Indian Journal of Medical Research

REVIEW ARTICLE
Year
: 2015  |  Volume : 141  |  Issue : 4  |  Page : 389--397

Survivin: A molecular biomarker in cancer


Praveen Kumar Jaiswal1, Apul Goel2, RD Mittal3,  
1 Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow; Department of Urology, King George's Medical University, Lucknow, India
2 Department of Urology, King George's Medical University, Lucknow, India
3 Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Correspondence Address:
R D Mittal
Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, Uttar Pradesh
India

Abstract

Survivin, a member of the inhibitor of apoptosis (IAP) protein family that inhibits caspases and blocks cell death, is highly expressed in most cancers and is associated with a poor clinical outcome. Survivin has consistently been identified by molecular profiling analysis to be associated with high tumour grade cancers, different disease survival and recurrence. Polymorphisms in the survivin gene are emerging as powerful tools to study the biology of the disease and have the potential to be used in disease prognosis and diagnosis. The survivin gene polymorphisms have also been reported to influence tumour aggressiveness as well as survival of cancer patients. The differential expression of survivin in cancer cells compared to normal tissues and its role as a nodal protein in a number of cellular pathways make it a high target for different therapeutics. This review discusses the complex circuitry of survivin in human cancers and gene variants of survivin, and highlights novel therapy that targets this important protein.



How to cite this article:
Jaiswal PK, Goel A, Mittal R D. Survivin: A molecular biomarker in cancer.Indian J Med Res 2015;141:389-397


How to cite this URL:
Jaiswal PK, Goel A, Mittal R D. Survivin: A molecular biomarker in cancer. Indian J Med Res [serial online] 2015 [cited 2019 Oct 16 ];141:389-397
Available from: http://www.ijmr.org.in/text.asp?2015/141/4/389/159250


Full Text

 Introduction



Cancer remains the second leading cause of death after cardiovascular diseases globally. Increasing evidence indicates that the unique member of the inhibitor of apoptosis (IAP) protein family, survivin, is not only an essential protein molecule for the regulation of mitosis and apoptotic inhibition but it also plays a role in certain physiological processes as well as in pathological conditions such as carcinogenesis in many human organs/cells. Eight members of the family of inhibitors of apoptosis proteins (IAPs) are reported, including X-linked inhibitor of apoptosis (XIAP), cIAP1, cIAP2, NAIP (NLR family, apoptosis inhibitory protein), livin, ILP2 (IAP-like protein 2), BRUCE and survivin [1],[2],[3] .

Survivin is an inhibitor of apoptosis protein and is expressed in a large number of malignancies [4] . Its expression levels correlate with more aggressive disease and poor clinical outcome. Survivin expression is minimal in normal tissues, therefore, it has become a lead target for both as a tumour diagnostic, prognostic and as well as for anti-cancer therapies. Overexpression of survivin in cancer may overcome cell cycle checkpoints to facilitate aberrant progression of transformed cells through mitosis [5] .

Survivin is expressed highly at G2/M phase and declines rapidly in G1 phase of cell cycle. This is largely transcriptionally controlled and involves cell cycle-dependent elements (CDEs) and cell cycle homology regions (CHRs) located in survivin gene promoter [6] . several single nucleotide polymorphisms (SNPs) have been identified in survivin gene, such as -31G/C, -1547A/G, -625G/C and -644C/T. Polymorphism at -31G/C in survivin is a common mutation in cancer cell lines leading to overexpression of survivin due to functional disruption of binding at the CDE/CHR repressor motifs [7] .

This review provides a brief description of the structure of survivin gene/protein, survivin expression and function in apoptosis, and gene variants of survivin.

 Overview of survivin structure and functions



The gene encoding human survivin was cloned by Ambrosini et al[8] in 1997. Survivin spans 14.7 kb at the telomeric end of chromosome 17 and encodes the 16.5 kD wild-type survivin protein of 142 amino acids in length [9] .

As the smallest member of the IAP family, all survivin isoforms characterized so far contain only one of the characteristic N-terminal BIR (Baculovirus IAP Repeats) domains; and an alpha-helix replaces the IAP characteristic RING finger domain involved in zinc ion-binding with the BIR domain [ ] [Figure 1] [8] . The BIR domain is supposed to be important for anti-apoptotic function, whereas the coiled domain probably interacts with tubulin structures [9]. The survivin gene locus encodes multiple genetic splice variants with unique properties and functions. These isoforms include survivin, survivin-2B, survivin-ΔEx-3, survivin-3B, and survivin-2-alpha. Transcription and translation of these isoforms have been demonstrated by several groups of investigators [10],[11],[12] . In malignant cells, all these isoforms are expressed at a very high rate as compared with normal tissues. Survivin has a dual function, playing both a role in cell death regulation and mitotic progression.{Figure 1}

Survivin can be co-immunoprecipitated with caspases-3, -7, and -9 and it suppresses apoptosis induced by overexpression of these caspases, implying that survivin also is a caspase inhibitor [13] . It also inhibits cell death by interfering with caspase-9 processing, the main inhibitor in intrinsic pathway of apoptosis [14] . Activation of cell death pathways can be initiated through different mechanisms, including through ligand binding (FasL, TNF) to a death receptor on the cell surface (extrinsic pathway) or via direct mitochondrial signaling (intrinsic pathway). The mitochondrial pathway is initiated by activation of the Bax/Bcl-2 pathway leading to the release of apoptotic factors such as cytochrome c (cyt c) and apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space into the cytoplasm. The release of cytochrome c from mitochondria results in caspase-3 activation through formation of the cytochrome c/Apaf-1/caspase-9 apoptosome complex. Caspase-3 cleaves a number of substrates including cytoskeletal proteins and DNA. Caspase-activated DNase (CAD) and inhibitor of CAD (ICAD) initiate cleavage and fragmentation of DNA. The IAPs inhibit cell death by physically interacting with caspases. Survivin has been shown to inhibit apoptosis through caspase-dependent and independent pathways [Figure 2].{Figure 2}

Consistent with the lack of a structural caspase activation and recruitment domain (CARD) motif, survivin does not directly bind to and inhibit caspases [15] . Instead, it interacts with several adaptor or cofactor molecules, one example being X-linked IAP (XIAP). By interacting with XIAP, survivin enhances XIAP stability. It can further act by sequestering SMAC/DIABLO (second mitochondria-derived activator of caspases/direct IAP binding protein with low pI), preventing XIAP's inhibition [16] . In each case, survivin enhances XIAP's inhibitor activity of caspase-9 dependent cell death [17] and of death receptor mediated apoptosis [18] .

 Regulation of survivin and p [53]



The p [53] protein is a transcription factor, which can induce apoptosis by regulating the apoptotic genes. Survivin is a target of p [53] for its action and downregulation, and p [53] may induce apoptosis by antagonizing the anti-apoptotic activity of survivin. Survivin may also influence p[53] activity through regulation of mouse double minute 2 homolog (mdm2) and proteosome [19] . However, the negative regulation of survivin by p [53] is poorly understood. Survivin promoter has a p [53] binding element. It may be possible that p [53] directly binds survivin promoter alone or in combination with other protein(s) to repress survivin. E2F (a transcriptional activator) may also bind survivin promoter [20] . Since p [53] has affinity with E2F, it is possible that both form a (p [53] -E2F) complex that represses survivin gene expression [21],[22],[23] . It also interacts with transcriptional repressor (sin3) and histone deacetylases (HDAC) that together can form a p53-sin3-HDAC complex and binds survivin promoter to repress it [21],[24] . p[53] represses survivin through a cascade, which involves protein p [21] complex p21/cip1, which is a p53-induced gene that inhibits cyclin-dependent kinase 2 (cdk2) to prevent phosphorylation of retinoblastoma (RB) proteins [25] . This results in the accumulation of hypophosphorylated pRB. This protein binds E2F family transcription factor and forms a pRB-E2F complex, which may repress survivin gene expression [20],[21],[26],[27] .

 Survivin expression and its role in different cancer



Regulatory mechanisms of survivin expression are yet not fully understood. At the transcriptional level, survivin expression has been demonstrated to involve cell-cycle-dependent element/cell cycle gene homology region (CDE/CHR) G1 repressor elements in the BIRC5 (baculoviral iaprepeat containing 5) promoter [4] .

Survivin is expressed in embryonic and foetal tissues, but is undetectable in normal adult tissues [8] . However, overexpression of survivin has been reported in almost all human malignancies including bladder cancer, lung cancer, breast cancer, stomach, oesophagus, liver, ovarian cancers and haematological cancers [8],[28] . Based on detection of protein by immunohistochemistry and mRNA by polymerase chain reaction techniques, overexpression of survivin has been reported in various human malignancies [Table 1].{Table 1}

Almost all cancers have alternative survivin expression profile compared to normal tissues. Survivin is one of the important genes involved in tumour aggressiveness and therapy resistance. Salz et al[45] showed that survivin expression induced transcriptional changes in the tissue microenvironment further promoting tumourigenesis in the bladder tissue. Khan et al[46] reported higher expression of survivin as a critical factor for radioresistance in head and neck squamous cell carcinoma (HNSCC) cell lines. Dysregulation of oncoapoptotic genes, growth factors, receptors and their downstream signaling pathway components represent a central driving force in tumour development in different cancer [47] .

DNA polymorphisms with more than one variant (allele) having a frequency greater than 1 per cent in a human population have been estimated to occur on the average at one in every 1000 base pairs throughout the human genome [48] . The incidences of polymorphism in genomic DNA, their susceptibility to genetic al­terations, and the risk of tumour progression in patients with cancer can vary substantially between different racial groups [49],[50],[51] . Although most polymorphisms are functionally neutral, some affect regulation of gene expression or the function of the coded protein [52] .

The survivin gene codifies a multifunctional protein involved in the regulation of the cell cycle and inhibition of the apoptotic pathway, and a polymorphism located in its promoter region is associated with gene regulation. Most of the polymorphic studies are confined in promoter region among which the single nucleotide polymorphism (SNP) at -31G/C is most studied in all cancers in comparison to other polymorphic sites [53],[54],[55],[56] . The following are some examples of the survivin gene polymorphisms that were found to be associated with cancer:

Breast cancer

Breast cancer is the most common malignancy among women, accounting for nearly one in three cancers diagnosed among women in the United States, and it is the second leading cause of cancer death among women [57] . A hospital-based case control study by Ulybina et al[58] showed no risk for breast cancer with survivin gene variants at +9194A/G. However, Boidot et al[59] showed that survivin expression might induce breast tumour proliferation by promoting genetic instability.

Bladder cancer

A case control study conducted in Japan showed two survivin polymorphisms associate with higher risk of bladder cancer [60] . A hospital-based study from north India [53] showed that individuals with CC genotype of survivin -31G/C had 2.6 folds higher risk for bladder cancer. A study in Taiwanese population showed increased bladder cancer risk with G/C genotype [61] .

Colorectal cancer

Colorectal cancer is a major cause of morbidity and mortality worldwide. Alterations in pathways regulating important biological processes including cell survival, cell proliferation, epithelial to mesenchymal transition and stroma production have been shown to contribute to colorectal carcinogenesis and tumour progression. A real time PCR study showed association between survivin 31G/C and development of colorectal cancer [62] . Another study showed that the frequencies of the survivin -31C allele and CC genotype were significantly higher in colorectal cancer patients than in healthy subjects [63] . Variant CC genotype of -31G/C of survivin, expressed 1.6 fold higher mRNA levels compared to cases with the -31G/G and -31G/C genotypes [63] .

Endometrial cancer

There is only one study on endometrial cancer and survivin gene polymorphism till date. Survivin is upregulated in endometrial cancer (EC). The presence of allele C of -31G/C was found to be significantly increased in EC tissues compared to the healthy tissues in case of Iranian population [54] .

Oesophageal cancer

A case control study from north India showed that SNP -31G/C was found to be significantly associated with oesophageal cancer susceptibility at variant CC genotype [64] . A study in Chinese population suggested that survivin promoter polymorphisms -625G/C might influence the susceptibility to oesophageal cancer by influencing survivin expression [65] .

Gastric cancer

A study in Chinese population has demonstrated that survivin -31G/C polymorphism may be involved in distal gastric carcinogenesis and tumour differentiation [65] . Another study on Brazilian population suggests that presence of C allele of -31G/C gene polymorphism may be a risk factor for gastric cancer [66] .

Head and neck cancer

In a study conducted in Serbian population, -31G/C gene polymorphism in the promoter region of the survivin gene showed no association with risk for head and neck cancer [67] . Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC). Survivin showed the most promising biomarker of radioresponse in case of head and neck cancer cell lines [68] .

Hepatocellular carcinoma

Early detection of hepatocellular carcinoma (HCC) is seldom available because of the lack of reliable markers. A study from Taiwanese population suggested that survivin T9809C SNP might contribute to the prediction of susceptibility and pathological development to HCC while other polymorphisms of survivin at -31G/C and -241C/T did not show any association with HCC [69] . Survivin -31G/C promoter polymorphism has not shown any major role in genetic susceptibility to hepatocellular carcinogenesis in Turkish population [70] . SNPs of survivin at -31G/C and -625G/C did not show any significant association with HCC in Chinese Han population [55] . Survivin+9194A/G polymorphism also did not show any significant association with hepatocellular carcinoma in Korean population [71] .

Lung cancer

A study conducted in Korean population showed that only the -31G/C genotype distribution was significantly different between the cases and controls. Individuals with at least one -31G allele were at a significantly decreased risk of lung cancer compared to those individuals with the -31CC genotype [72] . Polymorphism in survivin may be a genetic modifier for non-small cell lung cancer prognosis in Chinese population [73] . The BIRC5 promoter polymorphism at nucleotide -31 did not influence the expression of survivin mRNA and protein in non-small cell lung cancer cells and tumours in a study reported in Czech population [74] .

Oral cancer

A study conducted in Taiwanese population reported significantly higher risk for oral cancer with -31GG, +9194GG, and +9809 TT homozygotes of survivin gene variants in comparison to wild type genotype [75] . An expression study by Khan et al[46] showed 72 per cent of survivin expression in tissue samples of oral cancer. Lauxen et al[44] showed >75 per cent expression of survivin protein in oral squamous cell carcinoma (OSCC) tissue samples.

Pancreatic cancer

Only one study has been reported on pancreatic cancer and survivin gene polymorphism which showed significant association of survivin -31G/C with advanced tumour stage as well as the presence of lymph node metastasis [56] .

Renal cell carcinoma

There is only one study reported in renal cell carcinoma (RCC) and survivin gene polymorphism showing a significantly increased occurrence of RCC associated with the CC genotype [76] . The polymorphism was associated with risk of developing advanced stage and moderately differentiated RCC. Patients carrying the CC genotype had a significantly greater prevalence of high clinical stage disease [76] .

 Role of survivin in cancer therapy



Evidences indicate that the expression of survivin is altered in cancer, and that certain changes may be directly implicated in the carcinogenic process. Due to its role as a cancer gene intersecting multiple cellular networks, survivin has been vigorously used as a cancer drug target. While comparing with other apoptosis-based cancer therapies [77] , survivin provides several advantages. Firstly, the disabling survivin is expected to compromise multiple signaling networks required for tumorous maintenance [78] . Second, survivin may be a unique target for molecular antagonists, cancer vaccine and gene therapy. Thirdly, expression of survivin is regulated by Wnt signaling pathway that has main role in stem cells and it is possible that survivin antagonists may affect cancer stem cells [79] . Fourth, survivin is important in tumour formation/progression, especially angiogenesis [80] , and survivin inhibitors have been shown to act on both the transformed population and endothelial cells in tumour. Fifth, although survivin expression has been shown in cytokine stimulated haematopoietic progenitors and in activated T cells, targeting this pathway does not affect the normal cells or tissues suggesting a favourable toxicity profile of survivin based therapeutics. Survivin-directed immunotherapy has been on the move and several phase I trials with administration of survivin peptides or survivin directed autologous cytotoxic T lymphocytes (CTL) generated ex vivo have been completed [81],[82] . Survivin-based vaccination was found to be safe, with no side effects and associated with antigen-specific immunologic responses [81],[83] . Different strategies have been targeted for inhibition of survivin in vivo such as identification of a specifically interacting peptide. This peptide can recognize survivin intracellularly and cause the degradation of the ligand survivin complex [84] . Further, survivin inhibition can be achieved by targeting with nano-based drug delivery devices coupled with biocompatible natural product derived therapeutics [85] . Other strategies under investigation to target survivin include antisense oligonucleotides, siRNA [86] , ribozymes, immunotherapy and small molecular weight molecules. These include use of the antisense oligonucleotide LY2181308, the low molecular weight molecule inhibitor YM155 and survivin-directed autologous CTL. The optimum use of survivin in the treatment of cancer is likely to be in combination with conventional cancer therapies for different cancer [44],[86],[87],[89],[90] .

 Conclusion



Since its discovery in 1997, survivin has provided unique opportunities for basic and translational studies. There are multiple strategies targeting the survivin network which have quickly passed proof of principle, and many have entered in the clinical trials in humans [14] . However, the results of these trials are still awaited. Further research in identifying the novel targets of survivin and understanding their biological functions will enhance our knowledge about the role of these novel regulators in tumour genesis and will facilitate the potential diagnosis and treatment of cancer.

 Acknowledgment



The first author (PKJ) acknowledges the University Grants Commission (UGC), New Delhi, India, for providing Junior Research Fellowship (JRF).

References

1Altieri DC. Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 2008; 8 : 61-70.
2Hunter AM, LaCasse EC, Korneluk RG. The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 2007; 12 : 1543-68.
3Schimmer AD. Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res 2004; 64 : 7183-90.
4Altieri DC. Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 2003; 22 : 8581-9.
5Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional and therapeutic biology of survivin. Cancer Lett 2006; 244 : 164-71.
6Altieri DC, Marchisio PC. Survivin apoptosis: an interloper between cell death and cell proliferation in cancer. Lab Invest 1999; 79 : 1327-33.
7Xu Y, Fang F, Ludewig G, Jones G, Jones D. A mutation found in the promoter region of the human survivin gene is correlated to overexpression of survivin in cancer cells. DNA Cell Biol 2004; 23 : 527-37.
8Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Mad 1997; 3 : 917-21.
9Wheatley SP, McNeish IA. Survivin: a protein with dual roles in mitosis and apoptosis. Int Rev Cytol 2005; 247 : 35-88.
10Badran A, Yoshida A, Ishikawa K, Goi T, Yamaguchi A, Ueda T, et al. Identification of a novel splice variant of the human anti-apoptopsis gene survivin. Biochem Biophys Res Commun 2004; 314 : 902-7.
11Caldas H, Honsey LE, Altura RA. Survivin 2alpha: a novel survivin splice variant expressed in human malignancies. Mol Cancer 2005; 4 : 11.
12Yamada Y, Kuroiwa T, Nakagawa T, Kajimoto Y, Dohi T, Azuma H, et al. Transcriptional expression of survivin and its splice variants in brain tumors in humans. J Neurosurg 2003; 99 : 738-45.
13Tamm I, Want 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; 59 : 5315-20.
14Altieri DC. Targeted therapy by disabling crossroad signaling networks: the survivin paradigm. Mol Cancer Ther 2006; 5 : 478-82.
15Li C, Wu Z, Liu M, Pazgier M, Lu W. Chemically synthesized human survivin does not inhibit caspase-3. Protein Sci 2008; 17 : 1624-9.
16Sun C, Nettesheim D, Liu Z, Olejniczak ET. Solution structure of human survivin and its binding interface with Smac/Diablo. Biochemistry 2005; 44 : 11-7.
17Dohi T, Okada K, Xia F, Wilford CE, Samuel T, Welsh K, et al. An IAP-IAP complex inhibits apoptosis. J Biol Chem 2004; 279 : 34087-90.
18Sensintaffar J, Scott FL, Peach R, Hager JH. XIAP is not required for human tumor cell survival in the absence of an exogenous death signal. BMC Cancer 2010; 10 : 11.
19Wang Z, Fukuda S, Pelus LM. Survivin regulates the p53 tumor suppressor gene family. Oncogene 2004; 23 : 8146-53.
20Jiang Y, Saavedra HI, Holloway MP, Leone G, Altura RA. Aberrant regulation of survivin by the RB/E2F family of proteins. J Biol Chem 2004; 279 : 40511-20.
21Hoffman 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 : 3247-57.
22O'Connor DJ, Lam EW, Griffin S, Zhong S, Leighton LC, Burbidge SA, et al. Physical and functional interactions between p53 and cell cycle co-operating transcription factors, E2F1 and DP1. EMBO J 1995; 14 : 6184-92.
23Hsieh JK, Yap D, O'Connor DJ, Fogal V, Fallis L, Chan F, et al. Novel function of the cyclin A binding site of E2F in regulating p53-induced apoptosis in response to DNA damage. Mol Cell Biol 2002; 22 : 78-93.
24Mirza 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 : 2613-22.
25Löhr K, Möritz C, Contente A, Dobbelstein M. p21/CDKN1A mediates negative regulation of transcription by p53. J Biol Chem 2003; 278 : 32507-16.
26Li W, Fan J, Bertino JR. Selective sensitization of retinoblastoma protein-deficient sarcoma cells to doxorubicin by flavopiridol-mediated inhibition of cyclin-dependent kinase 2 kinase activity. Cancer Res 2001; 61 : 2579-82.
27Flatt PM, Tang LJ, Scatena CD, Szak ST, Pietenpol JA. p53 regulation of G(2) checkpoint is retinoblastoma protein dependent. Mol Cell Biol 2000; 20 : 4210-23.
28Fukuda S, Pelus LM. Survivin, a cancer target with an emerging role in normal adults tissues. Mol Cancer Ther 2006; 5 : 1087-98.
29Monzo M, Rosell R, Felip E, Astudillo J, Sanchez JJ, Maestre J, et al. A novel anti-apoptosis gene: re-expression of survivin messenger RNA as a prognosis marker in non-small-cell lung cancers. J Clin Oncol 1999; 17 : 2100-4.
30Grabowski P, Kuhnel T, Muhr-Wilkenshoff F, Heine B, Stein H, Hopfner M, et al. Prognostic value of nuclear survivin expression in oesophageal squamous cell carcinoma. Br J Cancer 2003; 88 : 115-9.
31Tanaka K, Iwamoto S, Gon G, Nohara T, Iwamoto M, Tanigawa N. Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res 2000; 6 : 127-34.
32Nasu S, Yagihashi A, Izawa A, Saito K, Asanuma K, Nakamura M, et al. Survivin mRNA expression in patients with breast cancer. Anticancer Res 2002; 22 : 1839-43.
33Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T. Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer 2001; 92 :
34271-8.
35Sarela AI, Verbeke CS, Ramsdale J, Davies CL, Markham AF, Guillou PJ. Expression of survivin, a novel inhibitor of apoptosis and cell cycle regulatory protein, in pancreatic adenocarcinoma. Br J Cancer 2002; 86 : 886-92.
36Cohen C, Lohmann CM, Cotsonis G, Lawson D, Santoianni R. Survivin expression in ovarian carcinoma: correlation with apoptotic markers and prognosis. Mod Pathol 2003; 16 : 574-83.
37Nasr MR, El-Zammar O. Comparison of pHH3, Ki-67, and survivin immunoreactivity in benign and malignant melanocytic lesions. Am J Dermatopathol 2008; 30 : 117-22.
38Sarela AI, Macadam RC, Farmery SM, Markham AF, Guillou PJ. Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma. Gut 2000; 46 : 645-50.
39Ikeguchi M, Ueda T, Sakatani T, Hirooka Y, Kaibara N. Expression of survivin messenger RNA correlates with poor prognosis in patients with hepatocellular carcinoma. Diagn Mol Pathol 2002; 11 : 33-40.
40Ito T, Shiraki K, Sugimoto K, Yamanaka T, Fujikawa K, Ito M, et al. Survivin promotes cell proliferation in human hepatocellular carcinoma. Hepatology 2000; 31 : 1080-5.
41Yu J, Leung WK, Ebert MP, Ng EK, Go MY, Wang HB, et al. Increased expression of survivin in gastric cancer patients and in first degree relatives. Br J Cancer 2002; 87 : 91-7.
42Lehner R, Lucia MS, Jarboe EA, Orlicky D, Shroyer AL, McGregor JA, et al. Immunohistochemical localization of the IAP protein survivin in bladder mucosa and transitional cell carcinoma. Appl Immunohistochem Mol Morphol 2002; 10 : 134-8.
43Mori A, Wada H, Nishimura Y, Okamoto T, Takemoto Y, Kakishita E. Expression of the antiapoptosis gene survivin in human leukemia. Int J Hematol 2002; 75 : 161-5.
44Khan Z, Tiwari RP, Mulherkar R, Sah NK, Prasad GB, Shrivastava BR, et al. Detection of survivin and p53 in human oral cancer: correlation with clinicopathologic findings. Head Neck 2009; 31 : 1039-48.
45Lauxen I, Oliveira MG, Rados PV, Lingen MW, Nor JF, Sant'ana Filho M. Immunoprofiling of oral squamous cell carcinomas reveals high p63 and survivin expression. Oral Dis 2014; 20 : e76-80.
46Salz W, Eisenberg D, Plescia J, Garlick DS, Weiss RM, Wu XR, et al. A survivin gene signature predicts aggressive tumor behavior. Cancer Res 2005; 65 : 3531-4.
47Khan Z, Khan N, Tiwari RP, Patro IK, Prasad GB, Bisen PS. Down-regulation of survivin by oxaliplatin diminishes radioresistance of head and neck squamous carcinoma cells. Radiother Oncol 2010; 96 : 267-73.
48Khan Z, Bisen PS. Oncoapoptotic signaling and deregulated target genes in cancers: special reference to oral cancer. Biochim Biophys Acta 2013; 1836 : 123-45.
49Sherry ST, Ward M, Sirotkin K. dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome Res 1999; 9 : 677-9.
50Perez LO, Abba MC, Dulout FN, Golijow CD. Evaluation of p53 codon 72 polymorphism in adenocarcinomas of the colon and rectum in La Plata, Argentina. World J Gastroenterol 2006; 12 : 1426-9.
51Bojesen SE, Nordestgaard BG. The common germline Arg72Pro polymorphism of p53 and increased longevity in humans. Cell Cycle 2008; 7 : 158-63.
52Katkoori VR, Jia X, Shanmugam C, Wan W, Meleth S, Bumpers H, et al. Prognostic significance of p53 codon 72 polymorphism differs with race in colorectal adenocarcinoma. Clin Cancer Res 2009; 15 : 2406-16.
53Costa S, Pinto D, Pereira D, Rodrigues H, Cameselle-Teijeiro J, Medeiros R, et al. Importance of TP53 codon 72 and intron 3 duplication 16bp polymorphisms in prediction of susceptibility on breast cancer. BMC Cancer 2008; 8 : 32.
54Jaiswal PK, Goel A, Mandhani A, Mittal RD. Functional polymorphisms in promoter survivin gene and its association with susceptibility to bladder cancer in North Indian cohort. Mol Biol Rep 2012; 39 : 5615-21.
55Zahedi P, Aminimoghaddam S, Sayahpour FA, Haghpanah V, Amiri P, Fereidoni F, et al. Association of survivin gene polymorphism with endometrial cancer. Int J Gynecol Cancer 2012; 22 : 35-7.
56Li Y, Wang J, Jiang F, Lin W, Meng W. Association of polymorphisms in survivin gene with the risk of hepatocellular carcinoma in Chinese h0 an population: a case control study. BMC Med Genet 2012; 13 : 1.
57Theodoropoulos GE, Michalopoulos NV, Panoussopoulos SG, Taka S, Gazouli M. Effects of caspase-9 and survivin gene polymorphisms in pancreatic cancer risk and tumor characteristics. Pancreas 2010; 39 : 976-80.
58Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343 : 78-85.
59Ulybina YM, Kuligina ES, Mitiushkina NV, Sherina NY, Baholdin DV, Voskresenskiy DA, et al. Distribution of coding apoptotic gene polymorphisms in women with extreme phenotypes of breast cancer predisposition and tolerance. Tumori 2011; 97 : 248-51.
60Boidot R, Vegran F, Jacob D, Chevrier S, Gangneux N, Taboureau J, et al. The expression of BIRC5 is correlated with loss of specific chromosomal regions in breast carcinomas. Genes Chromosomes Cancer 2008; 47 : 299-308.
61Kawata N, Tsuchiya N, Horikawa Y, Inoue T, Tsuruta H, Maita S, et al. Two survivin polymorphisms are cooperatively associated with bladder cancer susceptibility. Int J Cancer 2011; 129 : 1872-80.
62Wang YH, Chiou HY, Lin CT, Hsieh HY, Wu CC, Hsu CD, et al. Association between survivin gene promoter -31C/G polymorphism and urothelial carcinoma risk in Taiwanese population. Urology 2009; 73 : 670-4.
63Antonacopoulou AG, Floratou K, Bravou V, Kottorou A, Dimitrakopoulos FI, Marousi S, et al. The survivin -31 snp in human colorectal cancer correlates with survivin splice variant expression and improved overall survival. Cell Oncol 2011; 34 : 381-91.
64Gazouli M, Tzanakis N, Rallis G, Theodoropoulos G, Papaconstantinou I, Kostakis A, et al. Survivin -31G/C promoter polymorphism and sporadic colorectal cancer. Int J Colorectal Dis 2009; 24 : 145-50.
65Upadhyay R, Khurana R, Kumar S, Ghoshal UC, Mittal B. Role of survivin gene promoter polymorphism (-31G>C) in susceptibility and survival of esophageal cancer in northern India. Ann Surg Oncol 2011; 18 : 880-7.
66Yang L, Zhu H, Zhou B, Gu H, Yan H, Tang N, et al. The association between the survivin C-31G polymorphism and gastric cancer risk in a Chinese population. Dig Dis Sci 2009; 54 : 1021-8.
67Borges Bdo N, Burbano RR, Harada ML. Survivin -31C/G polymorphism and gastric cancer risk in a Brazilian population. Clin Exp Med 2011; 11 : 189-93.
68Kostiæ M, Nikoliæ N, Iliæ B, Carkiæ J, Milenkoviæ S, Vukadinoviæ M. Analysis of polymorphism in the survivin gene promoter as a potential risk factor for head and neck cancers development. Srp Arh Celok Lek 2013; 141 : 304-7.
69Farnebo L, Jerhammar F, Ceder R, Grafström RC, Vainikka L, Thunell L, et al. Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines. J Oral Pathol Med 2011; 40 : 739-46.
70Hsieh YS, Tsai CM, Yeh CB, Yang SF, Hsieh YH, Weng CJ. Survivin T9809C, an SNP located in 3'-UTR, displays a correlation with the risk and clinicopathological development of hepatocellular carcinoma. Ann Surg Oncol 2012; 19 (Suppl 3) : S625-33.
71Bayram S, Akkýz H, Bekar A, Akgöllü E. The association between the survivin -31G/C promoter polymorphism and hepatocellular carcinoma risk in a Turkish population. Cancer Epidemiol 2011; 35 : 555-9.
72Lee JS, Kim JH, Park BL, Cheong HS, Kim JY, Park TJ, et al. Lack of Association of BIRC5 polymorphisms with clearance of HBV infection and HCC occurrence in a Korean population. Genomics Inform 2009; 7 : 195-202.
73Jang JS, Kim KM, Kang KH, Choi JE, Lee WK, Kim CH, et al. Polymorphisms in the survivin gene and the risk of lung cancer. Lung Cancer 2008; 60 : 31-9.
74Dai J, Jin G, Dong J, Chen Y, Xu L, Hu Z, et al. Prognostic significance of survivin polymorphisms on non-small cell lung cancer survival. J Thorac Oncol 2010; 5 : 1748-54.
75Krepela E, Dankova P, Moravcikova E, Krepelova A, Prochazka J, Cermak J, et al. Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma. Int J Oncol 2009; 35 : 1449-62.
76Weng CJ, Hsieh YH, Chen MK, Tsai CM, Lin CW, Yang SF. Survivin SNP-carcinogen interactions in oral cancer. J Dent Res 2012; 91 : 358-63.
77Qin C, Cao Q, Li P, Ju X, Wang M, Chen J, et al. Functional promoter -31G>C variant in survivin gene is associated with risk and progression of renal cell cancer in a Chinese population. PLoS One 2012; 7 : e28829.
78Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell 2003; 3 : 17-22.
79Sawyers C. Targeted cancer therapy. Nature 2004; 432 : 294-7.
80Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414 : 105-11.
81Sakao S, Taraseviciene-Stewart L, Lee JD, Wood K, Cool CD, Voelkel NF. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. FASEB J 2005; 19 : 1178-80.
82Hirschowitz EA, Foody T, Kryscio R, Dickson L, Sturgill J, Yannelli J. Autologous dendritic cell vaccines for non-small-cell lung cancer. J Clin Oncol 2004; 22 : 2808-15.
83Tsuruma T, Hata F, Torigoe T, Furuhata T, Idenoue S, Kurotaki T, et al. Phase I clinical study of antiapoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer. J Transl Med 2004; 2 : 19.
84Otto K, Andersen MH, Eggert A, Keikavoussi P, Pedersen LØ, Rath JC, et al. Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin. Vaccine 2005; 23 : 884-9.
85Groner B, Weiss A. Targeting survivin in cancer: novel drug development approaches. BioDrugs 2014; 28 : 27-39.
86Kanwar JR, Kamalapuram SK, Kanwar RK. Survivin signaling in clinical oncology: a multifaceted dragon. Med Res Rev 2013; 33 : 765-89.
87Khan Z, Tiwari RP, Khan N, Prasad GB, Bisen PS. Induction of apoptosis and sensitization of head and neck squamous carcinoma cells to cisplatin by targeting survivin gene expression. Curr Gene Ther 2012; 12 : 444-53.
88Bisen PS, Khan Z, Bundela S. Biology of oral cancer key apoptotic regulators. Boca Ratan, FL, USA: CRC Press, Taylor and Francis Group; 2014. p. 272.
89Ryan BM, O'Donovan N, Duffy MJ. Survivin: a new target for anti-cancer therapy. Cancer Treat Rev 2009; 35 : 553-62.
90Pennati M, Folini M, Zaffaroni N. Targeting survivin in cancer therapy. Expert Opin Ther Targets 2008; 12 : 463-76.