Prognostic implications of the subcellular localization of survivin in glioblastomas treated with radiotherapy plus concomitant and adjuvant temozolomide

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OBJECTIVE

Currently, the standard treatment protocol for patients with newly diagnosed glioblastoma (GBM) includes surgery, radiotherapy, and concomitant and adjuvant temozolomide (TMZ). Various prognostic biomarkers for GBM have been described, including survivin expression. The aim of this study was to determine whether the subcellular localization of survivin correlates with GBM prognosis in patients who received the standard treatment protocol.

METHODS

The authors retrospectively examined the subcellular localization of survivin (nuclear, cytoplasmic, or both) using immunohistochemistry in 50 patients with GBM who had received the standard treatment. The relationship between survivin localization and overall survival (OS) was assessed with uni- and multivariate analyses including other clinicopathological factors (age, sex, Karnofsky Performance Scale [KPS] score, extent of resection, the use of second-line bevacizumab, O6-methylguanine-DNA methyltransferase [MGMT] status, and MIB-1 labeling index).

RESULTS

Log-rank tests revealed that patient age, KPS score, extent of resection, MGMT status, and survivin localization (p < 0.0001) significantly correlated with OS. Multivariate analysis indicated that patient age, MGMT status, and survivin localization significantly correlated with OS. Patients with nuclear localization of survivin had a significantly shorter OS than those in whom survivin expression was exclusively cytoplasmic (median OS 19.5 vs 31.7 months, respectively, HR 5.690, 95% CI 2.068–17.612, p = 0.0006). There was no significant difference in OS between patents whose survivin expression was exclusively nuclear or nuclear/cytoplasmic.

CONCLUSIONS

Nuclear expression of survivin is a factor for a poor prognosis in GBM patients. Subcellular localization of survivin can help to predict OS in GBM patients treated with the standard protocol.

ABBREVIATIONS DC = dendritic cell; GBM = glioblastoma; KPS = Karnofsky Performance Scale; LI = labeling index; MGMT = O6-methylguanine-DNA methyltransferase; OS = overall survival; siRNA = short interfering RNA; TMZ = temozolomide.
Article Information

Contributor Notes

Correspondence Taiichi Saito, Department of Neurosurgery, Hiroshima University, Graduate School of Biomedical and Health Science, 81, Hiroshima 734-8551, Japan. email: taiichis@gmail.com.INCLUDE WHEN CITING Published online April 21, 2017; DOI: 10.3171/2016.11.JNS162326.Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

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References
  • 1

    Caldas HHonsey LEAltura RA: Survivin 2α: a novel Survivin splice variant expressed in human malignancies. Mol Cancer 4:112005

  • 2

    Chakravarti ANoll EBlack PMFinkelstein DFFinkelstein DMDyson NJ: Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol 20:106310682002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Chakravarti AZhai GGZhang MMalhotra RLatham DEDelaney MA: Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms. Oncogene 23:749475062004

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Cheng SMChang YCLiu CYLee JYChan HHKuo CW: YM155 down-regulates survivin and XIAP, modulates autophagy and induces autophagy-dependent DNA damage in breast cancer cells. Br J Pharmacol 172:2142342015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Cruz RQMorais CMCardoso AMSilva SGVale MLMarques EF: Enhancing glioblastoma cell sensitivity to chemotherapeutics: A strategy involving survivin gene silencing mediated by gemini surfactant-based complexes. Eur J Pharm Biopharm 104:7182016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Cui DXu QWang KChe X: Gli1 is a potential target for alleviating multidrug resistance of gliomas. J Neurol Sci 288:1561662010

  • 7

    Guo HWang YSong TXin TZheng ZZhong P: Silencing of survivin using YM155 inhibits invasion and suppresses proliferation in glioma cells. Cell Biochem Biophys 71:5875932015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Guzman JRFukuda SPelus LM: Inhibition of caspase-3 by Survivin prevents Wee1 Kinase degradation and promotes cell survival by maintaining phosphorylation of p34Cdc2. Gene Ther Mol Biol 13B:2642732009

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Harper JWElledge SJ: The DNA damage response: ten years after. Mol Cell 28:7397452007

  • 10

    Hegi MEDiserens ACGorlia THamou MFde Tribolet NWeller M: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:99710032005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Kim CHWoo SJPark JSKim HSPark MYPark SD: Enhanced antitumour immunity by combined use of temozolomide and TAT-survivin pulsed dendritic cells in a murine glioma. Immunology 122:6156222007

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Kumar BYadav ALang JCCipolla MJSchmitt ACArradaza N: YM155 reverses cisplatin resistance in head and neck cancer by decreasing cytoplasmic survivin levels. Mol Cancer Ther 11:198819982012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Lai PCChen SHYang SHCheng CCChiu THHuang YT: Novel survivin inhibitor YM155 elicits cytotoxicity in glioblastoma cell lines with normal or deficiency DNA-dependent protein kinase activity. Pediatr Neonatol 53:1992042012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Lam NChambers CR: Temozolomide plus radiotherapy for glioblastoma in a Canadian province: efficacy versus effectiveness and the impact of O6-methylguanine-DNA-methyltransferase promoter methylation. J Oncol Pharm Pract 18:2292382012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Lanvin OMonferran SDelmas CCouderc BToulas CCohen-Jonathan-Moyal E: Radiation-induced mitotic cell death and glioblastoma radioresistance: a new regulating pathway controlled by integrin-linked kinase, hypoxia-inducible factor 1 alpha and survivin in U87 cells. Eur J Cancer 49:288428912013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Li YLiu DZhou YLi YXie JLee RJ: Silencing of survivin expression leads to reduced proliferation and cell cycle arrest in cancer cells. J Cancer 6:118711942015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Mahotka CLiebmann JWenzel MSuschek CVSchmitt MGabbert HE: Differential subcellular localization of functionally divergent survivin splice variants. Cell Death Differ 9:133413422002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Mahotka CWenzel MSpringer EGabbert HEGerharz CD: Survivin-ΔEx3 and survivin-2B: two novel splice variants of the apoptosis inhibitor survivin with different anti-apoptotic properties. Cancer Res 59:609761021999

    • Search Google Scholar
    • Export Citation
  • 19

    Nakahara TKita AYamanaka KMori MAmino NTakeuchi M: Broad spectrum and potent antitumor activities of YM155, a novel small-molecule survivin suppressant, in a wide variety of human cancer cell lines and xenograft models. Cancer Sci 102:6146212011

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Nakahara TKita AYamanaka KMori MAmino NTakeuchi M: YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res 67:801480212007. (Erratum in Cancer Res 72: 3886 2012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Newlands ESStevens MFWedge SRWheelhouse RTBrock C: Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 23:35611997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Perry JAKornbluth S: Cdc25 and Wee1: analogous opposites?. Cell Div 2:122007

  • 23

    Quillien VLavenu AKarayan-Tapon LCarpentier CLabussière MLesimple T: Comparative assessment of 5 methods (methylation-specific polymerase chain reaction, MethyLight, pyrosequencing, methylation-sensitive high-resolution melting, and immunohistochemistry) to analyze O6-methylguanine-DNA-methyltranferase in a series of 100 glioblastoma patients. Cancer 118:420142112012

    • Search Google Scholar
    • Export Citation
  • 24

    Reichert SRödel CMirsch JHarter PNTomicic MTMittelbronn M: Survivin inhibition and DNA double-strand break repair: a molecular mechanism to overcome radioresistance in glioblastoma. Radiother Oncol 101:51582011

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Roos WPBatista LFNaumann SCWick WWeller MMenck CF: Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 26:1861972007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Sah NKKhan ZKhan GJBisen PS: Structural, functional and therapeutic biology of survivin. Cancer Lett 244:1641712006

  • 27

    Saito TArifin MTHama SKajiwara YSugiyama KYamasaki F: Survivin subcellular localization in high-grade astrocytomas: simultaneous expression in both nucleus and cytoplasm is negative prognostic marker. J Neurooncol 82:1931982007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Saito THama SIzumi HYamasaki FKajiwara YMatsuura S: Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells. Br J Cancer 98:3453552008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Shirai KSuzuki YOka KNoda SEKatoh HSuzuki Y: Nuclear survivin expression predicts poorer prognosis in glioblastoma. J Neurooncol 91:3533582009

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Stupp RMason WPvan den Bent MJWeller MFisher BTaphoorn MJ: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:9879962005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Virrey JJGuan SLi WSchönthal AHChen TCHofman FM: Increased survivin expression confers chemoresistance to tumor-associated endothelial cells. Am J Pathol 173:5755852008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Xie DZeng YXWang HJWen JMTao YSham JS: Expression of cytoplasmic and nuclear Survivin in primary and secondary human glioblastoma. Br J Cancer 94:1081142006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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