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BIRC5 (baculoviral IAP repeat containing 5)

Written2019-01Paola Cristina Branco, Paula Christine Jimenez, João Agostinho Machado-Neto, Letícia Veras Costa-Lotufo
Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, pbranco@usp.br (PCB); jamchadoneto@usp.br (JAM-N); costalotufo@usp.br (LVC-L) Brazil; Department of Marine Sciences, Federal University of Sao Paulo, Santos, paulacjimenez@gmail.com (PCJ), Brazil.

Abstract BIRC5, also known as survivin, has been implicated in cell cycle progression and apoptosis avoidance. BIRC5 is highly expressed in embryonic tissues, however very low or absent in adult tissues. BIRC5 overexpression has been frequently associated to cancer development, a poor prognosis and chemoresistance. Besides that, different BIRC5 isoforms has been characterized and related to better or worse chemotherapy responses depending on the isoform and the cancer type. So far, many efforts have been conducted in order to deplete BIRC5 in cancer cells, including gene therapy, pharmacological and nanotechnological approaches. In this review, we will discuss the role of BIRC5 in cancer cell biology and its clinical significance, demonstrating its DNA/RNA and protein aspects, also its relevance for diagnosis and prognosis, and advances as a target for the treatment of different cancer types.

Keywords BIRC5; Cell cycle progression; Apoptosis; Cancer

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Identity

Alias_namesAPI4
apoptosis inhibitor 4
baculoviral IAP repeat-containing 5
Alias_symbol (synonym)EPR-1
survivin
Other aliasBaculoviral IAP Repeat Containing 5
surviving
HGNC (Hugo) BIRC5
LocusID (NCBI) 332
Atlas_Id 797
Location_base_pair Starts at 78214196 and ends at 78225635 bp from pter ( according to hg19-Feb_2009)  [Mapping BIRC5.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

 
  Figure 1. BIRC5 structure and its splices variants. BIRC5 (also kwon as survivin) presents at least five variants with biological relevance for cancer. A. The protein structure of the most common variant observed presents 142 aa and is composed of a BIR domain that is responsible for its anti-apoptotic activity and a coiled coil. B. The BIRC5 pre mRNA of the most common expressed variant is composed of 3 exons that codifies the BIR domain and the exon 4 that codifies the coiled coil. This variant present anti-apoptotic activity. Survivin Ex3 has its exon 3 deleted and an insertion of a 3'UTR, this isoform codes a protein of 143 aa and also exerts anti-apoptotic functions. Survivin-2B presents an insertion of an exon 2b located between exon 2 and exon 3, generates a protein of 165 aa with pro-apoptotic characteristics. Survivin-2α is characterized by the presence of exon 1 and 2 and the insertion of a 3'UTR, this isoform codifies a protein of 74 aa with pro-apoptotic functions. Survivin-3B presents the insertion of exon 3 b between exon 3 and exon 4, which generates a protein of 165 aa with anti-apoptotic properties. Survivin-3α presents a deletion of exon 3 and generates a protein of 78 aa whose function remain controversial. Arrows indicate the stop codon. UTR- untranslated region. Red line indicates the BIR structure.
Description The entire BIRC5 gene is approximately 11.4 Kb (start: 78214186 and end: 78225636 bp; orientation: Plus strand).
Transcription There are three transcript variants deposited in the NCBI database (https://www.ncbi.nlm.nih.gov/gene). In general, they present three exons (exon 1, 2 and 3) that are responsible for encoding the BIR domain, which is conserved in all BIRC family members, and the exon 4 that is related to the coiled-coil (CC) domain. Variant 1 is the predominant transcript (cDNA: 2574 bp), and encodes isoform 1 (142 amino acids [aa]). Variant 2 lacks an exon in the 3' coding region, which results in a frameshift (cDNA: 2537 bp) and, thus, in a changed protein (143 aa) with a different C-terminus from that of isoform 1 (isoform 2, also known survivin-ΔEx3). Variant 3 exhibits an alternate in-frame segment (cDNA: 2724 bp) and generates a longer (165 aa) and distinct protein (isoform 3, also known survivin-2B), compared to isoform 1. Moreover, three additional transcript variants are reported in Ensembl (http://www.ensembl.org/): a transcript variant containing 568 bp, which generates a protein of 74 aa (also known as Survivin-2α); a transcript variant with 492 bp (cDNA) that produces a protein of 121 aa (also known as Survivin-3B); and a transcript variant comprised of 386 bp (cDNA) that gives a protein of 78 aa (also known as Survivin-3α) (Figure 1).

Protein

Description The IAPs (Inhibitors of Apoptosis Proteins) are a family of proteins primarily known for inhibiting caspase activity, either directly or indirectly, thus preventing apoptotic cell death (Gyrd-Hansen and Meier, 2010). Still, the IAPs are further implicated in key roles in other processes, such as cell cycle, cell migration, inflammation and, even, in the innate immune response (de Almagro and Vucic, 2012).
Structurally, members of the IAPs are characterized by the presence of at least one BIR (Baculovirus IAP repeat) domain, which contains nearly 80 amino acid residues and carries Zn2+ in the center. Such domain is a highly conserved sequence that mediates protein-protein interactions, an essential feature for their anti-apoptotic function. Within the eight human IAPs recognized ( NAIP [BIRC1], BIRC2 [cIAP1], BIRC3 [cIAP2], XIAP [BIRC4], survivin [BIRC5], BIRC6 [bruce], BIRC7 [livin] and BIRC8 [ILP-2]) there may be between one and three BIR domains, typically arranged in their N-terminal portion (Budhidarmo and Day, 2015; Lopez and Meier, 2010).
BIRC5 (survivin), the smallest among the IAPs (16.5 kDa), was discovered in 1997 (Ambrosini et al., 1997), is 142 amino acids (aa) long and has a single BIR domain (Peery et al., 2017). This protein is presented as a stable loop-shaped homodimer, formed by interactions of the N-terminal region through a predominantly hydrophobic interface (Chantalat et al., 2000; Verdecia et al., 2000). Furthermore, on the C-terminal portion, survivin carries an alpha-helix CC (coiled coil) domain, its unique structure (Chantalat et al., 2000; Coumar et al., 2013) which convenes the ability to associate to microtubules and a range of other proteins involved, mainly, in the process of mitosis, and further allowing for translocation among the different cellular compartments, such as mitochondria, cytoplasm and nucleus (Rodel et al., 2012) (Figure 1).
Since BIRC5 is connected to a diverse network of biochemical processes and therefore has remarkable multifunctionality, its modulation in cancer therapy continues to be extensively explored. Several survivin inhibitors have been identified by in vitro and in silico methods, such as antisense oligonucleotides, siRNA, dominant-negative mutants, peptidomimetic molecules and other small inhibitory molecules, and even as anticancer vaccine (Fenstermaker et al., 2016; Sarvagalla et al., 2016).
Expression BIRC5 is normally expressed in embryonic tissues and during fetal development, as well as in fast dividing normal cells (like bone marrow stem cells, basal epithelial cells and thymocytes, even if at lower concentrations), but is virtually undetectable in fully differentiated and healthy adult tissues (Adida et al., 1998; Sah et al., 2006; Stauber et al., 2007). Throughout the cell cycle, BIRC5 is expressed only during mitosis, in a highly regulated manner comprising the chromosomal passenger complex (CPC), as it interacts with tubulin and kinetochores during metaphase, then participates in central spindle organization and cytokinesis, throughout anaphase (Szafer-Glusman et al., 2011).
However, BIRC5 is expressed in cells that undergo malignant transformation, being overexpressed in numerous tumors (Altieri, 2001; LaCasse et al., 2008). Recent studies evidenced that transcriptional activation is not the only cause for BIRC5 overexpression, but also post-transcriptional regulation, specially coordinated by many alternative polyadenylation (APA) sites. For instance, in ovarian cancer, aberrant APA leads to shortening of the 3'-UTR region, enabling escape from negative regulation of miRNAs and causing up-regulation of BIRC5 (He et al., 2016).
Clinically, overexpression of BIRC5 has been correlated with a poor prognosis of cancer, resistance to apoptosis induced by chemotherapy, decreased survival of patients and greater chances of relapse (Islam et al., 2000; Rodel et al., 2012).
Localisation BIRC5 is located both in the cytoplasm and in the nucleus. Nuclear expression has been associated with a poor prognosis and chemoresistance (Du et al., 2015), which may differ among the different types of cancers (Shintani et al., 2013). BIRC5 splice variants were also related to subcellular localization. This has been shown in samples from acute myeloid leukemia patients, where wild-type survivin and the 2B splice variant were expressed in the nucleus, cytoplasm or both, whereas the ΔEx3 isoform was only expressed in the nucleus (Serrano-Lopez et al., 2013). However, considering pro-survival factors, localization is not the only relevant feature: it has been recently demonstrated that BIRC5 can be packaged into extracellular vesicles (endosomes) and its delivery may be guided by antiapoptosis stimuli from cancer cells and tumor microenvironment, inducing pro-survival competences in fibroblasts after treatment with paclitaxel. Conversely, knockdown of BIRC5 in those vesicles promoted increased cell sensitivity to chemotherapeutic agents (Kreger et al., 2016).
 
  Figure 2. BIRC5: a multitask protein. BIRC5 (survivin) acts on cytoplasm and nucleus and is involved different cellular functions: cell survival, cell cycle progression, mitotic spindle formation and transcription activation. In cytoplasm, BIRC5 modulates apoptosis pathway by binding to and blocking initiator caspase 9 and effectors caspases 3 and 7, demonstrating to be involved in extrinsic and intrinsic apoptosis and contributing to cell survival. BIRC5 may be blocked by SMAC/DIABLO, a factor released by mitochondria. Also BIRC5 potentiates apoptosis inhibition through stabilization of BIRC4 (also kwon as XIAP). TGF-β signaling negatively regulates BIRC 5 by phosphorylating SMAD protein. p53-mediated signaling also downregulates BIRC5 functions. CDC phosphorylates BIRC5 and promotes its binding to CDK4 that may be translocated to nucleus, and thus promotes cell cycle progression. In nucleus, BIRC5 is involved in the mitotic spindle formation modulated by Wnt pathway through the phosphorylation inhibiton and nuclear translocation of β-catenin activating BIRC5 and associated to other proteins (not shown) form the Chromosomal Passenger Complex (CPC). The transcription activation of BIRC5 mRNA is mainly promoted by β-catenin, STAT3 (signal transducer and activator of transcription-3) and HIF 1 α (hypoxia-inducible factor-1α).
Function Studies have shown that overexpression of BIRC5 inhibits both the intrinsic and extrinsic pathways of apoptosis and the depletion of survivin in human cell culture impairs apoptosis and triggers cell division defects (Li et al., 1998; Roy et al., 2015). The antiapoptotic mechanism of BIRC5 still needs to be better clarified, however, both the direct or indirect binding of BIRC5 to caspases are proposed (Figure 2) (Altieri, 2013; Garg et al., 2016; Li et al., 1998). Evidences also indicate that BIRC5 binds to XIAP, one of the best studied IAPs, forming a complex that protects XIAP against ubiquitination and proteosomal degradation. This complex then activates multiple signaling pathways, including NF-κB, inhibits caspases CASP3, CASP7 and CASP9, suppresses apoptosis and accelerates tumor progression. Other cytoprotective mechanisms have been proposed for BIRC5, including the ability of mitochondrial BIRC5 to sequester the pro-apoptotic DIABLO (Smac) protein from its binding to BIRC4 (also known as XIAP), or even preventing its release from mitochondria (Altieri, 2013; Coumar et al., 2013; Song et al., 2003).
Interaction of BIRC5 with CDK4 has been associated with progression of the cell cycle. In mitosis, BIRC5 plays a key role in integrating the transient chromosome complex (CPC), along with INCENP, CDCA8 (borealin) and AURKB, which controls the formation and stabilization of the mitotic spindle (Altieri, 2013; Coumar et al., 2013). Activation of Wnt signaling induces β-catenin ( CTNNB1) and BIRC5 nuclear translocation, which contributes in mitotic spindle formation, further regulating CPC, β-catenin, STAT3 and HIF1A (Figure 2). BIRC5 also appears to be involved in the cellular response to stress through the interaction with various chaperones, such as AIP, HSPD1 (HSP60) and HSP90AA1 (HSP90) (Altieri, 2013; Fortugno et al., 2003). Moreover, BIRC5 also partakes in the process of autophagy (Wang et al., 2011) and in DNA repair among several tumor cell lines (Jiang et al., 2009).
BIRC5 has also been shown to induce cell motility, metastasis and increased colonization capacity by AKT-mediated upregulation of the α5 integrin pathway in a melanoma model (McKenzie et al., 2013). Additionally, BIRC5 plays an important role in angiogenesis, contributing to endothelial cell proliferation and migration, which was then linked to increased β-catenin protein levels that consequently promotes an elevated expression of BIRC5 and VEGF (Fernandez et al., 2014). BIRC5 is also directly involved in enhancing anoikis resistance through miR-141/KLF12/Sp1/survivin axis. It is a consensus that anoikis resistance is crucial for establishing a metastatic niche and consequently promoting cancer progression and dissemination (Mak et al., 2017).
Dissimilar functions have been attributed to the different isoforms of BIRC5. Survivin-2α and survivin-2B portray a proapoptotic activity profile, whereas Survivin-ΔEx3 and Survivin-3B show prominent antiapoptotic activity, with similar activities to those of survivin itself. These distinct variants can predict aggressiveness of cancer phenotype, thus contributing to prognosis (Caldas et al., 2005).
BIRC5 can be released from tumor cells in exosomes (Khan et al., 2011). This information provided new insights into biomarkers for determination of early diagnosis and also to predict prognosis. In this context, the splice variant survivin-2B, in breast cancer, was shown to be expressed mostly in primary tumors and exclusively in early stage disease. Conversely, Survivin-ΔEx3 variant was most commonly expressed in late stages of breast cancer (Khan et al., 2014). Survivin-2B has been further reported to promote cell death in some cancer cells by promoting autophagy followed by cell death induced by accumulation and stabilization of IKBKB (IKKB) in the nucleus (Shi et al., 2014).
Homology The BIRC5 gene is highly homologous among different species, as shown in Table 1, which demonstrates the comparison of variant 1 among different species.
Table 1. Comparative identity of human BIRC5 with other species
% Identity for: Homo sapiens BIRC5SymbolProteinDNA
vs. P. troglodytesBIRC598.398.8
vs. M. mulattaBIRC597.997.9
vs. C. lupusBIRC590.890.1
vs. B. taurusBIRC590.190.1
vs. M. musculusBirc583.682.6
vs. R. norvegicusBirc583.081.3
vs. G. gallusBIRC560.665.7
vs. X. tropicalisbirc5.257.864.2
vs. D. rerioBirc5a54.358.0

(Source: http://www.ncbi.nlm.nih.gov/homologene)

Mutations

Somatic Recurrent mutations in the BIRC5 gene are rare. Among the 47,119 unique samples reported in COSMIC (Catalogue of Somatic Mutations in Cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic), only 43 presented BIRC5 mutations (29 missense substitutions, 8 synonymous substitutions, 3 nonsense substitutions and 2 frameshift insertions). Similar findings are reported in cBioPortal (http://www.cbioportal.org) among the 55,481 cancer samples accessed, that show somatic mutations in BIRC5 occur in merely 0.2% of the tested samples (corresponding to 116 mutations, of which 65 are missense substitutions, 50 truncated genes or 1 other mutation). When mutations, amplifications, deep deletions and multiple alterations were considered, the total of cancer samples with any type of genetic alteration in BIRC5 was 969 (1.7%).

Implicated in

  
Entity Angiosarcoma
Note In a cohort including 85 samples from angiosarcoma patients and 88 controls (54 hemangioma and 34 pyogenic granuloma), nuclear BIRC5 expression was observed in all angiosarcoma patients, but in fewer than 7% of the control group. This data indicates that BIRC5 expression may be used as a diagnosis tool in angiosarcoma (Tsuneki et al., 2017). In addition, genetic or pharmacological BIRC5 inhibition reduces cell proliferation in ISO-HAS-B human angiosarcoma cells (Tsuneki et al., 2017).
  
  
Entity Brain cancer
Note Western blot analysis revealed that BIRC5 was expressed in 60.3% of glioma samples, which was associated with a reduced apoptosis ratio and high-grade tumors (Bae et al., 2017). In agreement, samples obtained from gliosarcoma patients presented elevated expression of BIRC5 in the nucleus of tumor cells collected from brain lesions, when compared to normal brain cells (Chen et al., 2010).
BIRC5 expression was also associated to radioresistance: ionization of glioblastoma cell lines promoted BIRC5 upregulation, which mediated dedifferentiation to a stem-like phenotype and, consequently, induced a radioresistant phenotype (Dahan et al., 2014).
Treatment of glioma cells with the survivin inhibitor YM155 overcomes resistance to TRAIL-induced apoptosis, by downregulating MCL1 and BIRC5 (Premkumar et al., 2013). In glioblastoma cell lines, YM155 treatment reduced BIRC5 expression, and induced apoptosis and DNA fragmentation (Lai et al., 2012). Similar results were reported by Jane and colleagues (Jane et al., 2013), where YM155 downregulated BIRC5 and MCL1 expression and inhibited cell growth in malignant human glioma cells. Interestingly, in resistant glioma cell lines attributed to EGFR activation, YM155 alone did not present any significant effects, however in combination with ABT-373, a BH3-only mimetic that targets the prosurvival members of the BCL2 family, a synergic effect mediated by caspase activation was observed (Jane et al., 2013).
Depletion of BIRC5 levels mediated by parthenolide treatment induced apoptosis and cell cycle arrest in glioblastoma cell lines (Tang et al., 2015). Cucurbitacin-I, another natural product, induced cell death in malignant glioma cells, while promoting G2/M accumulation, depletion of p-STAT3, p-STAT5, p-JAK1 and p- JAK2 levels, and downregulation of AURKA, AURKB and BIRC5 (Premkumar et al., 2015).
Medulloblastoma also presents elevated level of BIRC5 expression, as observed for other brain cancers. Similarly, antagonists of BIRC5 impaired proliferation and survival of both murine and human medulloblastoma cells (Brun et al., 2015).
High BIRC5 expression was associated to advanced stages and sporadic tumors in patients aged greater than 12 months (Islam et al., 2000), which negatively impacted clinical outcomes (Azuhata et al., 2001). In addition, BIRC5/p53 and BIRC5/FAS ratios have been implicated in neuroblastoma prognosis (Sandler et al., 2002; Tajiri et al., 2001). In neuroblastoma and oligodendroglioma cell lines, BIRC5 silencing reduced cell viability while further inducing mitotic catastrophe and cell death by caspase-dependent and -independent pathways (Shankar et al., 2001).
  
  
Entity Breast cancer
Note BIRC5 protein expression was found in 78% of high-grade and 21.4% of low-grade patients with ductal carcinoma in situ, indicating that BIRC5 expression is associated with an advanced stage phenotype in breast cancer (Chade et al., 2018). In addition, increased Estrogen positive breast cancer subtypes have been connected to increased BIRC5 regulation, w levels of BIRC5 mRNA (2.24 fold) were observed in whole blood samples from breast cancer patients when compared to healthy donors (Wang et al., 2016).
hich was reverted by treatment with the natural compound myricetin, enhancing apoptosis (Jiao and Zhang, 2016). In triple negative breast cancer, chemoresistance and metastasis were associated to elevated DEPTOR protein expression that, in turn, induced a higher expression of BIRC5, both in vitro and in vivo (Parvani et al., 2015). Survivin and survivin-ΔEx3 were overexpressed and associated to chemoresistance in non-responder samples using ex vivo organotypic cultures of primary human breast tumors (Faversani et al., 2014). Using shRNA targeting BIRC5 splice variants isoforms, Zheng and colleagues (Zheng et al., 2011) demonstrated that apoptosis rates were improved considerably by survivin depletion, but survivin-ϚEx3 isoform silencing only moderately inhibited cell survival and growth in a breast cancer model.
In breast cancer cells, combined therapy using panobinostat with gemcitabine markedly diminished BIRC5 expression (Budman et al., 2012). Similarly, SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) combined with paclitaxel treatment demonstrated positive results regarding BIRC5 downregulation (Panayotopoulou et al., 2017).
Chemoresistance was also related to the extracellular LGALS1 (galectin-1) expression that, moreover, contributes to cancer progression and doxorubicin resistance in triple negative breast cancer. It must be stated, herein, that galectin-1 expression is mediated by STAT3 activation, which is a transcription factor that culminates in BIRC5 upregulation, corroborating the role of BIRC5 in chemoresistance in breast cancer cells (Nam et al., 2017). The function for STAT3 in BIRC5 upregulation in breast cancer cells was also confirmed by Wang and colleagues (Wang et al., 2015), who demonstrated that MIR204 inhibits STAT3 activation and BIRC5 expression.
BIRC5 also participates on the invasive phenotype by regulating the expression of the vascular endothelial growth factor-C ( VEGFC) at both protein and mRNA levels, which culminates in a raised metastasis rate in breast cancer (Cai et al., 2012). In agreement, elevated BIRC5 expression was associated with poor prognostic in stage II/III breast cancer patients (Hamy et al., 2016). The authors proposed that BIRC5 expression might be theranostic, and suggest that high BIRC5-expressing breast cancer patients would be randomized to receive BIRC5 targeting drugs (Hamy et al., 2016).
A recent study that evaluate the transcriptome of primary breast cancer patients, demonstrated that, along with NEK2 and TOP2A, BIRC5 gene was amplified in obese breast cancer patients, reinforcing that this gene may be druggable for this population (Nuncia-Cantarero et al., 2018). One factor that may explain such observation is the synthesis of visfatin, an adipokine secreted by adipocytes, macrophages and inflamed endothelial tissue, which was found to be increased in obese and breast cancer patients, while exerting a protective effect on BIRC5, raising its levels and, thus, contributing to tumor progression (Gholinejad et al., 2017).
In breast cancer cell lines, including triple negative phenotype and tamoxifen-resistant cells, YM155, a BIRC5 inhibitor, as previously mentioned, reduces cell viability, with IC50 values in the low nanomolar range, and induced autophagy (Cheng et al., 2015).
In breast cancer cell lines, ABT-263 (navitoclax), a BCL2 family protein inhibitor, promoted a negative modulation of BIRC5 levels in MDA-MB-231, but not in MCF-7, which was associated with a higher sensitivity to the drug (Lee et al., 2018).
  
  
Entity Cervical carcinoma
Note In a recent meta-analysis including eleven studies and a total of 865 cervical carcinoma patients, Cheng and colleagues (Cheng et al., 2016) reported that elevated BIRC5 expression was positively associated with aggressive clinicopathological features, lymph node metastasis and poor survival outcomes.
  
  
Entity Colorectal cancer
Note Immunohistochemical analysis evidenced that patients with colorectal adenocarcinomas exhibited higher BIRC5 levels compared to adjacent non-tumor colorectal mucosa. In the same study, the authors demonstrated that BIRC5 silencing, by siRNA, suppressed survival and cell invasion, and induced cell cycle G0/G1 arrest and apoptosis in colorectal cancer cells (Wang et al., 2017b). BIRC5 splice variants were also evaluated in colorectal cancer, and the distribution of mRNA observed was the following: 48% of wild-type survivin, 38% of survivin-2B isoform and 29% of survivin-ΔEx3 isoform. The mRNA expression of wild-survivin and survivin-ΔEx3 was related with tumor size and invasion, respectively (Pavlidou et al., 2011). In contrast, BIRC5 levels were not associated with patients with advanced colorectal adenoma (Choi et al., 2017).
Elevated expression of BIRC5 was also correlated with levels of CD133+, which is associated to chemoresistance to 5-fluorouracil, in colon cancer cells. The elevated expression of BIRC5 induced by activation of the CXCL12/ CXCR4 signaling pathway in cells exposed to radiation may be a crucial factor for the acquisition of chemoresistance in this cancer type (Wang et al., 2017a). However, no association was found between expression of BIRC5 and invasion, lymph node metastasis, nor histologic differentiation (Li et al., 2017). Survivin depletion by the EpCAM-aptamer-guided BIRC5 RNAi enhanced colorectal cancer stem cells sensitivity to 5-FU and oxaliplatin, further inducing apoptosis, reducing tumor growth and improving the overall survival in a colorectal cancer xenograft model (AlShamaileh et al., 2017).
The use of natural products was also implicated in reduction of BIRC5 levels, such as tanshinone I, an active compound from traditional Chinese herbal medicine (Lu et al., 2016), and the Pinus roxburghii essential oil (Sajid et al., 2018). Additionally, treatment with tamoxifen β-estradiol or a combination of these two agents promoted decreased BIRC5 levels and impaired cell migration in colorectal cancer cells (Ou et al., 2017). In colon cancer cells, dimethoxy curcumin inhibited cell growth, increased apoptosis, reduced cell migration, downregulated BIRC5 expression and enhanced CDH1 (E-cadherin) in vitro and in vivo (Chen et al., 2016).
Treatment failure in colorectal cancer was previously associated to the presence of stem cells bearing a KRAS mutation, which, then, become resistant to chemotherapy. Treatment with Omega-3 fatty acid DHA promoted a reduction of cell viability, with caspase-3 activation mediated by a decrease in transcript and protein levels of BIRC5 and, moreover, an increase in MIR16-1 expression levels, suggesting that BIRC5 and microRNA-16-1 to be promising molecular targets of DHA (Sam et al., 2018).
  
  
Entity Endometrial cancer
Note In endometrial cancer, BIRC5 was identified to be critical for NEF2-driven progestin resistance. The authors also demonstrated that BIRC5 silencing enabled restoration of progestin sensitivity in NRF2-overexpressing RL-95-2 cells (Fan et al., 2017).
  
  
Entity Gastric cancer
Note Gastric adenocarcinoma patients undergoing gastrectomy were evaluated for the expression of markers with relevance for tumor progression and prognosis. Among them, 93.9 % of samples from gastric cancer patients presented nuclear sub-localization of BIRC5, which was associated with a poor prognosis (Lins et al., 2016). It has been demonstrated that BIRC5 upregulation increased VEGF expression in gastric cancer (Zhang et al., 2014). The authors also demonstrated that 51.3% of gastric carcinoma samples presented BIRC5 expression, which was located mainly in the cytoplasm of tumor cells, associated with lymph node metastasis and reduction of overall survival in the univariate analysis (Zhang et al., 2014).
BIRC5 knockdown using shRNA promoted an elevated sensitivity to radiation and chemotherapy using 5-FU, demonstrating that the modulation of BIRC5 levels may be an important adjuvant therapy for gastric cancer patients (Shen et al., 2012). In agreement, BIRC5 silencing mediated by siRNA increased apoptosis rates, inhibited cell proliferation in a cisplatin-resistant cell line (Li et al., 2014) and impaired cell migration in gastric cancer cells (Li et al., 2015).
  
  
Entity Head and neck squamous cell carcinoma
Note Hih levels of BIRC5 was observed in samples from head and neck squamous cell carcinoma patients, which was associated with poor survival outcomes and chemotherapy resistance (Zhang et al., 2015a) In head and neck squamous cell carcinoma cells, a treatment targeting BIRC5 by using YM155 increased apoptotic and autophagic cell deaths, suppressing pro-survival pathways (Zhang et al., 2015a). Similarly, treatment with an aliphatic hydroxamate-based compound targeting BIRC5 reduced survivin levels through LKB1/AMPK/p38MAPK signaling, and further enhanced p63 phosphorylation and p21 activation (Yen et al., 2018).
  
  
Entity Hepatocellular carcinoma
Note In SMMC-7721 hepatocellular carcinoma cells, treatment with berbamine, a natural compound from Chinese medicine, promoted upregulation of p53 expression and downregulation of BIRC5, which further triggered mitochondria signaling pathway-mediated apoptosis (Cao et al., 2018).
  
  
Entity Kidney cancer
Note In renal cell carcinoma patients, high BIRC5 expression was associated with increased TNM stage and high Fuhrman grade, which indicates that BIRC5 may be a good prognosis predictor (Ma et al., 2017). Furthermore, BIRC5 has been associated with tumor progression and chemoresistance to temsirolimus, an MTOR inhibitor. Strategies that abrogate survivin expression, such as shRNA-mediated BIRC5 silencing or pharmacological approach (YM155), reduced chemoresistance of renal cell carcinoma cells in vitro and in vivo (Carew et al., 2015).
Other signaling pathways seem to converge to the induction of BIRC5 expression in renal cell carcinoma. For instance, combined treatment between the histone deacetylase (HDAC) inhibitor OBP-801 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 synergistically inhibited cell growth and induced apoptosis in renal cell carcinoma through BIRC5 downregulation (Yamada et al., 2013).
  
  
Entity Leukemia
Note In chronic myeloid leukemia, the oncogenic signaling induced byBCR/ ABL1 leads to BIRC5 upregulation by activating the JAK2/STAT3 pathway. Moreover, BIRC5 silencing promoted pronounced cytotoxic effect in both imatinib-sensitive and -resistant chronic myeloid leukemia cell lines, a similar effect to that observed after treatment with shepherdin, a cell-permeable peptidomimetic compound that downregulates BIRC5. These findings indicate that survivin may be a target in BIRC5-overexpressing leukemias (Stella et al., 2013). The combined use of C82 (a Wnt/β-catenin signaling modulator) and nilotinib in chronic myeloid leukemia progenitor cells inhibited the expression of CD44, MYC, BIRC5, p-CRKL and p-STAT5 (Zhou et al., 2017)
In acute myeloid leukemia, BIRC5 overexpression is involved in drug resistance of leukemia stem cells, regulated by the ERK/MSK/Sp1/MYC axis (Zhang et al., 2015b). Interestingly, BIRC5 depletion, by siRNA, reduced cell proliferation, induced apoptosis, and synergistically enhanced cytotoxicity of etoposide in acute myeloid leukemia cells (Karami et al., 2013). Other molecular signaling that has been involved in acute myeloid leukemia resistance is the expression of MUC1 (MUC1-C), an oncoprotein critical for the onset of tumorigenesis, which is overexpressed in acute myeloid leukemia blasts and leukemia stem cells. It has been demonstrated that targeting MUC1-C reduced BIRC5 levels and increased sensitivity to cytarabine, indicating that BIRC5 is involved in multiple signaling pathways required for survival in leukemia cells (Stroopinsky et al., 2018).
Acute lymphoblastic leukemia (ALL) patients also presented elevated levels of BIRC5 and VEGF, especially prior to treatment with an association of idarubicin, cytosine arabinoside and etoposide. Nevertheless, those levels decreased after treatment (Yang et al., 2013). In children diagnosed with acute lymphoblastic leukemia, BIRC5 expression was higher compared to healthy donors. The same group of patients was monitored during the entire treatment period and those who went in to complete remission of the disease presented decreased levels of BIRC5, compared to diagnosis sample. In contrast, BIRC5 protein levels were elevated in non-survived ALL patients (Yahya et al., 2012). In acute lymphoblastic leukemia primary samples and cell lines, treatment with YM155 exhibited elevated cytotoxicity by induction of DNA damage, leading to phosphorylation of CHEK2 and H2AFX and promoting suppression of BIRC5 expression (Chang et al., 2015).
It is well accepted that leukemia stem cells contribute to a reduced treatment efficacy and also to chemoresistance. The natural product curcumin decreased BIRC5 levels in leukemia stem cell-like KG1a in a combined treatment with busulfan, which may overcome such chemoresistant of leukemia stem cells (Weng et al., 2015).
Furthermore, Li and colleagues (Li et al., 2018) observed an association between the presence of C allele of BIRC5 polymorphism rs9904341, but not of rs8073069, and an increased risk of acute leukemia development in a cohort including 182 childhood acute leukemia patients and 200 controls.
  
  
Entity Liver cancer
Note In samples from hepatocarcinoma patients, 55.4% of tumor tissues were positive for BIRC5 expression, which was higher when compared to non-tumor adjacent tissues (2%). Additionally, BIRC5 expression has been directly correlated with unfavorable clinical staging and tumor score, and the presence of extrahepatic metastasis. The authors also demonstrated a positive correlation between BIRC5 and VEGF expression, implying that besides avoiding apoptosis, BIRC5 may induces angiogenesis contribute to tumor dissemination (Tian et al., 2018).
  
  
Entity Lung cancer
Note A meta-analysis study including 3,206 non-small cells lung cancer (NSCLC) patients and 816 normal controls, BIRC5 was found to be overexpressed in tumor samples and strongly correlated with histological differentiation, tumor-node-metastasis stage and lymph node metastasis, which indicates that BIRC5 may be a tumor progression marker for such cancer type (Duan et al., 2016). Another study indicated that BIRC5 may be involved in chemoresistance of NSCLC cells (Hu et al., 2016). Additionally, it was demonstrated that the GC+CC genotypes in the promoter region (-31) of the BIRC5 gene (polymorphism rs9904341) were significantly associated with EGFR mutations in a cohort of 360 lung cancer patients (Liu et al., 2016).
Recently, BIRC5 was identified as a target of MIR195, a microRNA that induced apoptosis and senescence in NSCLC cells (Yu et al., 2018). A combined therapy using the natural product resveratrol and the epidermal growth factor receptor (EGFR) inhibitor erlotinib promoted an increase in cell death mediated by BIRC5 depletion in NSCLC cells (Nie et al., 2015). Similarly, depletion of BIRC5 induced by treatment with YM155 increased the sensitivity of such cells to radiation (Hu et al., 2015). Treatment with the natural product fisetin also increased sensitivity to cisplatin in cisplatin-resistant NSCLC cells by modulation of MAPK/BIRC5/Caspase axis (Zhuo et al., 2015).
Lung cancer stem cells were more sensitive to FL118, a BIRC5 inhibitor, than cisplatin. Additionally, FL118 downregulated cancer stem cell related markers, which may improve drug-sensitivity in this kind of tumor cells (Wang et al., 2017c).
  
  
Entity Lymphoma
Note In non-Hodgkin lymphoma, specifically the aggressive subtype extranodal natural killer/T-cell lymphoma, which is frequently associated with resistance to anthracyclines, presence of BIRC5 serum levels were detected in approximately 25% of patients, which is associated with advanced stages of the disease. In addition, the percentage of lymphoma cells that demonstrated BIRC5 nuclear localization was significantly associated with BIRC5 serum concentration (Kim et al., 2015).
BIRC5 expression was positive in 40% of lymph node biopsy of diffuse large B-cell lymphoma patients. Such observation correlated with unfavorable factors for therapy response and predicted shorter survival outcomes (Markovic et al., 2012). A meta-analysis, including 17 studies and 1,352 diffuse large B-cell lymphoma patients, found positive BIRC5 expression to be associated with advanced clinical stages and reduced overall survival (Zhang et al., 2015c).
The combinatory use of bendamustine and rituximab associated with BIRC5 inhibitor, YM155, presented potentiating effects on induction of cell death by triggering DNA damage and cell cycle arrest in lymphoma cells, and, moreover, reduced tumor size and metastatic capacity in diffuse large B-cell lymphoma xenograft murine models (Kaneko et al., 2014). A combined treatment of rituximab and YM155 was shown to reduce tumor growth more effectively than monotherapy (Kita et al., 2012). In B and T cell lymphoma cells, BIRC5 abrogation using the non-toxic tellurium compound, AS101, has overcome chemoresistance, sensitizing these cells to paclitaxel (Danoch et al., 2015). BIRC5 expression presented anti-apoptotic functions and is regulated by NF-κB and PI3K/AKT signaling pathways in nasal NK/T-cell lymphoma cells (Sun et al., 2015).
  
  
Entity Malignant pleural mesothelioma
Note In two independent cohorts of malignant pleural mesothelioma patients, nuclear BIRC5 expression in both, pre- and post-chemotherapy tissues, was associated with shorter freedom from recurrence and overall survival, indicating that BIRC5 expression may be a prognostic factor for poor clinical outcomes in this cancer type (Meerang et al., 2016).
  
  
Entity Melanoma
Note BIRC5 expression was previously demonstrated in melanoma and melanocytic nevus, which demonstrated all nevi, regardless of histologic type, expressed detectable levels of BIRC5 (Yan et al., 2006). Additionally, a cytoplasmic staining of BIRC5 was evidenced in dysplastic nevi (Florell et al., 2005). In normal melanocytes, it was demonstrated that p53 and RB1 are required to repress BIRC5 expression. A role for E2F2 in the negative regulation of BIRC5 expression was also pointed out (Raj et al., 2008). Increased BIRC5 expression was observed in vivo in melanocytes that were more resistant to UV-induced apoptosis, which was further associated to lower rates of spontaneous apoptosis, earlier melanocytic tumor development and increased tendency for lymph node and lung metastasis (Thomas et al., 2007). Furthermore, BIRC5 overexpression in melanocytes activated the AKT and MAPK signaling pathways, acquiring a more invasive phenotype, and demonstrating the involvement of BIRC5 on the onset and progression of melanoma (McKenzie et al., 2013).
In melanoma cells, BIRC5 was associated to enhanced AKT and MAPK signaling dependent migration and invasion, as well as to the upregulation of ITGA5 (α5 integrin) (McKenzie et al., 2010). BIRC5 silencing through RNA interference promoted cell cycle arrest and reduced cell proliferation and metastasis in vivo and in vitro in melanoma models. Moreover, as observed for other tumor types, BIRC5 inhibition led to increased sensitivity to chemotherapy in melanoma cells (Kedinger et al., 2013). In another study, a proposed strategy to overcome chemoresistance and to promote melanoma cell death was the combination of vemurafenib and Nutlin-3, whose synergism was responsible for BIRC5 depletion and apoptosis induction (Ji et al., 2013).
Pharmacological suppression of BIRC5 expression, using YM155, increased apoptosis induction and tumor regression in melanoma xenograft models. In the same study, combined treatment of YM155 and docetaxel presented potentiating effects in induction of apoptosis compared to monotherapy, corroborating the notion that targeting BIRC5 may be an interesting approach in melanoma management (Yamanaka et al., 2011). Similar results were obtained using natural compounds extracted from plants that target BIRC5 through β-catenin and STAT3 suppression (Habibie et al., 2014).
Another alternative approach for targeting BIRC5 was the generation of recombinant fusion proteins containing the TAT protein transduction domain and either wild-type survivin (TAT-Surv-WT) or a dominant- negative mutant (TAT-Surv-T34A). The mutant promoted in vitro cell death through apoptosis and DNA fragmentation in melanoma cells. In vivo injections of such mutant in melanoma xenograft mice increased apoptosis, induced aberrant nuclei formation and impaired tumor growth (Yan et al., 2006).
BIRC5 mRNA was detected in 98% of samples from metastatic melanoma patients. High BIRC5 mRNA levels were significantly associated with poor overall survival (Takeuchi et al., 2005).
  
  
Entity Multiple myeloma
Note BIRC5 expression was positive in 35% of samples from newly diagnosed multiple myeloma patients, but no association with clinical and laboratorial characteristics, treatment response and survival outcomes was found (Zeng et al., 2014). On the other hand, Yang and colleagues (Yang et al., 2016b), in a study that evaluated the efficacy of a combination treatment with fludarabine, vincristine, epirubicin, dexamethasone and thalidomide (FVADT) chemotherapy regimen for refractory multiple myeloma patients, reported that complete remission and efficacy rates were significantly lower in the BIRC5-positive group, when compared with the BIRC5-negative group.
  
  
Entity Myxoid liposarcoma
Note Using high-throughput drug screen and myxoid liposarcoma cell lines, BIRC5 has been identified as a relevant protein important for cell survival (de Graaff et al., 2017).
  
  
Entity Oral squamous cell carcinoma
Note Elevated BIRC5 mRNA expression was observed in samples from oral squamous cell carcinoma patients compared to peritumoral or normal tissues (Li et al., 2012). Still, such increase was shown to be insufficient to drive tumor progression in oral squamous cell carcinoma, however nuclear expression of BIRC5 was correlated with tumor stage and differentiation grade (Liu et al., 2017). Additionally, the authors suggested that nuclear localization of BIRC5 has been due to the acetylation at K129 in the protein C-terminal region (Liu et al., 2017). In oral squamous cell carcinoma cells, treatment with YM155 reduced BIRC5 levels and increased apoptosis rates (Yan and Su, 2017).
  
  
Entity Ovarian cancer
Note High BIRC5 levels correlate with advanced stage, metastasis and poor disease-free survival in ovarian cancer (Aune et al., 2011; No et al., 2011). Moreover, BIRC5 serum levels were significantly higher, while DIABLO (Smac) levels were significantly lower in patients with serous ovarian carcinoma when compared to healthy controls (Dobrzycka et al., 2015).
The association of nuclear and cytoplasmic BIRC5 expression and prognosis remains controversial in ovarian cancer. The evaluation of BIRC5 expression in patients treated with taxane and platinum agents concluded that, in this treatment regimen, higher nuclear BIRC5 expression was associated with reduced risk of disease recurrence and death (Felisiak-Golabek et al., 2011). By contrast, another study reported that nuclear BIRC5 was significantly associated with chemoresistance to taxane-based chemotherapy, predicting poor progression-free survival (Du et al., 2015). Immunohistochemistry analysis revealed that BIRC5 expression presented a positive correlation with FIGO stage in epithelial ovarian cancer, benign epithelial ovarian tumor tissue and borderline ovarian tumor tissues (Ju et al., 2016).
BIRC5 splices variants were also correlated to the development of ovarian cancer and resistance to chemotherapy. Taxane-resistant ovarian cancer cells expressed higher BIRC5 mRNA levels than their taxane-sensitive counterparts. Survivin-2B expression was significantly higher in taxane-resistant cells, when compared to sensitive cells (Vivas-Mejia et al., 2011).
YM155 treatment induced BIRC5 downregulation, cell growth inhibition, cell cycle arrest, reactive oxygen species formation and apoptosis, and enhanced docetaxel efficacy in ovarian cancer cell lines (Hou et al., 2018). In agreement, in ovarian cancer cells, BIRC5 knockdown enhanced cisplatin sensitivity in resistant cancer cells, inducing apoptosis and inhibiting the invasive process through downregulation of MMP2 (Jiang et al., 2013).
  
  
Entity Pancreatic cancer
Note In a cohort of 51 pancreatic adenocarcinoma patients, BIRC5 expression was found in 49% of samples and was associated with poor survival outcomes (Contis et al., 2018). Similar results were reported by Zhou and colleagues (Zhou et al., 2018), who described that nuclear BIRC5 was higher in tumor compared to non-tumor pancreatic tissues, and a high nuclear BIRC5 expression was an independent predictor of disease-specific survival in ductal pancreatic adenocarcinoma patients. In pancreatic cancer models, FL118, a BIRC5 inhibitor, reduced cell viability, including for stem cell like and cisplatin-resistant cells, and decreased xenograft tumor growth and metastasis (Ling et al., 2018).
  
  
Entity Prostate cancer
Note BIRC5 levels was not detected in normal tissues, slightly detected in benign prostate hyperplasia tissues and considerably higher in prostate adenocarcinoma, which was positively correlated with higher tumor stage (Eslami et al., 2016). In agreement, increased BIRC5 levels were also associated with poor survival outcomes in prostate cancer patients (Xu et al., 2015).
In a cohort including 157 prostate cancer patients and 145 controls, genetic polymorphisms c.-31G>C (rs9904341), c.454G>A (rs2071214), and c. *148T>C (rs1042489) of BIRC5 were associated with risk for prostate cancer development (Karimian et al., 2018).
Treatment with BIRC5 inhibitor (YM155) inhibited cell growth, cell migration and invasion in prostate cancer cells (Xu et al., 2015). Overexpression of miR-494 (a microRNA targeting BIRC5) and/or BIRC5 silencing using shRNA attenuated cell growth in vitro and in vivo (Zhu et al., 2016). Moreover, treatment of prostate cancer cells with a selective inhibitor of nuclear export, KPT-330, inhibited proliferation and promoted apoptosis of tumor cells, by increasing protein degradation of exportin XPO1, BIRC5 and CCND1, further leading to cell cycle arrest and apoptosis (Gravina et al., 2015). Natural products, such as the triterpenoid pristimerin, demonstrated that BIRC5 levels may modulate therapeutic responses, once BIRC5-overexpressing prostate cancer cells became resistant to pristimerin (Liu et al., 2014).
  
  
Entity Salivary adenoid cystic carcinoma
Note In SACC-83 salivary adenoid cystic carcinoma cells, treatment with simvastatin reduced cell viability and induced apoptosis by decreasing BIRC5 levels (Cai et al., 2018).
  
  
Entity Thyroid cancer
Note Nicotinamide phosphorybosiltransferase (NAMPT), a marker for thyroid cancer that is positively associated with tumor stage and metastasis, presented a positive correlation with BIRC5 (survivin) and survivin splice variant º, but not with survivin-2B, expressions, reinforcing that survivin and its variant ΔEx3 are associated with poor prognosis and advanced stage cancer (Sawicka-Gutaj et al., 2015).
  
  
Entity Urinary tract cancer
Note In SK-NEP-1 Wilms tumor cells, YM155 treatment reduced cell proliferation, induced apoptosis and inhibited growth of xenograft tumors. Interestingly, YM155 treatment promoted an elevation in levels of other BIRC-related genes, such as BIRC3 and BIRC8, suggesting that the regulation of cell death induced by BIRC5 suppression is highly orchestrated with other members of the IAP family (Tao et al., 2012).
  

To be noted

Pharmacological Advances for BIRC5 inhibition
A novel survivin inhibitor developed in 2012, FL118, presents structural similarities to irinotecan. Such molecule selectively inhibits survivin promoter activity and gene expression in a TP53 status-independent manner. Additionally, it promotes the inhibition of three additional cancer-associated survival genes ( MCL1, BIRC4 and BIRC3) (Ling et al., 2012). FL118 was able to suppress BIRC5 expression in cancer stem cells in a lung cancer model (Wang et al., 2017c), which are known to be a cell population that presents chemoresistance and are responsible for disease recurrence in multiple type of cancer (Zhao, 2016).
Vaccines against BIRC5
Survivin-2B80-88 (AYACNTSTL) is an antigenic peptide that can be recognized by CD8+ cells and demonstrated promising results as a potent immunogenic cancer vaccine (Idenoue et al., 2005). By using an HLA-A24/survivin-2B80-88 tetramer, the number of cytotoxic T-lymphocytes precursors in peripheral blood mononuclear cells of HLA-A24+ cancer patients was increased. Interestingly, cytotoxic cells positive for this peptide were found among peripheral blood mononuclear cells obtained from 100% of patients with breast cancers (n=7), 83% with colorectal cancers (n=7) and 57% with gastric cancers (n=7) (Idenoue et al., 2005).
Dendritic cells vaccines using recombinant BIRC5 were tested in hormone refractory prostate cancer patients and results revealed cellular response, disease stabilization, partial tumor remission and no adverse events (Xi et al., 2015).
Using the DepoVax platform, a BIRC5 vaccine was developed (DPX-Survivac) and produced antigen-specific immune responses in ovarian cancer patients. Of note, 12 out of 18 ovarian patients remained without clinical progression after a 6-month treatment (Berinstein et al., 2015).
A study using vaccination with a long BIRC5 peptide demonstrated a BIRC5-specific CD8-mediated tumor cell lysis and, more importantly, the presence of circulating anti-BIRC5 antibodies was found in both, murine glioblastoma models and human glioblastoma patients following vaccination. The same vaccine showed promising results in GL261 glioma and B16 melanoma murine models (Fenstermaker et al., 2018).
Gene Therapy targeting BIRC5
Gene therapy has already been used as an approach for inhibiting the expression of BIRC5 and to improve cell death induction in cancer. A combined gene therapy using BIRC5 siRNA and the fusion suicide gene yCDglyTK system displayed a relevant antitumor effect, inducing apoptosis more efficiently and eradicating colon cancer cells. Furthermore, this therapeutic system was able to inhibit the migration of colon cancer cells in vitro (Ye et al., 2017).
Gene therapy using degradable heparin-polyethyleneimine (HPEI) nanoparticles to deliver a dominant-negative human BIRC5 T34A (hs-T34A) gene was also used in ovarian cancer with promising results. HPEI nanoparticles effectively delivered the hs-T34A into ovarian carcinoma cells with low systemic cytotoxicity. Additionally, intraperitoneal administration of HPEI/hs-T34A complexes inhibited tumor growth in ovarian cancer xenograft murine model (Luo et al., 2016). The use of packaging RNA (pRNA) of bacteriophage phi29 DNA-packaging motor to carry siRNA for combined BIRC5 and metallothionein silencing presented a stronger effect on reducing cell proliferation and aggressiveness in ovarian tumor cell lines than either one applied alone (Tarapore et al., 2011).
Adeno-associated virus (aaV)-mediated the dominant-negative human BIRC5 T34A (raaV-Sur-Mut(T34a)) delivery inhibited cell proliferation, induced apoptosis and sensitized gastric cancer cells to 5-FU in vitro and impaired tumor growth in vivo (Dang et al., 2015).
Nanotechonology for BIRC5 depletion
Several nanotechnology-based systems were developed to improve the delivery of siRNA or shRNA targeting BIRC5 in cancer cells, including a Fe3O4 core covered respectively by a polyacrylate (PA) or polyethyleneimine (PEI) layer (Fe3O4-PA-PEI) (Arami et al., 2016). Moreover, magnetic nanoparticles containing polyethyleneglycol-lactate polymer (PEG-LAC) have also been used for such means, as well as other systems, like chitosan and polyethyleneimine (PEI) (Arami et al., 2017), poly(ethylene glycol)-modified chitosan (PEG-CS) (Sun et al., 2016), NDCONH(CH2) 2NH-VDGR/survivin (Bi et al., 2016) and monomethoxypolyethylene glycol-chitosan (mPEG-CS) (Yang et al., 2016a). These systems have been shown to inhibit expression of BIRC5, increase apoptosis, reduce cell proliferation and metastasis, and to shrink tumor size in multiple cancer models.
Nanoparticles were also developed for co-delivery of siRNA targeting BIRC5 and paclitaxel, which constrained tumor growth, prolonged survival and augmented anticancer properties of paclitaxel in murine cancer models (Jin et al., 2018; Salzano et al., 2015).
A summary of approaches to BIRC5 targeting in cancer is described in Table 2.
Table 2. Summary of BIRC5 targeting strategies in cancer.
Pharmacological approaches
DrugCladeCancer typeReferences
YM155Small-molecule survivin inhibitorMultiple cancer typesCheng et al., 2014; Jane et al., 2013; Kita et al., 2012; Lai et al., 2012
FL118Small-molecule survivin inhibitorCancer Stem CellWang et al., 2017
Vaccines
VaccineCladeCancer TypeReferences
Survivin-2B80-88Antigenic peptideBreast cancer; Gastric cancer; Colorectal cancerIdonoue et al., 2005
Dendritic Cell VaccinesDendritic cells vaccines using recombinant BIRC5Hormone refractory prostate cancer patientsXi et al., 2015
DPX-SurvivacBIRC 5 vaccine developed based on DepoVax platformOvarian cancerBerinstein et al., 2015
SurVaxMLong BIRC5 peptideGliobastomaFernstermarker et al., 2018
Gene Therapy
StrategyCancer TypeReferences
Suicide gene yCDglyTK combined with BIRC5 siRNAColon cancer cellsYe et al., 2017
Heparin-polyethyleneimine (HPEI) nanoparticles to deliver a dominant-negative human BIRC5 T34A (hs-T34A)Ovarian carcinomaLuo et al.,2016
Packaging RNA (pRNA) of bacteriophage phi29 DNA-packaging motor to carry BIRC 5 and methallotionein siRNAOvarian carcinomaTarapore et al., 2011
Adeno-associated virus (aaV)-mediated the dominant-negative human BIRC5 T34A (raaV-Sur- Mut(T34a)Gastric cancerDang et al., 2015
Nanotechnology
Strategy of useNanoparticleCancer TypeReferences
Nanoparticles for siRNA deliveryFe3O4 core covered respectively by polyacrylate (PA) and polyethyleneimine (PEI) layer (Fe3O4-PA-PEI)Breast cancerArami et al., 2016
Magnetic nanoparticles containing polyethyleneglycol-lactate polymer (PEG-LAC), chitosan, and polyethyleneimine (PEI)Breast cancer and LeukemiaArami et al., 2017
Poly(ethylene glycol)-modified chitosan (PEG-CS)Murine breast cancerSun et al., 2016
NDCONH(CH2)2NH-VDGR/survivinBreast cancerBi et al., 2016
Nanoparticles for shRNA deliveryMonomethoxypolyethylene glycol-chitosan (mPEG-CS)Prostate cancerYang et al., 2015
Nanoparticles for combinatory treatmentNanoparticles were also developed for co-delivery of siRNA targeting BIRC5 and paclitaxelMurine cancer modelsJin et al., 2018; Salzano et al., 2015

Funding: Process numbers: 2017/09022-8 and 2015/17177-6, Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

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Nuclear survivin expression is a positive prognostic factor in taxane-platinum-treated ovarian cancer patients
Felisiak-Golabek A, Rembiszewska A, Rzepecka IK, Szafron L, Madry R, Murawska M, Napiorkowski T, Sobiczewski P, Osuch B, Kupryjanczyk J; Polish Ovarian Cancer Study Group (POCSG)
J Ovarian Res 2011 Nov 10;4(1):20
PMID 22075440
 
Survivin Monoclonal Antibodies Detect Survivin Cell Surface Expression and Inhibit Tumor Growth In Vivo
Fenstermaker RA, Figel SA, Qiu J, Barone TA, Dharma SS, Winograd EK, Galbo PM, Wiltsie LM, Ciesielski MJ
Clin Cancer Res 2018 Jun 1;24(11):2642-2652
PMID 29540489
 
Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced β-catenin/Tcf-Lef dependent transcription
Fernández JG, Rodríguez DA, Valenzuela M, Calderon C, Urzúa U, Munroe D, Rosas C, Lemus D, Díaz N, Wright MC, Leyton L, Tapia JC, Quest AF
Mol Cancer 2014 Sep 9;13:209
PMID 25204429
 
Proliferation, apoptosis, and survivin expression in a spectrum of melanocytic nevi
Florell SR, Bowen AR, Hanks AN, Murphy KJ, Grossman D
J Cutan Pathol 2005 Jan;32(1):45-9
PMID 15660660
 
Regulation of survivin function by Hsp90
Fortugno P, Beltrami E, Plescia J, Fontana J, Pradhan D, Marchisio PC, Sessa WC, Altieri DC
Proc Natl Acad Sci U S A 2003 Nov 25;100(24):13791-6
PMID 14614132
 
Survivin: a unique target for tumor therapy
Garg H, Suri P, Gupta JC, Talwar GP, Dubey S
Cancer Cell Int 2016 Jun 23;16:49
PMID 27340370
 
Extracellular NAMPT/Visfatin induces proliferation through ERK1/2 and AKT and inhibits apoptosis in breast cancer cells
Gholinejad Z, Kheiripour N, Nourbakhsh M, Ilbeigi D, Behroozfar K, Hesari Z, Golestani A, Shabani M, Einollahi N
Peptides 2017 Jun;92:9-15
PMID 28442350
 
KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin [corrected] in prostate cancer models
Gravina GL, Mancini A, Sanita P, Vitale F, Marampon F, Ventura L, Landesman Y, McCauley D, Kauffman M, Shacham S, Festuccia C
BMC Cancer 2015 Dec 1;15:941
PMID 26620414
 
IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer
Gyrd-Hansen M, Meier P
Nat Rev Cancer 2010 Aug;10(8):561-74
PMID 20651737
 
Survivin suppression through STAT3/β-catenin is essential for resveratrol-induced melanoma apoptosis
Habibie, Yokoyama S, Abdelhamed S, Awale S, Sakurai H, Hayakawa Y, Saiki I
Int J Oncol 2014 Aug;45(2):895-901
PMID 24946930
 
BIRC5 (survivin): a pejorative prognostic marker in stage II/III breast cancer with no response to neoadjuvant chemotherapy
Hamy AS, Bieche I, Lehmann-Che J, Scott V, Bertheau P, Guinebretière JM, Matthieu MC, Sigal-Zafrani B, Tembo O, Marty M, Asselain B, Spyratos F, de Cremoux P
Breast Cancer Res Treat 2016 Oct;159(3):499-511
PMID 27592112
 
Aberrant Alternative Polyadenylation is Responsible for Survivin Up-regulation in Ovarian Cancer
He XJ, Zhang Q, Ma LP, Li N, Chang XH, Zhang YJ
Chin Med J (Engl) 2016 May 20;129(10):1140-6
PMID 27174320
 
YM155 enhances docetaxel efficacy in ovarian cancer
Hou LJ, Huang XX, Xu LN, Zhang YY, Zhao N, Ou RY, Li WF, Zhang WJ, Jiang QW, Yang Y, Wei MN, Huang JR, Wang K, Yuan ML, Xing ZH, Shi Z, Yan XJ
Am J Transl Res 2018 Mar 15;10(3):696-708
PMID 29636860
 
The mechanism of radiosensitization by YM155, a novel small molecule inhibitor of survivin expression, is associated with DNA damage repair
Hu S, Fu S, Xu X, Chen L, Xu J, Li B, Qu Y, Yu H, Lu S, Li W
Cell Physiol Biochem 2015;37(3):1219-30
PMID 26418254
 
Periostin Contributes to Cisplatin Resistance in Human Non-Small Cell Lung Cancer A549 Cells via Activation of Stat3 and Akt and Upregulation of Survivin
Hu W, Jin P, Liu W
Cell Physiol Biochem 2016;38(3):1199-208
PMID 26982182
 
A potent immunogenic general cancer vaccine that targets survivin, an inhibitor of apoptosis proteins
Idenoue S, Hirohashi Y, Torigoe T, Sato Y, Tamura Y, Hariu H, Yamamoto M, Kurotaki T, Tsuruma T, Asanuma H, Kanaseki T, Ikeda H, Kashiwagi K, Okazaki M, Sasaki K, Sato T, Ohmura T, Hata F, Yamaguchi K, Hirata K, Sato N
Clin Cancer Res 2005 Feb 15;11(4):1474-82
PMID 15746049
 
High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma
Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, Ohira M, Hashizume K, Kobayashi H, Kaneko Y, Nakagawara A
Oncogene 2000 Feb 3;19(5):617-23
PMID 10698506
 
YM-155 potentiates the effect of ABT-737 in malignant human glioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context
Jane EP, Premkumar DR, DiDomenico JD, Hu B, Cheng SY, Pollack IF
Mol Cancer Ther 2013 Mar;12(3):326-38
PMID 23325792
 
Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth
Ji Z, Kumar R, Taylor M, Rajadurai A, Marzuka-Alcalá A, Chen YE, Njauw CN, Flaherty K, Jönsson G, Tsao H
Clin Cancer Res 2013 Aug 15;19(16):4383-91
PMID 23812671
 
Survivin may enhance DNA double-strand break repair capability by up-regulating Ku70 in human KB cells
Jiang G, Ren B, Xu L, Song S, Zhu C, Ye F
Anticancer Res 2009 Jan;29(1):223-8
PMID 19331153
 
Knockdown of survivin contributes to antitumor activity in cisplatin-resistant ovarian cancer cells
Jiang L, Luo RY, Yang J, Cheng YX
Mol Med Rep 2013 Feb;7(2):425-30
PMID 23229441
 
Myricetin suppresses p21-activated kinase 1 in human breast cancer MCF-7 cells through downstream signaling of the β-catenin pathway
Jiao D, Zhang XD
Oncol Rep 2016 Jul;36(1):342-8
PMID 27122002
 
Smart polymeric nanoparticles with pH-responsive and PEG-detachable properties for co-delivering paclitaxel and survivin siRNA to enhance antitumor outcomes
Jin M, Jin G, Kang L, Chen L, Gao Z, Huang W
Int J Nanomedicine 2018 Apr 20;13:2405-2426
PMID 29719390
 
Expression and clinical implication of Beclin1, HMGB1, p62, survivin, BRCA1 and ERCC1 in epithelial ovarian tumor tissues
Ju LL, Zhao CY, Ye KF, Yang H, Zhang J
Eur Rev Med Pharmacol Sci 2016 May;20(10):1993-2003
PMID 27249597
 
Combination of YM155, a survivin suppressant, with bendamustine and rituximab: a new combination therapy to treat relapsed/refractory diffuse large B-cell lymphoma
Kaneko N, Mitsuoka K, Amino N, Yamanaka K, Kita A, Mori M, Miyoshi S, Kuromitsu S
Clin Cancer Res 2014 Apr 1;20(7):1814-22
PMID 24486595
 
siRNA-mediated silencing of survivin inhibits proliferation and enhances etoposide chemosensitivity in acute myeloid leukemia cells
Karami H, Baradaran B, Esfahani A, Estiar MA, Naghavi-Behzad M, Sakhinia M, Sakhinia E
Asian Pac J Cancer Prev 2013;14(12):7719-24
PMID 24460358
 
Survivin polymorphisms and susceptibility to prostate cancer: A genetic association study and an in silico analysis
Karimian M, Aftabi Y, Mazoochi T, Babaei F, Khamechian T, Boojari H, Nikzad H
EXCLI J 2018 May 18;17:479-491
PMID 30034311
 
Sticky siRNAs targeting survivin and cyclin B1 exert an antitumoral effect on melanoma subcutaneous xenografts and lung metastases
Kedinger V, Meulle A, Zounib O, Bonnet ME, Gossart JB, Benoit E, Messmer M, Shankaranarayanan P, Behr JP, Erbacher P, Bolcato-Bellemin AL
BMC Cancer 2013 Jul 9;13:338
PMID 23835136
 
Early diagnostic value of survivin and its alternative splice variants in breast cancer
Khan S, Bennit HF, Turay D, Perez M, Mirshahidi S, Yuan Y, Wall NR
BMC Cancer 2014 Mar 12;14:176
PMID 24620748
 
Survivin is released from cancer cells via exosomes
Khan S, Jutzy JM, Aspe JR, McGregor DW, Neidigh JW, Wall NR
Apoptosis 2011 Jan;16(1):1-12
PMID 20717727
 
Serum survivin and vascular endothelial growth factor in extranodal NK/T-cell lymphoma, nasal type: implications for a potential new prognostic indicator
Kim SJ, Hong M, Do IG, Lee SH, Ryu KJ, Yoo HY, Hong JY, Ko YH, Kim WS
Haematologica 2015 Mar;100(3):e106-9
PMID 25480498
 
Sepantronium bromide (YM155) enhances response of human B-cell non-Hodgkin lymphoma to rituximab
Kita A, Mitsuoka K, Kaneko N, Nakata M, Yamanaka K, Jitsuoka M, Miyoshi S, Noda A, Mori M, Nakahara T, Sasamata M
J Pharmacol Exp Ther 2012 Oct;343(1):178-83
PMID 22787117
 
The Enrichment of Survivin in Exosomes from Breast Cancer Cells Treated with Paclitaxel Promotes Cell Survival and Chemoresistance
Kreger BT, Johansen ER, Cerione RA, Antonyak MA
Cancers (Basel) 2016 Dec 9;8(12)
PMID 27941677
 
IAP-targeted therapies for cancer
LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S, Korneluk RG
Oncogene 2008 Oct 20;27(48):6252-75
PMID 18931692
 
Novel survivin inhibitor YM155 elicits cytotoxicity in glioblastoma cell lines with normal or deficiency DNA-dependent protein kinase activity
Lai PC, Chen SH, Yang SH, Cheng CC, Chiu TH, Huang YT
Pediatr Neonatol 2012 Jun;53(3):199-204
PMID 22770110
 
Human breast cancer cells display different sensitivities to ABT-263 based on the level of survivin
Lee EY, Gong EY, Shin JS, Moon JH, Shim HJ, Kim SM, Lee S, Jeong J, Gong JH, Kim MJ, Lee DH, Park YS, Shin J, Hong SW, Kim YS, Jin DH
Toxicol In Vitro 2018 Feb;46:229-236
PMID 28947240
 
Control of apoptosis and mitotic spindle checkpoint by survivin
Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC
Nature 1998 Dec 10;396(6711):580-4
PMID 9859993
 
Expression of survivin and caspase 3 in oral squamous cell carcinoma and peritumoral tissue
Li SX, Chai L, Cai ZG, Jin LJ, Chen Y, Wu HR, Sun Z
Asian Pac J Cancer Prev 2012;13(10):5027-31
PMID 23244104
 
Clinicopathologic Significance of Survivin Expression in Relation to CD133 Expression in Surgically Resected Stage II or III Colorectal Cancer
Li W, Lee MR, Choi E, Cho MY
J Pathol Transl Med 2017 Jan;51(1):17-23
PMID 27989099
 
Correlation between survivin polymorphism and acute leukemia of children
Li WX, Li YK, Lin HT
Exp Ther Med 2018 Mar;15(3):2941-2945
PMID 29456699
 
Downregulation of survivin inhibits proliferation and migration of human gastric carcinoma cells
Li Y, Zhou Y, Zheng J, Niu C, Liu B, Wang M, Fang H, Hou C
Int J Clin Exp Pathol 2015 Feb 1;8(2):1731-6
PMID 25973061
 
Inhibitory effect of survivin-targeting small interfering RNA on gastric cancer cells
Li YH, Chen M, Zhang M, Zhang XQ, Zhang S, Yu CG, Xu ZM, Zou XP
Genet Mol Res 2014 Aug 28;13(3):6786-803
PMID 25177958
 
A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity
Ling X, Cao S, Cheng Q, Keefe JT, Rustum YM, Li F
PLoS One 2012;7(9):e45571
PMID 23029106
 
An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer
Ling X, Wu W, Fan C, Xu C, Liao J, Rich LJ, Huang RY, Repasky EA, Wang X, Li F
J Exp Clin Cancer Res 2018 Oct 3;37(1):240
PMID 30285798
 
EXPRESSION OF E-CADHERIN AND WNT PATHWAY PROTEINS BETACATENIN, APC, TCF-4 AND SURVIVIN IN GASTRIC ADENOCARCINOMA: CLINICAL AND PATHOLOGICAL IMPLICATION
Lins RR, Oshima CT, Oliveira LA, Silva MS, Mader AM, Waisberg J
Arq Bras Cir Dig 2016 Nov-Dec;29(4):227-231
PMID 28076475
 
Nuclear survivin promoted by acetylation is associated with the aggressive phenotype of oral squamous cell carcinoma
Liu S, Shi L, Yang X, Ye D, Wang T, Dong C, Guo W, Liao Y, Song H, Xu D, Hu J, Zhang Z, Deng J
Cell Cycle 2017 May 3;16(9):894-902
PMID 28384094
 
Association between survivin genetic polymorphisms and epidermal growth factor receptor mutation in non-small-cell lung cancer
Liu TC, Hsieh MJ, Wu WJ, Chou YE, Chiang WL, Yang SF, Su SC, Tsao TC
Int J Med Sci 2016 Nov 23;13(12):929-935
PMID 27994498
 
Ubiquitin-proteasomal degradation of antiapoptotic survivin facilitates induction of apoptosis in prostate cancer cells by pristimerin
Liu YB, Gao X, Deeb D, Brigolin C, Zhang Y, Shaw J, Pindolia K, Gautam SC
Int J Oncol 2014 Oct;45(4):1735-41
PMID 25175770
 
To fight or die - inhibitor of apoptosis proteins at the crossroad of innate immunity and death
Lopez J, Meier P
Curr Opin Cell Biol 2010 Dec;22(6):872-81
PMID 20888210
 
Efficient inhibition of ovarian cancer by degradable nanoparticle-delivered survivin T34A gene
Luo L, Du T, Zhang J, Zhao W, Cheng H, Yang Y, Wu Y, Wang C, Men K, Gou M
Int J Nanomedicine 2016 Feb 2;11:501-12
PMID 26893558
 
Clinicopathological and prognostic significance of survivin expression in renal cancer patients: a meta-analysis
Ma C, Lu B, Sun E
Postgrad Med J 2017 Apr;93(1098):186-192
PMID 27489375
 
MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis
Mak CS, Yung MM, Hui LM, Leung LL, Liang R, Chen K, Liu SS, Qin Y, Leung TH, Lee KF, Chan KK, Ngan HY, Chan DW
Mol Cancer 2017 Jan 17;16(1):11
PMID 28095864
 
Survivin expression in patients with newly diagnosed nodal diffuse large B cell lymphoma (DLBCL)
Markovic O, Marisavljevic D, Cemerikic-Martinovic V, Martinovic T, Filipovic B, Stanisavljevic D, Zivković R, Hajder J, Stanisavljevic N, Mihaljevic B
Med Oncol 2012 Dec;29(5):3515-21
PMID 22528517
 
Survivin promotion of melanoma metastasis requires upregulation of α5 integrin
McKenzie JA, Liu T, Jung JY, Jones BB, Ekiz HA, Welm AL, Grossman D
Carcinogenesis 2013 Sep;34(9):2137-44
PMID 23640047
 
Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma
Meerang M, Bérard K, Friess M, Bitanihirwe BK, Soltermann A, Vrugt B, Felley-Bosco E, Bueno R, Richards WG, Seifert B, Stahel R, Weder W, Opitz I
Mol Oncol 2016 Oct;10(8):1255-65
PMID 27378628
 
YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts
Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, Tominaga F, Hatakeyama S, Kinoyama I, Matsuhisa A, Kudoh M, Sasamata M
Cancer Res 2007 Sep 1;67(17):8014-21
PMID 17804712
 
Binding of galectin-1 to integrin β1 potentiates drug resistance by promoting survivin expression in breast cancer cells
Nam K, Son SH, Oh S, Jeon D, Kim H, Noh DY, Kim S, Shin I
Oncotarget 2017 May 30;8(22):35804-35823
PMID 28415760
 
Synergistic Induction of Erlotinib-Mediated Apoptosis by Resveratrol in Human Non-Small-Cell Lung Cancer Cells by Down-Regulating Survivin and Up-Regulating PUMA
Nie P, Hu W, Zhang T, Yang Y, Hou B, Zou Z
Cell Physiol Biochem 2015;35(6):2255-71
PMID 25895606
 
Quantitative detection of serum survivin and its relationship with prognostic factors in ovarian cancer
No JH, Jeon YT, Kim YB, Song YS
Gynecol Obstet Invest 2011;71(2):136-40
PMID 21160138
 
Functional transcriptomic annotation and protein-protein interaction network analysis identify NEK2, BIRC5, and TOP2A as potential targets in obese patients with luminal A breast cancer
Nuncia-Cantarero M, Martinez-Canales S, Andrés-Pretel F, Santpere G, Ocaña A, Galan-Moya EM
Breast Cancer Res Treat 2018 Apr;168(3):613-623
PMID 29330624
 
Endocrine therapy inhibits proliferation and migration, promotes apoptosis and suppresses survivin protein expression in colorectal cancer cells
Ou QJ, Wu XJ, Peng JH, Zhang RX, Lu ZH, Jiang W, Zhang L, Pan ZZ, Wan DS, Fang YJ
Mol Med Rep 2017 Nov;16(5):5769-5778
PMID 28849238
 
Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells
Panayotopoulou EG, Müller AK, Börries M, Busch H, Hu G, Lev S
Oncotarget 2017 Jul 11;8(28):45088-45104
PMID 28187446
 
Deptor enhances triple-negative breast cancer metastasis and chemoresistance through coupling to survivin expression
Parvani JG, Davuluri G, Wendt MK, Espinosa C, Tian M, Danielpour D, Sossey-Alaoui K, Schiemann WP
Neoplasia 2015 Mar;17(3):317-28
PMID 25810016
 
Survivin isoforms and clinicopathological characteristics in colorectal adenocarcinomas using real-time qPCR
Pavlidou A, Dalamaga M, Kroupis C, Konstantoudakis G, Belimezi M, Athanasas G, Dimas K
World J Gastroenterol 2011 Mar 28;17(12):1614-21
PMID 21472129
 
Targeting survivin for therapeutic discovery: past, present, and future promises
Peery RC, Liu JY, Zhang JT
Drug Discov Today 2017 Oct;22(10):1466-1477
PMID 28577912
 
Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells
Premkumar DR, Jane EP, Pollack IF
Cancer Biol Ther 2015;16(2):233-43
PMID 25482928
 
Survivin as a prognostic/predictive marker and molecular target in cancer therapy
Rödel F, Sprenger T, Kaina B, Liersch T, Rödel C, Fulda S, Hehlgans S
Curr Med Chem 2012;19(22):3679-88
PMID 22680927
 
Survivin repression by p53, Rb and E2F2 in normal human melanocytes
Raj D, Liu T, Samadashwily G, Li F, Grossman D
Carcinogenesis 2008 Jan;29(1):194-201
PMID 17916908
 
Survivin and YM155: how faithful is the liaison? Biochim Biophys Acta
Rauch A, Hennig D, Schäfer C, Wirth M, Marx C, Heinzel T, Schneider G, Krämer OH
2014 Apr;1845(2):202-20 doi: 10
PMID 24440709
 
Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model
Roy K, Kanwar RK, Krishnakumar S, Cheung CH, Kanwar JR
Int J Nanomedicine 2015 Feb 2;10:1019-43
PMID 25678789
 
Structural, functional and therapeutic biology of survivin
Sah NK, Khan Z, Khan GJ, Bisen PS
Cancer Lett 2006 Dec 8;244(2):164-71
PMID 16621243
 
Pinus Roxburghii essential oil anticancer activity and chemical composition evaluation
Sajid A, Manzoor Q, Iqbal M, Tyagi AK, Sarfraz RA, Sajid A
EXCLI J 2018 Mar 12;17:233-245
PMID 29743861
 
Multifunctional Polymeric Micelles Co-loaded with Anti-Survivin siRNA and Paclitaxel Overcome Drug Resistance in an Animal Model of Ovarian Cancer
Salzano G, Navarro G, Trivedi MS, De Rosa G, Torchilin VP
Mol Cancer Ther 2015 Apr;14(4):1075-84
PMID 25657335
 
Omega-3 fatty acid DHA modulates p53, survivin, and microRNA-16-1 expression in KRAS-mutant colorectal cancer stem-like cells
Sam MR, Tavakoli-Mehr M, Safaralizadeh R
Genes Nutr 2018 Apr 2;13:8
PMID 29619114
 
The survivin:Fas ratio is predictive of recurrent disease in neuroblastoma
Sandler A, Scott D, Azuhata T, Takamizawa S, O'Dorisio S
J Pediatr Surg 2002 Mar;37(3):507-11
PMID 11877677
 
Nicotinamide phosphorybosiltransferase overexpression in thyroid malignancies and its correlation with tumor stage and with survivin/survivin ΔEx3 expression
Sawicka-Gutaj N, Waligórska-Stachura J, Andrusiewicz M, Biczysko M, Sowiński J, Skrobisz J, Ruchańa M
Tumour Biol 2015 Sep;36(10):7859-63
PMID 25946974
 
Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt signaling pathway and represents a favorable prognostic factor in patients with acute myeloid leukemia
Serrano-López J, Serrano J, Figueroa V, Torres-Gomez A, Tabares S, Casaño J, Fernandez-Escalada N, Sánchez-Garcia J
Haematologica 2013 Dec;98(12):1877-85
PMID 23812937
 
Survivin inhibition induces human neural tumor cell death through caspase-independent and -dependent pathways
Shankar SL, Mani S, O'Guin KN, Kandimalla ER, Agrawal S, Shafit-Zagardo B
J Neurochem 2001 Oct;79(2):426-36
PMID 11677271
 
Survivin knockdown enhances gastric cancer cell sensitivity to radiation and chemotherapy in vitro and in nude mice
Shen X, Zheng JY, Shi H, Zhang Z, Wang WZ
Am J Med Sci 2012 Jul;344(1):52-8
PMID 22261621
 
Survivin-2B promotes autophagy by accumulating IKK alpha in the nucleus of selenite-treated NB4 cells
Shi K, An J, Shan L, Jiang Q, Li F, Ci Y, Wu P, Duan J, Hui K, Yang Y, Xu C
Cell Death Dis 2014 Feb 20;5:e1071
PMID 24556686
 
Immunohistochemical expression of nuclear and cytoplasmic survivin in gastrointestinal carcinoma
Shintani M, Sangawa A, Yamao N, Kamoshida S
Int J Clin Exp Pathol 2013 Nov 15;6(12):2919-27
PMID 24294379
 
Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis
Song Z, Yao X, Wu M
J Biol Chem 2003 Jun 20;278(25):23130-40
PMID 12660240
 
Nuclear and cytoplasmic survivin: molecular mechanism, prognostic, and therapeutic potential
Stauber RH, Mann W, Knauer SK
Cancer Res 2007 Jul 1;67(13):5999-6002
PMID 17616652
 
Suppression of survivin induced by a BCR-ABL/JAK2/STAT3 pathway sensitizes imatinib-resistant CML cells to different cytotoxic drugs
Stella S, Tirrò E, Conte E, Stagno F, Di Raimondo F, Manzella L, Vigneri P
Mol Cancer Ther 2013 Jun;12(6):1085-98
PMID 23536723
 
MUC1-C drives myeloid leukaemogenesis and resistance to treatment by a survivin-mediated mechanism
Stroopinsky D, Rajabi H, Nahas M, Rosenblatt J, Rahimian M, Pyzer A, Tagde A, Kharbanda A, Jain S, Kufe T, Leaf RK, Anastasiadou E, Bar-Natan M, Orr S, Coll MD, Palmer K, Ephraim A, Cole L, Washington A, Kufe D, Avigan D
J Cell Mol Med 2018 May 15
PMID 29761849
 
LMP-1 induces survivin expression to inhibit cell apoptosis through the NF-κB and PI3K/Akt signaling pathways in nasal NK/T-cell lymphoma
Sun L, Zhao Y, Shi H, Ma C, Wei L
Oncol Rep 2015 May;33(5):2253-60
PMID 25760809
 
Chitosan-based nanoparticles for survivin targeted siRNA delivery in breast tumor therapy and preventing its metastasis
Sun P, Huang W, Jin M, Wang Q, Fan B, Kang L, Gao Z
Int J Nanomedicine 2016 Sep 27;11:4931-4945
PMID 27729789
 
Role of Survivin in cytokinesis revealed by a separation-of-function allele
Szafer-Glusman E, Fuller MT, Giansanti MG
Mol Biol Cell 2011 Oct;22(20):3779-90
 
Quick quantitative analysis of gene dosages associated with prognosis in neuroblastoma
Tajiri T, Tanaka S, Shono K, Kinoshita Y, Fujii Y, Suita S, Ihara K, Hara T
Cancer Lett 2001 May 10;166(1):89-94
PMID 11295291
 
Survivin expression by metastatic melanoma predicts poor disease outcome in patients receiving adjuvant polyvalent vaccine
Takeuchi H, Morton DL, Elashoff D, Hoon DS
Int J Cancer 2005 Dec 20;117(6):1032-8
PMID 15986442
 
Induction of survivin inhibition, G/M cell cycle arrest and autophagic on cell death in human malignant glioblastoma cells
Tang TK, Chiu SC, Lin CW, Su MJ, Liao MH
Chin J Physiol 2015 Apr 30;58(2):95-103
PMID 25858470
 
Survivin selective inhibitor YM155 induce apoptosis in SK-NEP-1 Wilms tumor cells
Tao YF, Lu J, Du XJ, Sun LC, Zhao X, Peng L, Cao L, Xiao PF, Pang L, Wu D, Wang N, Feng X, Li YH, Ni J, Wang J, Pan J
BMC Cancer 2012 Dec 26;12:619
PMID 23267699
 
Application of phi29 motor pRNA for targeted therapeutic delivery of siRNA silencing metallothionein-IIA and survivin in ovarian cancers
Tarapore P, Shu Y, Guo P, Ho SM
Mol Ther 2011 Feb;19(2):386-94
PMID 21063391
 
Melanocyte expression of survivin promotes development and metastasis of UV-induced melanoma in HGF-transgenic mice
Thomas J, Liu T, Cotter MA, Florell SR, Robinette K, Hanks AN, Grossman D
Cancer Res 2007 Jun 1;67(11):5172-8
PMID 17545596
 
Expressions and correlation analysis of HIF-1α, survivin and VEGF in patients with hepatocarcinoma
Tian QG, Wu YT, Liu Y, Zhang J, Song ZQ, Gao WF, Guo TK, He CH, Dai FR
Eur Rev Med Pharmacol Sci 2018 Jun;22(11):3378-3385
PMID 29917189
 
Survivin: A novel marker and potential therapeutic target for human angiosarcoma
Tsuneki M, Kinjo T, Mori T, Yoshida A, Kuyama K, Ohira A, Miyagi T, Takahashi K, Kawai A, Chuman H, Yamazaki N, Masuzawa M, Arakawa H
Cancer Sci 2017 Nov;108(11):2295-2305
PMID 28845553
 
Structure of the human anti-apoptotic protein survivin reveals a dimeric arrangement
Verdecia MA, Huang H, Dutil E, Kaiser DA, Hunter T, Noel JP
Nat Struct Biol 2000 Jul;7(7):602-8
PMID 10876248
 
Silencing survivin splice variant 2B leads to antitumor activity in taxane--resistant ovarian cancer
Vivas-Mejia PE, Rodriguez-Aguayo C, Han HD, Shahzad MM, Valiyeva F, Shibayama M, Chavez-Reyes A, Sood AK, Lopez-Berestein G
Clin Cancer Res 2011 Jun 1;17(11):3716-26
PMID 21512144
 
Activation of CXCL12/CXCR4 renders colorectal cancer cells less sensitive to radiotherapy via up-regulating the expression of survivin
Wang D, Jiao C, Zhu Y, Liang D, Zao M, Meng X, Gao J, He Y, Liu W, Hou J, Zhong Z, Cheng Z
Exp Biol Med (Maywood) 2017 Feb;242(4):429-435
PMID 27798120
 
Knockdown of PARP6 or survivin promotes cell apoptosis and inhibits cell invasion of colorectal adenocarcinoma cells
Wang H, Li S, Luo X, Song Z, Long X, Zhu X
Oncol Rep 2017 Apr;37(4):2245-2251
PMID 28260087
 
FL118, a novel survivin inhibitor, wins the battle against drug-resistant and metastatic lung cancers through inhibition of cancer stem cell-like properties
Wang J, Liu Z, Zhang D, Liu R, Lin Q, Liu J, Yang Z, Ma Q, Sun D, Zhou X, Jiang G
Am J Transl Res 2017 Aug 15;9(8):3676-3686
PMID 28861158
 
Induction of autophagy-dependent apoptosis by the survivin suppressant YM155 in prostate cancer cells
Wang Q, Chen Z, Diao X, Huang S
Cancer Lett 2011 Mar 1;302(1):29-36
 
Clinical significance of survivin and vascular endothelial growth factor mRNA detection in the peripheral whole blood of breast cancer patients
Wang S, Xu J, Zhang Q
Neoplasma 2016;63(1):133-40
PMID 26639243
 
MicroRNA-204 targets JAK2 in breast cancer and induces cell apoptosis through the STAT3/BCl-2/survivin pathway
Wang X, Qiu W, Zhang G, Xu S, Gao Q, Yang Z
Int J Clin Exp Pathol 2015 May 1;8(5):5017-25
PMID 26191195
 
Curcumin Enhanced Busulfan-Induced Apoptosis through Downregulating the Expression of Survivin in Leukemia Stem-Like KG1a Cells
Weng G, Zeng Y, Huang J, Fan J, Guo K
Biomed Res Int 2015;2015:630397
PMID 26557682
 
Survivin and PSMA Loaded Dendritic Cell Vaccine for the Treatment of Prostate Cancer
Xi HB, Wang GX, Fu B, Liu WP, Li Y
Biol Pharm Bull 2015;38(6):827-35
PMID 25787895
 
Dual inhibition of survivin and MAOA synergistically impairs growth of PTEN-negative prostate cancer
Xu S, Adisetiyo H, Tamura S, Grande F, Garofalo A, Roy-Burman P, Neamati N
Br J Cancer 2015 Jul 14;113(2):242-51
PMID 26103574
 
Serum Survivin and TP53 Gene Expression in Children with Acute Lymphoblastic Leukemia
Yahya RS, Fouda MI, El-Baz HA, Mosa TE, Elmaksoud MD
Iran J Public Health 2012;41(1):37-44
PMID 23113120
 
A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma
Yamada T, Horinaka M, Shinnoh M, Yoshioka T, Miki T, Sakai T
Int J Oncol 2013 Oct;43(4):1080-6
PMID 23900601
 
Antitumor activity of YM155, a selective small-molecule survivin suppressant, alone and in combination with docetaxel in human malignant melanoma models
Yamanaka K, Nakahara T, Yamauchi T, Kita A, Takeuchi M, Kiyonaga F, Kaneko N, Sasamata M
Clin Cancer Res 2011 Aug 15;17(16):5423-31
PMID 21737502
 
Induction of melanoma cell apoptosis and inhibition of tumor growth using a cell-permeable Survivin antagonist
Yan H, Thomas J, Liu T, Raj D, London N, Tandeski T, Leachman SA, Lee RM, Grossman D
Oncogene 2006 Nov 2;25(52):6968-74
PMID 16702945
 
YM155 Down-Regulates Survivin and Induces P53 Up-Regulated Modulator of Apoptosis (PUMA)-Dependent in Oral Squamous Cell Carcinoma Cells
Yan X, Su H
Med Sci Monit 2017 Apr 24;23:1963-1972
PMID 28435150
 
Effects of monomethoxypolyethylene glycol-chitosan nanoparticle-mediated dual silencing of livin and survivin genes in prostate cancer PC-3M cells
Yang AQ, Wang PJ, Huang T, Zhou WL, Landman J
Genet Mol Res 2016 Apr 4;15(2)
PMID 27173182
 
Effects of survivin on FVADT chemotherapy for refractory multiple myeloma
Yang H, Du X, Xi Y
Exp Ther Med 2016 Aug;12(2):771-776
PMID 27446274
 
Analysis of the expression levels of survivin and VEGF in patients with acute lymphoblastic leukemia
Yang M, Liu Y, Lu S, Wang Z, Wang R, Zi Y, Li J
Exp Ther Med 2013 Jan;5(1):305-307
PMID 23251288
 
Construction of a novel vector expressing Survivin-shRNA and fusion suicide gene yCDglyTK and its application in inhibiting proliferation and migration of colon cancer cells
Ye L, Yang Y, Ma XY, Li D, Xu ML, Tan P, Long LM, Wang HQ, Liu T, Guo YH
Exp Ther Med 2017 Nov;14(5):4721-4728
PMID 29201172
 
A Novel Hydroxamate-Based Compound WMJ-J-09 Causes Head and Neck Squamous Cell Carcinoma Cell Death via LKB1-AMPK-p38MAPK-p63-Survivin Cascade
Yen CS, Choy CS, Huang WJ, Huang SW, Lai PY, Yu MC, Shiue C, Hsu YF, Hsu MJ
Front Pharmacol 2018 Mar 1;9:167
PMID 29545751
 
miR-195 targets cyclin D3 and survivin to modulate the tumorigenesis of non-small cell lung cancer
Yu X, Zhang Y, Cavazos D, Ma X, Zhao Z, Du L, Pertsemlidis A
Cell Death Dis 2018 Feb 7;9(2):193
PMID 29416000
 
Bortezomib-based chemotherapy regimens can improve response in newly diagnosed multiple myeloma patients with bcl-2 and survivin overexpression
Zeng W, Meng F, Liu Z, Mao X, Luo L, Zheng M, Qin S, Liu W, Zhou J, Sun H, Huang L
Int J Clin Exp Pathol 2014 Jun 15;7(7):4239-46
PMID 25120804
 
Survivin gene expression increases gastric cancer cell lymphatic metastasis by upregulating vascular endothelial growth factor-C expression levels
Zhang J, Zhu Z, Sun Z, Sun X, Wang Z, Xu H
Mol Med Rep 2014 Feb;9(2):600-6
PMID 24337012
 
Dual induction of apoptotic and autophagic cell death by targeting survivin in head neck squamous cell carcinoma
Zhang L, Zhang W, Wang YF, Liu B, Zhang WF, Zhao YF, Kulkarni AB, Sun ZJ
Cell Death Dis 2015 May 28;6:e1771
PMID 26018732
 
Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway
Zhang Y, Chen HX, Zhou SY, Wang SX, Zheng K, Xu DD, Liu YT, Wang XY, Wang X, Yan HZ, Zhang L, Liu QY, Chen WQ, Wang YF
Mol Cancer 2015 Mar 7;14:56
PMID 25890196
 
Prognostic and Clinicopathological Value of Survivin in Diffuse Large B-cell Lymphoma: A Meta-Analysis
Zhang Y, Wang J, Sui X, Li Y, Lu K, Fang X, Jiang Y, Wang X
Medicine (Baltimore) 2015 Sep;94(36):e1432
PMID 26356696
 
Cancer stem cells and chemoresistance: The smartest survives the raid
Zhao J
Pharmacol Ther 2016 Apr;160:145-58
PMID 26899500
 
Levels of effectiveness of gene therapies targeting survivin and its splice variants in human breast cancer cells
Zheng WY, Kang YY, Li LF, Xu YX, Ma XY
Drug Discov Ther 2011 Dec;5(6):293-8
PMID 22466440
 
Combined inhibition of β-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo
Zhou H, Mak PY, Mu H, Mak DH, Zeng Z, Cortes J, Liu Q, Andreeff M, Carter BZ
Leukemia 2017 Oct;31(10):2065-2074
PMID 28321124
 
High nuclear Survivin expression as a poor prognostic marker in pancreatic ductal adenocarcinoma
Zhou L, Lu J, Liang ZY, Zhou WX, Yuan D, Li BQ, You L, Guo JC, Zhao YP
J Surg Oncol 2018 Dec;118(7):1115-1121
PMID 30261114
 
Targeting survivin using a combination of miR494 and survivin shRNA has synergistic effects on the suppression of prostate cancer growth
Zhu J, Sun C, Wang L, Xu M, Zang Y, Zhou Y, Liu X, Tao W, Xue B, Shan Y, Yang D
Mol Med Rep 2016 Feb;13(2):1602-10
PMID 26718651
 
Fisetin, a dietary bioflavonoid, reverses acquired Cisplatin-resistance of lung adenocarcinoma cells through MAPK/Survivin/Caspase pathway
Zhuo W, Zhang L, Zhu Y, Zhu B, Chen Z
Am J Transl Res 2015 Oct 15;7(10):2045-52
PMID 26692948
 
The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy
de Almagro MC, Vucic D
Exp Oncol 2012 Oct;34(3):200-11
PMID 23070005
 
High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth
de Graaff MA, Malu S, Guardiola I, Kruisselbrink AB, de Jong Y, Corver WE, Gelderblom H, Hwu P, Nielsen TO, Lazar AJ, Somaiah N, Bovée JVMG
Transl Oncol 2017 Aug;10(4):546-554
PMID 28654818
 

Citation

This paper should be referenced as such :
Branco PC, Jimenez PC, Machado-Neto JA, Costa-Lotufo LV
BIRC5 (baculoviral IAP repeat containing 5);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/BIRC5ID797ch17q25.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Breast: Ductal carcinoma
PGS1/BIRC5 (17q25)


External links

Nomenclature
HGNC (Hugo)BIRC5   593
Cards
AtlasBIRC5ID797ch17q25
Entrez_Gene (NCBI)BIRC5  332  baculoviral IAP repeat containing 5
AliasesAPI4; EPR-1
GeneCards (Weizmann)BIRC5
Ensembl hg19 (Hinxton)ENSG00000089685 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000089685 [Gene_View]  ENSG00000089685 [Sequence]  chr17:78214196-78225635 [Contig_View]  BIRC5 [Vega]
ICGC DataPortalENSG00000089685
TCGA cBioPortalBIRC5
AceView (NCBI)BIRC5
Genatlas (Paris)BIRC5
WikiGenes332
SOURCE (Princeton)BIRC5
Genetics Home Reference (NIH)BIRC5
Genomic and cartography
GoldenPath hg38 (UCSC)BIRC5  -     chr17:78214196-78225635 +  17q25.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)BIRC5  -     17q25.3   [Description]    (hg19-Feb_2009)
BIRC5 - 17q25.3 [CytoView hg19]  BIRC5 - 17q25.3 [CytoView hg38]
Mapping of homologs : NCBIBIRC5 [Mapview hg19]  BIRC5 [Mapview hg38]
OMIM603352   
Gene and transcription
Genbank (Entrez)AB028869 AB154416 AF077350 AI800528 AK223428
RefSeq transcript (Entrez)NM_001012270 NM_001012271 NM_001168
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)BIRC5
Cluster EST : UnigeneHs.744872 [ NCBI ]
CGAP (NCI)Hs.744872
Alternative Splicing GalleryENSG00000089685
Gene ExpressionBIRC5 [ NCBI-GEO ]   BIRC5 [ EBI - ARRAY_EXPRESS ]   BIRC5 [ SEEK ]   BIRC5 [ MEM ]
Gene Expression Viewer (FireBrowse)BIRC5 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)332
GTEX Portal (Tissue expression)BIRC5
Human Protein AtlasENSG00000089685-BIRC5 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO15392   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO15392  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO15392
Splice isoforms : SwissVarO15392
PhosPhoSitePlusO15392
Domaine pattern : Prosite (Expaxy)BIR_REPEAT_2 (PS50143)   
Domains : Interpro (EBI)BIR_rpt   
Domain families : Pfam (Sanger)BIR (PF00653)   
Domain families : Pfam (NCBI)pfam00653   
Domain families : Smart (EMBL)BIR (SM00238)  
Conserved Domain (NCBI)BIRC5
DMDM Disease mutations332
Blocks (Seattle)BIRC5
PDB (RSDB)1E31    1F3H    1XOX    2QFA    2RAW    2RAX    3UEC    3UED    3UEE    3UEF    3UEG    3UEH    3UEI    3UIG    3UIH    3UII    3UIJ    3UIK    4A0I    4A0J    4A0N   
PDB Europe1E31    1F3H    1XOX    2QFA    2RAW    2RAX    3UEC    3UED    3UEE    3UEF    3UEG    3UEH    3UEI    3UIG    3UIH    3UII    3UIJ    3UIK    4A0I    4A0J    4A0N   
PDB (PDBSum)1E31    1F3H    1XOX    2QFA    2RAW    2RAX    3UEC    3UED    3UEE    3UEF    3UEG    3UEH    3UEI    3UIG    3UIH    3UII    3UIJ    3UIK    4A0I    4A0J    4A0N   
PDB (IMB)1E31    1F3H    1XOX    2QFA    2RAW    2RAX    3UEC    3UED    3UEE    3UEF    3UEG    3UEH    3UEI    3UIG    3UIH    3UII    3UIJ    3UIK    4A0I    4A0J    4A0N   
Structural Biology KnowledgeBase1E31    1F3H    1XOX    2QFA    2RAW    2RAX    3UEC    3UED    3UEE    3UEF    3UEG    3UEH    3UEI    3UIG    3UIH    3UII    3UIJ    3UIK    4A0I    4A0J    4A0N   
SCOP (Structural Classification of Proteins)1E31    1F3H    1XOX    2QFA    2RAW    2RAX    3UEC    3UED    3UEE    3UEF    3UEG    3UEH    3UEI    3UIG    3UIH    3UII    3UIJ    3UIK    4A0I    4A0J    4A0N   
CATH (Classification of proteins structures)1E31    1F3H    1XOX    2QFA    2RAW    2RAX    3UEC    3UED    3UEE    3UEF    3UEG    3UEH    3UEI    3UIG    3UIH    3UII    3UIJ    3UIK    4A0I    4A0J    4A0N   
SuperfamilyO15392
Human Protein Atlas [tissue]ENSG00000089685-BIRC5 [tissue]
Peptide AtlasO15392
HPRD04520
IPIIPI00006210   IPI00218095   IPI00735946   IPI00784964   IPI00784916   IPI00784873   IPI00785191   IPI01018308   IPI01019070   IPI01020912   IPI00056412   IPI01014811   
Protein Interaction databases
DIP (DOE-UCLA)O15392
IntAct (EBI)O15392
FunCoupENSG00000089685
BioGRIDBIRC5
STRING (EMBL)BIRC5
ZODIACBIRC5
Ontologies - Pathways
QuickGOO15392
Ontology : AmiGOnuclear chromosome  chromosome, centromeric region  condensed chromosome kinetochore  cysteine-type endopeptidase inhibitor activity  protein binding  nucleus  nucleus  nucleoplasm  cytoplasm  cytoplasm  cytosol  cytosol  spindle microtubule  protein phosphorylation  apoptotic process  cell cycle  chromosome segregation  sensory perception of sound  microtubule binding  positive regulation of cell proliferation  Ran GTPase binding  negative regulation of endopeptidase activity  cytokine-mediated signaling pathway  enzyme binding  midbody  protein-containing complex localization  chromosome passenger complex  identical protein binding  regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of transcription, DNA-templated  metal ion binding  chaperone binding  cell division  mitotic spindle assembly  
Ontology : EGO-EBInuclear chromosome  chromosome, centromeric region  condensed chromosome kinetochore  cysteine-type endopeptidase inhibitor activity  protein binding  nucleus  nucleus  nucleoplasm  cytoplasm  cytoplasm  cytosol  cytosol  spindle microtubule  protein phosphorylation  apoptotic process  cell cycle  chromosome segregation  sensory perception of sound  microtubule binding  positive regulation of cell proliferation  Ran GTPase binding  negative regulation of endopeptidase activity  cytokine-mediated signaling pathway  enzyme binding  midbody  protein-containing complex localization  chromosome passenger complex  identical protein binding  regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of transcription, DNA-templated  metal ion binding  chaperone binding  cell division  mitotic spindle assembly  
Pathways : KEGGHippo signaling pathway    Hepatitis B    Pathways in cancer    Colorectal cancer   
REACTOMEO15392 [protein]
REACTOME PathwaysR-HSA-8951664 [pathway]   
NDEx NetworkBIRC5
Atlas of Cancer Signalling NetworkBIRC5
Wikipedia pathwaysBIRC5
Orthology - Evolution
OrthoDB332
GeneTree (enSembl)ENSG00000089685
Phylogenetic Trees/Animal Genes : TreeFamBIRC5
HOGENOMO15392
Homologs : HomoloGeneBIRC5
Homology/Alignments : Family Browser (UCSC)BIRC5
Gene fusions - Rearrangements
Fusion : MitelmanPGS1/BIRC5 [17q25.3/17q25.3]  [t(17;17)(q25;q25)]  
Fusion PortalPGS1 17q25.3 BIRC5 17q25.3 BRCA
Fusion : FusionGDB26843    36634    4183   
Fusion : QuiverBIRC5
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerBIRC5 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)BIRC5
dbVarBIRC5
ClinVarBIRC5
1000_GenomesBIRC5 
Exome Variant ServerBIRC5
ExAC (Exome Aggregation Consortium)ENSG00000089685
GNOMAD BrowserENSG00000089685
Varsome BrowserBIRC5
Genetic variants : HAPMAP332
Genomic Variants (DGV)BIRC5 [DGVbeta]
DECIPHERBIRC5 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisBIRC5 
Mutations
ICGC Data PortalBIRC5 
TCGA Data PortalBIRC5 
Broad Tumor PortalBIRC5
OASIS PortalBIRC5 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICBIRC5  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDBIRC5
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
BioMutasearch BIRC5
DgiDB (Drug Gene Interaction Database)BIRC5
DoCM (Curated mutations)BIRC5 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)BIRC5 (select a term)
intoGenBIRC5
NCG5 (London)BIRC5
Cancer3DBIRC5(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603352   
Orphanet
DisGeNETBIRC5
MedgenBIRC5
Genetic Testing Registry BIRC5
NextProtO15392 [Medical]
TSGene332
GENETestsBIRC5
Target ValidationBIRC5
Huge Navigator BIRC5 [HugePedia]
snp3D : Map Gene to Disease332
BioCentury BCIQBIRC5
ClinGenBIRC5
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD332
Chemical/Pharm GKB GenePA25362
Clinical trialBIRC5
Miscellaneous
canSAR (ICR)BIRC5 (select the gene name)
DataMed IndexBIRC5
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineBIRC5
EVEXBIRC5
GoPubMedBIRC5
iHOPBIRC5
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Apr 30 14:34:32 CEST 2019

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