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EIF5A2 is a novel chemoresistance gene in breast cancer

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Abstract

Background

The eIF5A2 gene (encoding the eukaryotic initiation factor 5A2) located at 3q26 is a putative oncogene that is overexpressed in colon and rectal carcinomas, lung cancer and hepatocellular carcinoma. EIF5A2 overexpression correlates significantly with tumor metastasis and is an adverse prognostic marker. However, eIF-5A2 overexpression in breast cancer and its effect on chemotherapy are unknown.

Methods

We measured eIF-5A2 expression and doxorubicin sensitivity in different human breast cancer cell lines (Bcap-1937, HCC1937, and MCF-7). To investigate a role for eIF-5A2 in chemoresistance, cells were treated with eIF-5A2-siRNA, exposed to various concentrations of doxorubicin, and toxicity was assayed by CCK-8 (cell counting kit).

Results

The eIF-5A2 expression levels varied among breast cancer cells. Higher expression levels correlated with decreased doxorubicin sensitivity. Silencing of eIF-5A2 significantly improved doxorubicin toxicity in all three breast cancer cell lines.

Conclusion

This study shows that eIF-5A2 plays an important role in doxorubicin chemoresistance in breast cancer cells.

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References

  1. Howlader N, Noone AM, Krapcho M: SEER CancerStatistics Review, 1975–2008, National Cancer Institute.Bethesda, MD, based on November 2010 SEER data submission, posted to the SEER website. http://seer.cancer.gov/csr/1975_2008/ (2011).

  2. Christensen LA, Finch RA, Booker AJ, Vasquez KM. Targeting oncogenes to improve breast cancer chemotherapy. Cancer Rese. 2006;66:4089–94.

    Article  CAS  Google Scholar 

  3. Antoon JW, White MD, Slaughter EM, Driver JL, Khalili HS, Elliott S, et al. Targeting NF κB mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2. Cancer Biol Ther. 2011;11:678–89.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. He QJ, Zeng WF, Sham JS, Xie D, Yang XW, Lin HL, et al. Recurrent genetic alterations in 26 colorectal carcinomas and 21 adenomas from Chinese patients. Cancer Genet Cytogenet. 2003;144:112–8.

    Article  CAS  PubMed  Google Scholar 

  5. Ried T, Knutzen R, Steinbeck R, Blegen H, Schröck E, Heselmeyer K, du Manoir S, Auer G. Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors. Genes Chromosome Cancer. 1996;15:234–45.

    Article  CAS  Google Scholar 

  6. Sham JS, Tang TC, Fang Y, Sun L, Qin LX, Wu QL, Xie D, Guan XY. Recurrent chromosome alterations in primary ovarian carcinoma in Chinese women. Cancer Genet Cytogenet. 2002;133:39–44.

    Article  CAS  PubMed  Google Scholar 

  7. Kettunen E, El-Rifai W, Björkqvist AM, Wolff H, Karjalainen A, Anttila S, et al. A broad amplification pattern at 3q in squamous cell lung cancer e a fluorescence in situ hybridization study. Cancer Genet Cytogenet. 2000;117:66–70.

    Article  CAS  PubMed  Google Scholar 

  8. Pack SD, Karkera JD, Zhuang Z, Pak ED, Balan KV, Hwu P, et al. Molecular cytogenetic fingerprinting of esophageal squamous cell carcinoma by comparative genomic hybridization reveals a consistent patter n of chromosomal alterations. Genes Chromosome Cancer. 1999;25:160–8.

    Article  CAS  Google Scholar 

  9. Guan XY, Fu SB, Xia JC, Fang Y, Sham JS, Du BD, et al. Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization. Cancer Genet Cytogenet. 2000;123:27–34.

    Article  CAS  PubMed  Google Scholar 

  10. Rao PH, Arias-Pulido H, Lu XY, Harris CP, Vargas H, Zhang FF, et al. Chromosomal amplifications, 3q gain and deletions of 2q33-q37 are the frequent genetic changes in cervical carcinoma. BMC Cancer. 2004;4:5.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Sattler HP, Rohde V, Bonkhoff H, Zwergel T, Wullich B. Comparative genomic hybridization reveals DNA copy number gains to frequently occur in human prostate cancer. Prostate. 1999;39:79–86.

    Article  CAS  PubMed  Google Scholar 

  12. Horlings HM, Lai C, Nuyten DS, Halfwerk H, Kristel P, van Beers E, et al. Gene expression signatures in breast cancer patients integration of DNA copy number alterations and prognostic. Clin Cancer Res. 2010;16:651–63.

    Article  CAS  PubMed  Google Scholar 

  13. Guan XY, Sham JS, Tang TC, Fang Y, Huo KK, Yang JM. Isolation of a novel candidate oncogene within a frequently amplified region at 3q26 in ovarian cancer. Cancer Res. 2001;61:3806–9.

    CAS  PubMed  Google Scholar 

  14. Guan XY, Fung JM, Ma NF, Lau SH, Tai LS, Xie D, et al. Oncogenic role of eIF-5A2 in the development of ovarian cancer. Cancer Res. 2004;64:4197–200.

    Article  CAS  PubMed  Google Scholar 

  15. Lee NP, Tsang FH, Shek FH, Mao M, Dai H, Zhang C, et al. Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma. Int J Cancer. 2010;127:968–76.

    Article  CAS  PubMed  Google Scholar 

  16. Yang GF, Xie D, Liu JH, Luo JH, Li LJ, Hua WF, et al. Expression and amplification of eIF-5A2 in human epithelial ovarian tumors and overexpression of EIF-5A2 is a new in dependent predictor of outcome in patients with ovarian carcinoma. Gynecol Oncol. 2009;112:314–8.

    Article  CAS  PubMed  Google Scholar 

  17. Luo JH, Hua WF, Rao HL, Liao YJ, Kung HF, Zeng YX, et al. Overexpression of EIF-5A2 predict s tumor recurrence and progression in pTa/pT1 urothelial carcinoma of the bladder. Cancer Sci. 2009;100:896–902.

    Article  CAS  PubMed  Google Scholar 

  18. He LR, Zhao HY, Li BK, Liu YH, Liu MZ, Guan XY, et al. Overexpression of eIF5A-2 is an adverse prognostic marker of survival in stage I non–small cell lung cancer patients. Int J Cancer. 2011;129:143–50.

    Article  CAS  PubMed  Google Scholar 

  19. Tang DJ, Dong SS, Ma NF, Xie D, Chen L, Fu L, et al. Overexpression of eukaryotic initiation factor 5A2 enhances cell motility and promotes tumor metastasis in hepatocellular carcinoma. Hepatology. 2010;51:1255–63.

    Article  CAS  PubMed  Google Scholar 

  20. Zhu W, Cai MY, Tong ZT, Dong SS, Mai SJ, Liao YJ, et al. Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial mesenchymal transition. Gut. 2012;61:562–75.

    Article  CAS  PubMed  Google Scholar 

  21. Zeng C, Liu Y, Hu YZ, Zhao QB, Chi SM. Inhibitory effect of Rab23 on growth and proliferation of breast cancer cells. Prog Mod Biomed. 2009;20:3811–5.

    Google Scholar 

  22. Bartucci M, Morelli C, Mauro L, Andò S, Surmacz E. Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7and ER-negative MDA-MB-231 breast cancer cells. Cancer Res. 2001;61:6747–54.

    CAS  PubMed  Google Scholar 

  23. Rowe DL, Ozbay T, O’Regan RM, Nahta R. Modulation of the BRCA1 protein and induction of apoptosis in triple negative breast cancer cell lines by the polyphenolic compound curcumin. Breast Cancer. 2009;3:61–75.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Cooper HL, Park MH, Folk JE. Posttranslational formation of hypusine in a single major protein occurs generally in growing cells and is associated with activation of lymphocyte growth. Cell. 1982;29:791–7.

    Article  CAS  PubMed  Google Scholar 

  25. Schnier J, Schwelberger HG, Smit-McBride Z, Kang HA, Hershey JW. Translation initiation factor 5A and its hypusine modification are essential for cell viability in the yeast Saccharomyces cerevisiae. Mol Cell Biol. 1991;11:3105–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Wohl T, Klier H, Ammer H, Lottspeich F, Magdolen V. The HYP2 gene of Saccharomyces cerevisiae is essential for aerobic growth: characterization of different isoforms of the hypusine-containing protein Hyp2p and analysis of gene disruption mutants. Mol Gen Genet. 1993;241:305–11.

    CAS  PubMed  Google Scholar 

  27. Benne R, Hershey JW. The mechanism of action of protein synthesis initiation factors from rabbit reticulocytes. J Biol Chem. 1978;253:3078–87.

    CAS  PubMed  Google Scholar 

  28. Kang HA, Hershey JW. Effect of initiation factor eIF-5A depletion on protein synthesis and proliferation of Saccharomyces cerevisiae. J Biol Chem. 1994;269:3934–40.

    CAS  PubMed  Google Scholar 

  29. Xu A, Jao DL, Chen KY. Identification of mRNA that binds to eukaryotic initiation factor 5A by affinity co-purification and differential display. Biochem J. 2004;384:585–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Zanelli CF, Valentini SR. Pkc1 acts throug h Zds1 and Gic1 to sup-press growth and cell polarity defects of a yeast eIF5A mutant. Genetics. 2005;171:1571–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Smit-McBride Z, Dever TE, Hershey JW, Merrick WC. Sequence determination and cDNA cloning of eukar yotic initiation factor 4D, the hypusine-containing protein. J Biol Chem. 1989;264:1578–83.

    CAS  PubMed  Google Scholar 

  32. Koettnitz K, Wohl T, Kappel B, Lottspeich F, Hauber J, Bevec D. Identification of a new member of the human eIF-5A gene family. Gene. 1995;159:283–4.

    Article  CAS  PubMed  Google Scholar 

  33. Clement PM, Henderson CA, Jenkins ZA, Smit-McBride Z, Wolff EC, Hershey JW, et al. Identification and characterization of eukaryotic initiation factor 5A-2. Eur J Biochem. 2003;270:4254–63.

    Article  CAS  PubMed  Google Scholar 

  34. Jenkins ZA, Haag PG, Johansson HE. Human eIF5A2 on chromo-some 3q25-q27 is a phylogenetically conserved vertebrate variant of eukaryotic translation initiation factor 5A with tissue-specific expression. Genomics. 2001;71:101–9.

    Article  CAS  PubMed  Google Scholar 

  35. Zhang W, Feng M, Zheng G, Chen Y, Wang X, Pen B, et al. Chemoresistance to 5-fluorouracil induces epithelial-mesenchymal transition via up-regulation of Snail in MCF7 human breast cancer cells. Biochem Biophys Res Commun. 2012;417:679–85.

    Article  CAS  PubMed  Google Scholar 

  36. Marchini S, Fruscio R, Clivio L, Beltrame L, Porcu L, Nerini IF, et al. Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer. Eur J Cancer. 2013;49:520–30.

    Article  CAS  PubMed  Google Scholar 

  37. Güngör C, Zander H, Effenberger KE, Vashist YK, Kalinina T, Izbicki JR, et al. Notch signaling activated by replication stress-induced expression of midline drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer. Cancer Res. 2011;71:5009–19.

    Article  PubMed  Google Scholar 

  38. Chen X, Lingala S, Khoobyari S, Nolta J, Zern MA, Wu J. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol. 2011;55:838–45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was financially supported by Science and Technology Planning Project of Zhejiang Province, China (No. 2012KYA071).

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Breast Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China

    Yu Liu, Feiya Du, Wei Chen, Minya Yao, Kezhen Lv & Peifen Fu

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  1. Yu Liu
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  2. Feiya Du
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  3. Wei Chen
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  4. Minya Yao
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  5. Kezhen Lv
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Corresponding author

Correspondence to Peifen Fu.

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Liu, Y., Du, F., Chen, W. et al. EIF5A2 is a novel chemoresistance gene in breast cancer. Breast Cancer 22, 602–607 (2015). https://doi.org/10.1007/s12282-014-0526-2

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  • DOI: https://doi.org/10.1007/s12282-014-0526-2

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