao SP, Li LD, Hu X, Wu J, Jin W. Loss of RAB1B promotes triple-negative breast cancer metastasis by activating TGF-beta/SMAD signaling. ONCOTARGET. 2015;6:16352–65.CrossRefPubMedPubMedCentral
29.
Proszek J, Roy A, Jakobsen AK, Frohlich R, Knudsen BR, Stougaard M. Topoisomerase I as a biomarker: Detection of activity at the single molecule level. Sensors (Basel). 2013;14:1195–207.CrossRef
30.
Lee Y, Lee C, Tsai H, An H, Lee C, Wu J, Chen C, Huang S, Hwang J, Cheng K, Leiw P, Chen C, Lin C. Targeting of topoisomerase i for prognoses and therapeutics of Camptothecin-Resistant ovarian cancer. PLoS One. 2015;10:e132579.
31.
Rømer MU, Nygård SB, Christensen IJ, Nielsen SL, Nielsen KV, Müller S, Smith DH, Vainer B, Nielsen HJ, Brünner N. Topoisomerase 1 (TOP1) gene copy number in stage III colorectal cancer patients and its relation to prognosis. MOL ONCOL. 2013;7:101–11.CrossRefPubMed
32.
33.
Naniwa J, Kigawa J, Kanamori Y, Itamochi H, Oishi T, Shimada M, Shimogai R, Kawaguchi W, Sato S, Terakawa N. Genetic diagnosis for chemosensitivity with drug-resistance genes in epithelial ovarian cancer. INT J GYNECOL CANCER. 2007;17:76–82.CrossRefPubMed
34.
35.
Chen T, Sun Y, Ji P, Kopetz S, Zhang W. Topoisomerase IIα in chromosome instability and personalized cancer therapy. Oncogene. 2015;34:4019–31.CrossRefPubMed
36.
Bonneau C, Rouzier R, Geyl C, Cortez A, Castela M, Lis R, Darai E, Touboul C. Predictive markers of chemoresistance in advanced stages epithelial ovarian carcinoma. GYNECOL ONCOL. 2015;136:112–20.CrossRefPubMed
37.
38.
Meisenberg C, Gilbert DC, Chalmers A, Haley V, Gollins S, Ward SE, El-Khamisy SF. Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan. MOL CANCER THER. 2015;14:575–85.CrossRefPubMed
39.
Jiang H, Sun HF, Gao SP, Li LD, Huang S, Hu X, Liu S, Wu J, Shao ZM, Jin W: SSBP1 suppresses TGF- -Driven Epithelial-to-Mesenchymal transition and metastasis in Triple-Negative breast cancer by regulating mitochondrial retrograde signaling. CANCER RES. 2016;76:952–64.CrossRefPubMed
40.
Zhang JW, Zhang SS, Song JR, Sun K, Zong C, Zhao QD, Liu WT, Li R, Wu MC, Wei LX. Autophagy inhibition switches low-dose camptothecin-induced premature senescence to apoptosis in human colorectal cancer cells. BIOCHEM PHARMACOL. 2014;90:265–75.CrossRefPubMed
41.
Li DD, Sun T, Wu XQ, Chen SP, Deng R, Jiang S, Feng GK, Pan JX, Zhang XS, Zeng YX, Zhu XF. The inhibition of autophagy sensitises colon cancer cells with wild-type p53 but not mutant p53 to topotecan treatment. PLoS One. 2012;7:e45058.CrossRefPubMedPubMedCentral
42.
Wang LF, Ting CY, Lo CK, Su JS, Mickley LA, Fojo AT, Whang-Peng J, Hwang J. Identification of mutations at DNA topoisomerase I responsible for camptothecin resistance. CANCER RES. 1997;57:1516–22.PubMed
43.
Zander SAL, Kersbergen A, van der Burg E, de Water N, van Tellingen O, Gunnarsdottir S, Jaspers JE, Pajic M, Nygren AOH, Jonkers J, Borst P, Rottenberg S. Sensitivity and acquired resistance of BRCA1;p53-Deficient mouse mammary tumors to the topoisomerase i inhibitor topotecan. CANCER RES. 2010;70:1700–10.CrossRefPubMed
44.
Faggad A, Darb-Esfahani S, Wirtz R, Sinn B, Sehouli J, Konsgen D, Lage H, Weichert W, Noske A, Budczies J, Muller BM, Buckendahl AC, Roske A, Eldin EN, Dietel M, Denkert C. Topoisomerase IIalpha mRNA and protein expression in ovarian carcinoma: Correlation with clinicopathological factors and prognosis. Mod Pathol. 2009;22:579–88.CrossRefPubMed
45.
Sherman-Baust CA, Kuhn E, Valle BL, Shih I, Kurman RJ, Wang TL, Amano T, Ko MS, Miyoshi I, Araki Y, Lehrmann E, Zhang Y, Becker KG, Morin PJ. A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development. J PATHOL. 2014;233:228–37.CrossRefPubMedPubMedCentral
46.
Ferrandina G, Petrillo M, Carbone A, Zannoni G, Martinelli E, Prisco M, Pignata S, Breda E, Savarese A, Scambia G. Prognostic role of topoisomerase-IIalpha in advanced ovarian cancer patients. Br J Cancer. 2008;98:1910–5.CrossRefPubMedPubMedCentral
47.
Vejpongsa P, Yeh ETH. Topoisomerase 2β: A promising molecular target for primary prevention of Anthracycline-Induced cardiotoxicity. CLIN PHARMACOL THER. 2013;95:45–52.CrossRefPubMed
48.
Azarova AM, Lyu YL, Lin CP, Tsai YC, Lau JY, Wang JC, Liu LF. Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc Natl Acad Sci U S A. 2007;104:11014–9.CrossRefPubMedPubMedCentral
49.
Song JH, Kweon SH, Kim HJ, Lee TH, Min WS, Kim HJ, Kim YK, Hwang SY, Kim TS. High TOP2B/TOP2A expression ratio at diagnosis correlates with favourable outcome for standard chemotherapy in acute myeloid leukaemia. Br J Cancer. 2012;107:108–15.CrossRefPubMedPubMedCentral
50.
Das CM, Zage PE, Taylor P, Aguilera D, Wolff JE, Lee D, Gopalakrishnan V. Chromatin remodelling at the topoisomerase II-beta promoter is associated with enhanced sensitivity to etoposide in human neuroblastoma cell lines. EUR J CANCER. 2010;46:2771–80.CrossRefPubMedPubMedCentral
51.
Withoff S, van der Zee AG, de Jong S, Hollema H, Smit EF, Mulder NH, de Vries EG. DNA topoisomerase IIalpha and -beta expression in human ovarian cancer. Br J Cancer. 1999;79:748–53.CrossRefPubMedPubMedCentral
52.
Xue X, Raynard S, Busygina V, Singh AK, Sung P. Role of replication protein a in double holliday junction dissolution mediated by the BLM-Topo IIIalpha-RMI1-RMI2 protein complex. J BIOL CHEM. 2013;288:14221–7.CrossRefPubMedPubMedCentral
53.
Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID. The Bloom’s syndrome gene product interacts with topoisomerase III. J BIOL CHEM. 2000;275:9636–44.CrossRefPubMed
54.
Hsieh MY, Fan JR, Chang HW, Chen HC, Shen TL, Teng SC, Yeh YH, Li TK. DNA topoisomerase III alpha regulates p53-Mediated tumor suppression. CLIN CANCER RES. 2014;20:1489–501.CrossRefPubMed
55.
Yang Y, McBride KM, Hensley S, Lu Y, Chedin F, Bedford MT. Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation. MOL CELL. 2014;53:484–97.CrossRefPubMedPubMedCentral
56.
Mohanty S, Town T, Yagi T, Scheidig C, Kwan KY, Allore HG, Flavell RA, Shaw AC. Defective p53 engagement after the induction of DNA damage in cells deficient in topoisomerase 3beta. Proc Natl Acad Sci U S A. 2008;105:5063–8.CrossRefPubMedPubMedCentral
57.
Oliveira-Costa JP, Zanetti J, Oliveira LR, Soares FA, Ramalho LZ, Silva RF, Garcia SB, Ribeiro-Silva A. Significance of topoisomerase IIIbeta expression in breast ductal carcinomas: Strong associations with disease-specific survival and metastasis. HUM PATHOL. 2010;41:1624–30.CrossRefPubMed
Metadata
Title
Targeting of topoisomerases for prognosis and drug resistance in ovarian cancer
Authors
Yang Bai
Liang-Dong Li
Jun Li
Xin Lu
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2016
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/s13048-016-0244-9

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