Skip to main content

Advertisement

SpringerLink
Log in

Survivin splice variants and their diagnostic significance

  • Review
  • Published:
Tumor Biology

Abstract

Survivin plays a crucial role in cell division particularly during the development of the fetus, in the onset and progression of most tumors and is found expressed in a few terminally differentiated cells. Altogether, there are ten splice variants of survivin, some of which are not yet satisfactorily characterized. Several isoforms may undergo homo/heterodimerization, particularly with the wild-type survivin to elicit a variety of biological functions. The detection of survivin and its splice variants not only suggests the onset, maintenance, and progression of cancer, but also the stage of certain cancers. Recent studies demonstrate that the presence of survivin in urine and blood samples of patients may suggest urogenital and bladder cancer hematologic malignancies, respectively. The expression of the survivin-3α splice variant is indicative of the onset and progression of breast cancer. Several companies have developed cancer diagnostic kits using survivin for detection of cancer. Some are also engaged in fine-tuning the type and stage-specific diagnosis of cancer based on survivin, its splice variants with and without other markers, such as hyaluronidase. Briefly, survivin and its splice variants hold a great biological significance, particularly in the diagnosis of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Yoshida A, Zokumasu K, Wano Y, Yamauchi T, Imamura S, Takagi K, et al. Marked upregulation of Survivin and Aurora-B kinase is associated with disease progression in the myelodysplastic syndromes. Haematologia. 2012;97:1372–9.

    Article  CAS  Google Scholar 

  2. Altieri DC. The molecular basis and potential role of survivin in cancer diagnosis and therapy. Trends Mol Med. 2001;7:542–7.

    Article  CAS  PubMed  Google Scholar 

  3. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997;3(8):917–1.

    Article  CAS  PubMed  Google Scholar 

  4. Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer. 1993;3(1):46–4.

    Article  Google Scholar 

  5. Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional and therapeutic biology of survivin. Cancer Lett. 2006;244:164–1.

    Article  CAS  PubMed  Google Scholar 

  6. Caldas H, Fangusaro JR, Boue DR, Holloway MP, Altura RA. Dissecting the role of endothelial SURVIVIN DeltaEx3 in angiogenesis. Blood. 2007;109:1479–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Węsierska-Gądek J, Schmid G. Transcriptional repression of anti-apoptotic proteins mediated by the tumor suppressor protein p53. Cancer Ther. 2007;5:203–2.

    Google Scholar 

  8. Caldas H, Honsey L, Altura R. Survivin 2alpha: a novel survivin splice variant expressed in human malignancies. Mol Cancer. 2005;4(1):11.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Tyner JW, Jemal AM, Thayer M, Druker BJ, Chang BH. Targeting survivin and p53 in pediatric acute lymphoblastic leukemia. Leukemia. 2012;26:623–2.

    Article  CAS  PubMed  Google Scholar 

  10. Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, et al. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 1998;58:5315–20.

    CAS  PubMed  Google Scholar 

  11. Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, et al. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry. 2001;40:1117–3.

    Article  CAS  PubMed  Google Scholar 

  12. http://en.wikipedia.org/wiki/Survivin, accessed on 24 March, 2015.

  13. Végran F, Boidot R, Oudin C, Defrain C, Rebucci M, Lizard-Nacol S. Association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancer. Oncogene. 2007;26:290–7.

    Article  PubMed  Google Scholar 

  14. Knauer SK, Bier C, Schlag P, Fritzmann J, Dietmaier W, Rodel F, et al. The survivin isoform survivin 3B is cytoprotective and can function as a chromosome passenger complex. Cell Cycle. 2007;6:1502–9.

    CAS  PubMed  Google Scholar 

  15. Mita AC, Mita MM, Nawrocki ST, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 2008;14:5000–5.

    Article  CAS  PubMed  Google Scholar 

  16. Li F, Altieri DC. Transcriptional analysis of human survivin gene expression. Biochem J. 1999;344:305–1.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Chu Y, Yao PY, Wang W, Wang D, Wang Z, Zhang L, et al. Aurora B kinase activation requires survivin priming phosphorylation by PLK1. J Mol Cell Biol. 2011;3:260–7.

    Article  CAS  PubMed  Google Scholar 

  18. Sally P, Wheatley, Henzing AJ, Dodson H, Khaled W, et al. Aurora-B phosphorylation in vitro identifies a residue of survivin that is essential for its localization and binding to inner centromere protein (INCENP) in vivo. JBC. 2004;279:5655–60.

    Article  Google Scholar 

  19. Suzuki A, Ito T, Kawano H, Hayashida M, Hayasaki Y, Tsutomi Y, et al. Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death. Oncogene. 2000;19:1346–3.

    Article  CAS  PubMed  Google Scholar 

  20. Tang L, Ling X, Liu W, Das GM, Li F. Transcriptional inhibition of p21WAF1/CIP1 gene (CDKN1) expression by survivin is at least partially p53-dependent: evidence for survivin acting as a transcription factor or co-factor. Biochem Biophys Res Commun. 2012;421:249–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Serrano-Lopez J, Serrano J, Figueroa V, Torres-Gomez A, Tabares S, Casaño J, et al. Cytoplasmic localization of wild type survivin is associated to constitutive activation of PI3k/akt signaling pathway and represents a favorable prognostic factor in acute myeloid leukemia patients. Haematology. 2013;98(12):1877–5.

    Article  CAS  Google Scholar 

  22. Sah NK, Munshi A, Nishikawa T, Mukhopadhyay T, Roth JA, Meyn RE. Adenovirus-mediated wild-type p53 radiosensitizes human tumor cells by suppressing DNA repair capacity. Mol Cancer Ther. 2003;2(11):1223–1.

    CAS  PubMed  Google Scholar 

  23. Smith ML, Seo YR. p53 regulation of DNA excision repair pathways. Mutagenesis. 2002;17(2):149–6.

    Article  CAS  PubMed  Google Scholar 

  24. Hwang SL, Hong YR, Sy WD, Chai CY, Lin HJ, Howng SL. Expression and mutation analysis of the p53 gene in astrocytoma. J Formos Med Assoc. 1999;98(1):31–8.

    CAS  PubMed  Google Scholar 

  25. Ford JM, Hanawalt PC. Expression of wild-type p53 is required for efficient global genomic nucleotide excision repair in UV-irradiated human fibroblasts. J Biol Chem. 1997;272(44):28073–80.

    Article  CAS  PubMed  Google Scholar 

  26. Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006;6:909–23.

    Article  CAS  PubMed  Google Scholar 

  27. Konduri SD, Medisetty R, Liu W, Kaipparettu BA, Srivastava P, Brauch H, et al. Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation. Proceed Natl Acad Sci. 2010;107(34):15081–6.

    Article  CAS  Google Scholar 

  28. Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S, et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene. 2002;21:2613–2.

    Article  CAS  PubMed  Google Scholar 

  29. Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem. 2002;277:3247–7.

    Article  CAS  PubMed  Google Scholar 

  30. Biodot R, Vegran F, Lizard-Nacol S. Transcriptional regulation of the survivin gene. Mol Biol Rep. 2014;41:233–00.

    Article  Google Scholar 

  31. Wang Z, Fukuda S, Pelus L. Survivin regulates the P53 tumor suppressor gene family. Oncogene. 2004;23:8146–3.

    Article  CAS  PubMed  Google Scholar 

  32. Zhou M, Gu L, Li F, Zhu Y, Woods WG, Findley HW. DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells. J Pharmacol Exp Ther. 2002;303:124–1.

    Article  CAS  PubMed  Google Scholar 

  33. Sah NK, Munshi A, Hobbs M, Carter BZ, Andreef M, Meyn RE. Effect of downregulation of survivin expression on radiosensitivity of human epidermoid carcinoma cells. Int J Radiat Oncol Biol Phys. 2006;66:852–9.

    Article  CAS  PubMed  Google Scholar 

  34. Zhu N, Gu L, Findley HW, Li F, Zhou M. An alternatively spliced survivin variant is positively regulated by p53 and sensitizes leukemia cells to chemotherapy. Oncogene. 2004;23:7545–1.

    Article  CAS  PubMed  Google Scholar 

  35. Badran A, Yoshida A, Ishikawa K, Goi T, Yamaguchi A, Ueda T, et al. Identification of a novel splice variant of the human anti-apoptosis gene survivin. Biochem Biophys Res Commun. 2004;314(3):902–7.

    Article  CAS  PubMed  Google Scholar 

  36. Mahotka C, Wenzel M, Springer E, Gabbert HE, Gerharz CD. Survivin-deltaEx3 and survivin-2B: two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. Cancer Res. 1999;59:6097–02.

    CAS  PubMed  Google Scholar 

  37. Mahotka C, Liebmann J, Wenzel M, Suschek CV, Schmitt M, Gabbert HE, et al. Differential subcellular localization of functionally divergent survivin splice variants. Cell Death Differ. 2002;9:1334–2.

    Article  CAS  PubMed  Google Scholar 

  38. Caldas H, Jiang Y, Holloway MP, Fangusaro J, Mahotka C, Conway EM, et al. Survivin splice variants regulate the balance between proliferation and cell death. Oncogene. 2005;24:1994–07.

    Article  CAS  PubMed  Google Scholar 

  39. Vietri MT, Cioffi M, Sessa M, Sica V, Molinari AM. Identification of a novel survivin splicing variant 3alpha in acute myeloid leukemia 2006. http://www.ncbi.nlm.nih.gov/nuccore/83744165. Accessed on 24th March 2015.

  40. Li F, Ling X. Survivin study: an update of “What is the Next Wave?”. J Cell Physiol. 2010;208(3):476–6.

    Article  Google Scholar 

  41. Noton EA, Colnaghi R, Tate S, Starck C, Carvalho A, KoFerrigno P, et al. Molecular analysis of survivin isoforms: evidence that alternatively spliced variants do not play a role in mitosis. J Biol Chem. 2006;281:1286–5.

    Article  CAS  PubMed  Google Scholar 

  42. Mola G, Vela E, Fernández-Figueras MT, Isamat M, Muñoz-Mármol AM. Exonization of Alu-generated splice variants in the survivin gene of human and non-human primates. J Mol Biol. 2007;366:1055–3.

    Article  CAS  PubMed  Google Scholar 

  43. Athanasoula KC, Gogas H, Polonifi K, Vaiopoulos AG, Polyzos A, Mantzourani M. Survivin beyond physiology: orchestration of multistep carcinogenesis and therapeutic potentials. Cancer Lett. 2014;347:175–2.

    Article  CAS  PubMed  Google Scholar 

  44. Wang HW, Sharp TV, Koumi A, Koentges G, Boshoff C. Characterization of an anti-apoptotic glycoprotein encoded by Kaposi’s sarcoma-associated herpesvirus which resembles a spliced variant of human survivin. EMBO J. 2002;21:2602–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Malcles M-H, Wang H-W, Koumi A, Tsai Y-H, Yu M, Godfrey A, et al. Characterisation of the anti-apoptotic function of survivin-ΔEx3 during TNFα-mediated cell death. Br J Cancer. 2007;96:1659–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ezziane Z. Molecular docking and analysis of survivin delta-Ex3 isoform protein. Open Med Chem J. 2008;2:16–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Espinosa M, Ceballos-Cancino G, Callaghan R, Maldonado V, Patiño N, Ruíz V, et al. Survivin isoform ∆Ex3 regulates tumor spheroid formation. Cancer Lett. 2012;318:61–7.

    Article  CAS  PubMed  Google Scholar 

  48. Lopergolo A, Tavecchio M, Lisanti S, Ghosh JC, Dohi T, Faversani A, et al. Chk2 phosphorylation of survivin-DeltaEx3 contributes to a DNA damage-sensing checkpoint in cancer. Cancer Res. 2012;72:3251–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Vandghanooni S, Eskandani M, Montazeri V, Halimi M, Babaei E, Feizi MAH. Survivin-deltaEx3: a novel biomarker for diagnosis of papillary thyroid carcinoma. J Cancer Res Ther. 2011;7:25–30.

    Google Scholar 

  50. Vivas-Mejia PE, Rodriguez-Aguayo C, Han H-D, Shahzad MMK, Valiyeva F, Shibayama M, et al. Silencing survivin splice variant 2B leads to antitumor activity in taxane-resistant ovarian cancer. Clin Cancer Res. 2011;17:3716–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Végran F, Boidot R, Bonnetain F, Cadouot M, Chevrier S, Lizard-Nacol S. Apoptosis gene signature of survivin and its splice variant expression in breast carcinoma. Endocr-Relat Cancer. 2011;18:783–2.

    Article  PubMed  Google Scholar 

  52. Shi K, An J, Jiang Q, Li F, Ci Y, Wu P, et al. Survivin 2B promotes autophagy by accumulating IKKalphain the nucleus of selenite-treated NB4 cells. Cell Death Dis. 2014;5:1071–80.

    Article  Google Scholar 

  53. Végran F, Mary R, Gibeaud A, Mirjolet C, Collin B, Oudot A, et al. Survivin-3B potentiates immune escape in cancer but also inhibits the toxicity of cancer chemotherapy. Cancer Res. 2013;73:5391–01.

    Article  PubMed  Google Scholar 

  54. http://www.uniprot.org/uniprot/O15392#O15392-4. Accessed on 24th March 2015.

  55. Huang Y, Chen X, Chen N, Nie L, Xu M, Zhou Q. Expression and prognostic significance of survivin splice variants in diffusely infiltrating astrocytoma. J Clin Pathol. 2011;64:953–9.

    Article  CAS  PubMed  Google Scholar 

  56. Javadhesari SM, Gharechahi J, Feizi MAH, Montazeri V, Halimi M. Transcriptional expression of survivin splice variants reveals differential expression of survivin-3α in breast cancer. Genet Test Mol Biomark. 2013;7:314–20.

    Article  Google Scholar 

  57. Zheng W, Ma X, Wei D, Wang T, Ma Y, Yang S. Molecular cloning and bioinformatics analysis of a novel spliced variant of survivin from human breast cancer cells. DNA Seq. 2005;16:321–8.

    Article  CAS  PubMed  Google Scholar 

  58. Wajapeyee N, Britto R, Ravishankar HM, Somasundaram K. Apoptosis induction by activator protein 2alpha involves transcriptional repression of Bcl-2. J Biol Chem. 2006;281:16207–19.

    Article  CAS  PubMed  Google Scholar 

  59. Esteve PO, Chin HG, Pradhan S. Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. Proc Natl Acad Sci U S A. 2005;102:1000–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Necochea-Campion R, Chen C-S, Mirshahidi S, Howard FD, Wall NR. Clinico-pathologic relevance of Survivin splice variant expression in cancer. Cancer Lett. 2013;339:167–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. de Necochea-Campion R, Ghochikyan A, Josephs SF, Zacharias S, Woods E, Karimi-Busheri F, et al. Expression of the epigenetic factor BORIS (CTCFL) in the human genome. J Transl Med. 2011;9:213.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Vegran F, Boidot R, Oudin C, Defrain C, Rebucci M, Lizard-Nacol S. Association of p53 gene alterations with the expression of anti-apoptotic survivin splice variants in breast cancer. Oncogene. 2007;26:290–7.

    Article  CAS  PubMed  Google Scholar 

  63. Shukla S, Kavak E, Gregory M, Imashimizu M, Shutinoski B, Kashlev M, et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature. 2011;479:74–9.

    Article  CAS  PubMed  Google Scholar 

  64. Will CL, Luhrmann R. Spliceosome structure and function. Cold Spring Harbor Perspect Biol. 2011;3(7):a003707.

  65. Hattori M, Sakamoto H, Satoh K, Yamamoto T. DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the promoter region of c-erbB-2 and survivin genes. Cancer Lett. 2001;169:155–4.

    Article  CAS  PubMed  Google Scholar 

  66. Yu J, Zhang H, Gu J, Lin S, Li J, Lu W, et al. Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma. BMC Cancer. 2004;4:65.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Wagner M, Schmelz K, Dorken B, Tamm I. Epigenetic and genetic analysis of the survivin promoter in acute myeloid leukemia. Leuk Res. 2008;32:1054–00.

    Article  CAS  PubMed  Google Scholar 

  68. Chen YK, Hsue SS, Lin LM. Survivin expression is regulated by an epigenetic mechanism for DMBA-induced hamster buccal-pouch squamous-cell carcinomas. Arch Oral Biol. 2005;50:593–8.

    Article  CAS  PubMed  Google Scholar 

  69. Tanaka C, Uzawa K, Shibahara T, Yokoe H, Noma H, Tanzawa H. Expression of an inhibitor of apoptosis, survivin, in oral carcinogenesis. J Dent Res. 2003;82:607–1.

    Article  CAS  PubMed  Google Scholar 

  70. Truong LN, Hertel KJ, Brachmann RK. p53 interacts with the spliceosomal protein SAP145 and affects pre-mRNA processing. AACR Meet Abstr. 2005;2005:1086.

    Google Scholar 

  71. Span PN, Tjan-Heijnen VCG, Heuvel JJTM, de Kok JB, Foekens JA, Sweep FCGJ. Do the survivin (BIRC5) splice variants modulate or add to the prognostic value of total survivin in breast cancer? Clin Chem. 2006;52:1693–700.

    Article  CAS  PubMed  Google Scholar 

  72. Span P, Tjan-Heijnen V, Manders P, van Tienoven D, Lehr J, Sweep F. High survivin predicts a poor response to endocrine therapy, but a good response to chemotherapy in advanced breast cancer. Breast Cancer Res Treat. 2006;98:223–30.

    Article  CAS  PubMed  Google Scholar 

  73. Vandghanooni S, Eskandani M, Montazeri V, Halimi M, Babaei E, Feizi MA. Survivin-deltaEx3: a novel biomarker for diagnosis of papillary thyroid carcinoma. J Cancer Res Ther. 2011;7:325–30.

    Article  PubMed  Google Scholar 

  74. Eissa S, Badr S, Barakat M, Zaghloul AS, Mohanad M. The diagnostic efficacy of urinary survivin and hyaluronidase mRNAs as urine markers in patients with bladder cancer. Clin Lab. 2013;59(7-8):893–00.

    CAS  PubMed  Google Scholar 

  75. Altieri DC. Targeting survivin in cancer. Cancer Lett. 2013;332:225–8.

    Article  CAS  PubMed  Google Scholar 

  76. Mobahat M, Narendran A, Riabowol K. Survivin as a preferential target for cancer therapy. Int J Mol Sci. 2014;15:2494–16.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ciesielski MJ, Qui J, Fenstermaker RA. Survivin as a cancer vaccine target. J Vaccines Vaccin. 2014;5:230.

    Google Scholar 

  78. Chantalat L, Skoufias DA, Kleman J-P, Jung B, Dideberg O, Margolis RL. Crystal structure of human survivin reveals a bow tie-shaped dimer with unusual alpha helical extensions. Mol Cell. 2000;6:183–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Life Sciences (Botany), T. N. B. College, Bhagalpur (T M Bhagalpur University, Bhagalpur), Bhagalpur, 812007, India

    Nand K. Sah

  2. School of Engineering, University of Warwick, Coventry, CV47AL, UK

    Chandrabhan Seniya

Authors
  1. Nand K. Sah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chandrabhan Seniya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nand K. Sah.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sah, N.K., Seniya, C. Survivin splice variants and their diagnostic significance. Tumor Biol. 36, 6623–6631 (2015). https://doi.org/10.1007/s13277-015-3865-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3865-5

Keywords

Search

Navigation