Survivin Clinical Features in Cervical Cancer

Miftakh Nur Rahman, Chyntia Resti Wijaya, Maria Novalentina


Cervical cancer is the primary lethal malignancy for women worldwide, but because it develops over time, it would be one of the most preventable types of cancer. Dysregulation of apoptosis in cells plays a critical role in the malignancy development. Survivin is the smallest inhibitor apoptotic protein (IAP) which has an important part in regulating cell division and inhibitor of apoptosis. This review focused on survivin features in cervical cancer from mechanisms of malignancy relationship to human papillomavirus (HPV) infection through E6 oncogenic protein, role as a biomarker in diagnosis, prognosis, staging and prediction of metastasis, and also as a target for therapy. Regulation of survivin divided into two main groups; cell cycle dependent and cell cycle independent pathway to maintain life and death balance. Survivin expression is upregulated by E6 protein simultaneously repressing p53. Thus cancerous cervical tissue developed. Survivin is also upregulated in hypoxia, a common condition in many tumors and increased angiogenesis. Survivin plays a major role in chemotherapy and radiation resistance in many cases of cervical cancer. As a target of therapy, survivin has a promising performance, suggested very specific and no issue of resistance and also reducing resistance to chemo and radiation therapy. The goal of treatment is to lower survivin expression through transcription inhibition, immunotherapy based on cytotoxic T cell (CTL) activity and gene therapy.


 Keywords: cervical cancer, survivin, HPV E6 oncoprotein, therapy

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NCI Dictionary of Cancer Terms [Internet]. National Cancer Institute. 2016 [cited 12 December 2016]. Available from: Link

Schiffman M, Castle P, Jeronimo J, Rodriguez A, Wacholder S. Human Papillomavirus and Cervical Cancer. The Lancet. 2007; 370(9590): 890-907. CrossRef

Sahasrabuddhe V, Luhn P, Wentzensen N. Human Papillomavirus and Cervical Cancer: Biomarkers for Improved Prevention Efforts. Future Microbiology. 2011; 6(9): 1083-98. CrossRef

Sanhueza C, Wehinger S, Castillo Bennett J, Valenzuela M, Owen GI, Quest AFG. The Twisted Survivin Connection to Angiogenesis. Mol Cancer. 14: 198. doi: 10.1186/s12943-015-0467-1. CrossRef

Kusuma F, Nuranna L, Rustamadji PD, Sutrisna B. Caspase 3 and Survivin Expressions as a Predictor of Response to Radiation Therapy in Advanced Stage Cervical Cancer. Indones J Obstet Gynecol. 2012; 35(3): 139-45. Link

Garg H, Suri P, Gupta JC, Talwar GP, Dubey S. Survivin: a Unique Target for Tumor Therapy. Cancer Cell Int. 2016; 16: 49. doi: 10.1186/s12935-016-0326-1. CrossRef

Chen X, Duan N, Zhang C, Zhang W. Survivin and Tumorigenesis: Molecular Mechanisms and Therapeutic Strategies. J Cancer. 2016; 7(3): 314-23. CrossRef

Fernández JG, Rodríguez DA, Valenzuela M, Calderon C, Urzúa U, Munroe D, et al. Survivin Expression Promotes VEGF-induced Tumor Angiogenesis via PI3K/Akt Enhanced β-Catenin/Tcf-Lef Dependent Transcription. Mol Cancer. 2014; 13: 209. doi: 10.1186/1476-4598-13-209. CrossRef

Liu HQ, Wang YH, Wang LL, Hao M. P16INK4A and Survivin: Diagnostic and Prognostic Markers in Cervical Intraepithelial Neoplasia and Cervical Squamous Cell Carcinoma. Exp Mol Pathol. 2015; 99(1): 44-9. CrossRef

Ciesielski MJ, Qiu J, Fenstermaker RA. Survivin as a Cancer Vaccine Target. J Vaccines Vaccin. 2014; 5: 3. doi: 10.4172/2157-7560.1000230. CrossRef

Altieri DC. Survivin, Cancer Networks and Pathway-Directed Drug Discovery. Nat Rev Cancer. 2008; 8(1): 61-70. CrossRef

Kogo R, How C, Chaudary N, Bruce J, Shi W, Hill RP, et al. The microRNA-218~Survivin Axis Regulates Migration, Invasion, and Lymph Node Metastasis in Cervical Cancer. Oncotarget. 2015; 6(2): 1090-100. CrossRef

Sandra F, Khosravi-Far R. Phosphorylated-Survivin at Ser81 Induced Protein Kinase A (PKA): A Back Loop. Indones Biomed J. 2011; 3(2): 138-42. CrossRef

Sandra F, Khosravi-Far R. Ser81 Survivin Induced Protein Kinase A (PKA)-dependent Phosphatidylinositol 3-kinase (PI3K) Activity. Indones Biomed J. 2014; 6(3): 157-62. CrossRef

Barrett RM, Osborne TP, Wheatley SP. Phosphorylation of Survivin at Threonine 34 Inhibits Its Mitotic Function and Enhances Its Cytoprotective Activity. Cell Cycle. 2009; 8(2): 278-83. CrossRef

Sandra F, Khosravi-Far R. Survivin S81A Enhanced TRAIL's Activity in Inducing Apoptosis. Indones Biomed J. 2010; 2(3); 113-7. CrossRef

Sukpan K, Settakorn J, Khunamornpong S, Cheewakriangkrai C, Srisomboon J, Siriaunkgul S. Expression of Survivin, CD117, and C-erbB-2 in Neuroendocrine Carcinoma of the Uterine Cervix. Int J Gynecol Cancer. 2011; 21(5): 911-7. CrossRef

Li Q, Zhao J, Liu J, Jia L, Huang H, Xu Y, et al. Survivin Stable Knockdown by siRNA Inhibits Tumor Cell Growth and Angiogenesis in Breast and Cervical Cancers. Cancer Biol Ther. 2006; 5(7): 860-66. CrossRef

Li F, Ackermann EJ, Bennett CF, Rothermel AL, Plescia J, Tognin S, et al. Pleiotropic Cell-division Defects and Apoptosis Induced by Interference with Survivin Function. Nat Cell Biol. 1999; 1(8): 461-6. CrossRef

Lippert BM, Knauer SK, Fetz V, Mann W, Stauber RH. Dynamic Survivin in Head and Neck Cancer: Molecular Mechanism and Therapeutic Potential. Int J Cancer. 2007; 121(6): 1169-74. CrossRef

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(16): 5000-5. CrossRef

Unruhe B, Schroder E, Wunsch D, Knauer S. An Old Flame Never Dies: Survivin in Cancer and Cellular Senescence. Gerontology. 2015; 62(2): 173-81. CrossRef

Beardmore VA, Ahonen LJ, Gorbsky GJ, Kallio MJ. Survivin Dynamics Increases at Centromeres during G2/M Phase Transition and is Regulated by Microtubule-attachment and Aurora B Kinase Activity. J Cell Sci. 2004; 117: 4033-42. CrossRef

Papanikolaou V, Iliopulos D, Dimou I, Dubos S, Kappas C, Kitsiou-Tzeli S, et al. Survivin Regulation by HER2 Through NF-kappaB and c-myc in Irradiated Breast Cancer Cells. J Cell Mol Med. 2011; 15(7): 1542-50. CrossRef

Mehrotra S, Languino LR, Raskett CM, Mercurio AM, Dohi T, Altieri DC. IAP regulation of metastasis. Cancer Cell. 2010, 17(1): 53-64. CrossRef

Komiya Y, Habas R. Wnt Signal Transduction Pathways. Organogenesis. 2008; 4(2): 68-75. Link

Tapia JC, Torres VA, Rodriguez DA, Leyton L, Quest AF. Casein Kinase 2 (CK2) Increases Survivin Expression via Enhanced Beta-catenin-T cell Factor/Lymphoid Enhancer Binding Factor-dependent Transcription. Proc Natl Acad Sci USA. 2006; 103(41): 15079-84. CrossRef

Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME. Vascular Endothelial Growth Factor in Eye Disease. Prog Retin Eye Res. 2008; 27(4): 331-71. CrossRef

Bai H, Ge S, Lu J, Qian G, Xu R. Hypoxia Inducible Factor-1α-mediated Activation of Survivin in Cervical Cancer Cells. J Obstet Gynaecol Res. 2012; 39(2): 555-63. CrossRef

Carpenter RL, Lo HW. STAT3 Target Genes Relevant to Human Cancers. Cancers (Basel). 2014; 6(2): 897-925. CrossRef

Wang H, Holloway MP, Ma L, Cooper ZA, Riolo M, Samkari A, et al. Acetylation Directs Survivin Nuclear Localization to Repress STAT3 Oncogenic Activity. J Biol Chem. 2010; 285(46): 36129-37. CrossRef

Chen Y, Li D, Liu H, Xu H, Zheng H, Qian F, et al. Notch-1 Signaling Facilitates Survivin Expression in Human Non-small Cell Lung Cancer Cells. Cancer Biol Ther. 2011; 11(1): 14-21. CrossRef

Derynck R, Akhurst RJ, Balmain A. TGF-beta Signaling in Tumor Suppression and Cancer Progression. Nat Genet. 2001; 29(2): 117-29. CrossRef

Song K, Shankar E, Yang J, Bane KL, Wahdan-Alaswad R, Danielpour D. Critical Role of a Survivin/TGF-β/mTORC1 Axis in IGF-I-mediated Growth of Prostate Epithelial cells. PLoS One. 2013; 8(5): e61896. doi: 10.1371/journal.pone.0061896. CrossRef

Branca M, Giorgi C, Santini D, Di Bonito L, Ciotti M, Costa S, et al. Survivin as a Marker of Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus and a Predictor of Virus Clearance and Prognosis in Cervical Cancer. Am J Clin Pathol. 2005; 124(1): 113-21. CrossRef

Li F. Role of Survivin and Its Splice Variants in Tumorigenesis. Br J Cancer. 2005; 92(2): 212-6. CrossRef

Borbely AA, Murvai M, Kónya J, Beck Z, Gergely L, Li F, et al. Effects of Human Papillomavirus Type 16 Oncoproteins on Survivin Gene Expression. J Gen Virol. 2006; 87(2): 287-94. CrossRef

Münger K, Howley PM. Human Papillomavirus Immortalization and Transformation Functions. Virus Res. 2002; 89(2): 213-28. Link

Grigore M, Teleman S, Ungureanu D, Mares A. Molecular Markers in Cervical Screening – a Promise for the Future. Romanian Rev Lab Med. 2013; 21(2): 231-9. CrossRef

Wu SF, Zhang JW, Qian WY, Yang YB, Liu Y, Dong Y, et al. Altered Expression of Survivin, Fas and FasL Contributed to Cervical Cancer Development and Metastasis. Eur Rev Med Pharmacol Sci. 2012; 16(15): 2044-50. Link

Lu D, Qian J, Yin X, Xiao Q, Wang C, Zeng Y. Expression of PTEN and Survivin in Cervical Cancer: Promising Biological Markers for Early Diagnosis and Prognostic Evaluation. Br J Biomed Sci. 2012; 69(4):143-6. Link

Xue Y, An R, Zhang D, Zhao J, Wang X, Yang L, et al. Detection of Survivin Expression in Cervical Cancer Cells using Molecular Beacon Imaging: New Strategy for the Diagnosis of Cervical Cancer. Eur J Obstet Gynecol Reprod Biol. 2011; 159(1): 204-8. CrossRef

Kim S, Hong R. Significance of Intracellular Localization of Survivin in Cervical Squamous Cell Lesions: Correlation with Disease Progression. Oncol Lett. 2014; 7(5): 1589-93. CrossRef

Cao XQ, Lu HS, Zhang L, Chen LL, Gan MF. MEKK3 and Survivin Expression in Cervical Cancer: Association with Clinicopathological Factors and Prognosis. Asian Pac J Cancer Prev. 2014; 15(13): 5271-6. Link

Cheng KY, Wang ZL, Gu QY, Hao M. Survivin Overexpression is Associated with Aggressive Clinicopathological Features in Cervical Carcinoma: A Meta-Analysis. PLOS ONE. 2016; 11(10): e0165117. doi: 10.1371/journal.pone.0165117. CrossRef

Grdina DJ, Murley JS, Miller RC, Mauceri HJ, Sutton HG, Li JJ, et al. A Survivin-associated Adaptive Response in Radiation Therapy. Cancer Res. 2013; 73(14): 4418-28. CrossRef

Saxena A, Yashar C, Taylor DD, Gercel-Taylor C. Cellular Response to Chemotherapy and Radiation in Cervical Cancer. Am J Obstet Gynecol. 2005; 192(5): 1399-403. CrossRef

Iida M, Banno K, Yanokura M, Nakamura K, Adachi M, Nogami Y, et al. Candidate Biomarkers for Cervical Cancer Treatment: Potential for Clinical Practice (Review). Mol Clin Oncol. 2014; 2(5): 647-55. CrossRef

Groner B, Weiss A. Targeting Survivin in Cancer: Novel Drug Development Approaches. BioDrugs. 2014; 28(1): 27-39. CrossRef

Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, et al. YM155, a Novel Small-molecule Survivin Suppressant, Induces Regression of Established Human Hormone-refractory Prostate Tumor Xenografts. Cancer Res. 2007; 67(17): 8014-21. CrossRef

Mobahat M, Narendran A, Riabowol K. Survivin as a Preferential Target for Cancer Therapy. Int J Mol Sci. 2014; 15(2): 2494-516. CrossRef

Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, et al. Natural Product Agonists of Peroxisome Proliferator-activated Receptor Gamma (PPARγ): a Review. Biochem Pharmacol. 2014; 92(1): 73-89. CrossRef

Carrasco RA, Stamm NB, Marcusson E, Sandusky G, Iversen P, Patel BKR. Antisense Inhibition of Survivin Expression as a Cancer Therapeutic. Mol Cancer Ther. 2011; 10(2): 221-32. CrossRef

Chi Y, Wang X, Yang Y, Zhang C, Ertl HCJ, Zhou D. Survivin-targeting Artificial MicroRNAs Mediated by Adenovirus Suppress Tumor Activity in Cancer Cells and Xenograft Models. Mol Ther Acids. 2014; 3(11): e208. doi: 10.1038/mtna.2014.59. CrossRef

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(4): 260-7. CrossRef

Tecleab A, Sebti SM. Depletion of K-Ras Promotes Proteasome Degradation of Survivin. Cell Cycle Georget Tex. 2013; 12(3): 522-32. CrossRef

Schmidt SM, Schag K, Müller MR, Weck MM, Appel S, Kanz L, et al. Survivin is a Shared Tumor-Associated Antigen Expressed in a Broad Variety of Malignancies and Recognized by Specific Cytotoxic T Cells. Blood. 2003; 102(2): 571-6. CrossRef

Menderes G, Black J, Schwab CL, Santin AD. Immunotherapy and Targeted Therapy for Cervical Cancer: an Update. Expert Rev Anticancer Ther. 2016; 16(1): 83-98. CrossRef

Lin CT, Wang CN, Lai CH. Immunotherapy for Advanced or Relapsed Cervical Cancer. Gynecol Minim Invasive Ther. 2013; 2(1): 3-7. CrossRef

Andersen MH, Straten PT. Survivin-A Universal Tumor Antigen. Histol Histopathol. 2002; 17(2): 669-75. Link

Pennati M, Folini M, Zaffaroni N. Targeting Survivin in Cancer Therapy: Fulfilled Promises and Open Questions. Carcinogenesis. 2007; 28(6): 1133-9. CrossRef

Mesri M, Wall NR, Li J, Kim RW, Altieri DC. Cancer Gene Therapy Using a Survivin Mutant Adenovirus. J Clin Invest. 2001; 108(7): 981-90. CrossRef

White MK, Hu W, Khalili K. The CRISPR/Cas9 Genome Editing Methodology as a Weapon Against Human Viruses. Discov Med. 2015; 19(105): 255-62. Link


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