Prognostic Significance Of Survivin Expression Research Articles

The prognostic role of survivin expression in breast cancer: A systematic review and meta-analysis.

Breast cancer is a heterogeneous condition with variations in histopathological, genomic, and biological characteristics. Although clinicopathological prognostic factors and gene expression profiles are commonly used to guide treatment decisions in patients with breast cancer, there is still a need for new prognostic markers. One potential marker is survivin, a protein belonging to the apoptosis inhibitor family. However, studies examining the relationship between survivin and prognosis in breast cancer have yielded inconsistent results. This study aimed to evaluate the impact of survivin expression on the prognosis of breast cancer patients through a meta-analysis. Studies evaluating survivin expression were sourced from the PubMed, Embase, and Cochrane databases. We conducted a meta-analysis based on full-text articles that evaluated the relationship between survivin expression and survival by immunochemistry or polymerase chain reaction. The studies were initially divided into 2 groups based on the evaluation of overall survival (OS) and disease-free survival (DFS). Subsequently, each group was further categorized according to the method used to detect survivin expression. Statistical analyses for this study were conducted using Stata and JAMOVI. After screening with keywords, we identified 24 retrospective studies evaluating OS and 15 retrospective studies evaluating DFS, which were included in the analysis. We found that the studies in the meta-analysis were not heterogeneous, and this remained consistent when categorizing the groups by survivin expression detection. Survivin expression was associated with OS (HR 1.23, 95% CI 0.81-1.65) and DFS (HR 0.89, CI 0.42-1.36), indicating poor prognosis. This significant relationship between survivin expression and survival persisted when the studies were categorized by the detection method, either immunohistochemistry or polymerase chain reaction. In this study, we evaluated the prognostic significance of survivin expression in patients with breast cancer through a meta-analysis. These results support the use of survivin expression as a prognostic marker in breast cancer, potentially guiding treatment decisions.

Prognostic significance of survivin expression in pediatric ewing sarcoma

Survivin is an inhibitor of apoptosis protein that inhibits caspases and blocks cell death. It is undetectable in most normal adult tissues. High survivin expression has been detected in various tumors and has been correlated with therapy resistance and poor outcome. We conducted this study to examine survivin expression in pediatric Ewing sarcoma (ES) and evaluate its role in predicting clinical outcome. Formalin-fixed paraffin-embedded tumor tissues from 108 pediatric ES patients were examined by immunostaining with survivin rabbit monoclonal antibodies. Survivin was detected in tumor tissues of 72 (66.7%) patients. High expression (≥50%) was detected in 18 (16.7%) patients. High survivin expression was shown to be a significant univariate parameter for poorer overall (OS) and event free survival (EFS) with p value 0.033, and 0.037 respectively. It was confirmed as an independent factor in multivariate analysis for OS (p: 0.041; HR: 1.97 with 95% CI of 1.03-3.79) and EFS (p: 0.049; HR: 1.86 with 95% CI of 1.00-3.46). These results suggest that high survivin expression identifies a group of patients with poor prognosis and this may help to refine risk adapted treatment; however, this needs to be confirmed in prospective studies.

The prognostic significance of survivin expression in patients with HNSCC: a systematic review and meta-analysis

BackgroundSurvivin has been recently identified as a promising novel therapeutic target and prognostic marker in different types of cancer. Here we conducted a comprehensive meta-analysis to better clarify they the precise prognostic and diagnostic value of survivin in head and neck squamous cell carcinoma (HNSCC).MethodsDatabase of PubMed (Medline), Embase, and Web of Science were systematically searched for related published literature up to September 2020. Pooled hazards ratios (HR) and related 95% confidence intervals (CI) were used to estimate the association of survivin expression and survival outcomes in HNSCC patients.ResultsTwenty eight studies with 4891 patients were finally included in this meta-analysis, the pooled analysis indicated that the survivin expression was significantly correlated with poorer overall survival (OS) (HR, 2.02; 95% CI, 1.65–2.47, P < 0.001), and poorer disease-free survival (DFS)/ disease-specific survival (DSS) (HR = 2.03, 95%CI: 1.64–2.52, P < 0.001; HR = 1.92, 95%CI: 1.41–2.60, P < 0.001, receptively). Similar results were observed in subgroup analysis stratified by different cancer types, such as laryngeal squamous cell carcinoma (LSCC) (HR = 1.35, 95%CI: 1.05–1.74, P < 0.001), oral squamous cell carcinomas (OSCC) (HR = 2.45, 95%CI: 1.89–3.17, P < 0.001), nasopharyngeal carcinoma (NPC) (HR = 2.53, 95%CI: 1.76–3.62, P < 0.001) and HNSCC (HR = 1.52, 95%CI: 1.25–1.86, P < 0.001). Furthermore, ethnicity-stratified analysis indicated that survivin was significantly associated with poorer OS among both Asian and Non- Asian HNSCC patients (HR = 2.16, 95%CI: 1.76–2.66; HR = 1.56, 95%CI: 1.33–1.82, respectively).ConclusionsOur results suggested that survivin is predictors of worse prognosis in HNSCC patients. Hence, survivin is a potential therapeutic target for HNSCC.

Prognostic Significance of Survivin Expression in Patients with Ovarian Carcinoma: A Meta-Analysis.

Background: Survivin belongs to the protein family of inhibitors of apoptosis (IAP) and is a regulator of the cell cycle and apoptosis. The aim of this study was to assess the clinical and prognostic significance of expression survivin in patients with ovarian cancer. Methods: We systematically searched for articles in PubMed, the American Chemical Society (Publications), Medline, the Royal Society of Chemistry, Scopus and the Web of Science. Patient clinical data, overall survival (OS), disease-free survival (DFS), and survivin expression were extracted from individual studies. We performed statistical analysis using the STATA 16 package. Eighteen publications containing data from 2233 patients with ovarian cancer were included in this meta-analysis. Results: We found an adverse effect of survivin expression on OS (risk ratio (HR): 1.60; 95% confidence interval (CI): 1.33–1.93, p = 0.00) but this was not observed on DFS (HR: 1.06; 95% CI: 0.55–2.05, p = 0.87). The analysis of clinicopathological parameters showed that survivin expression was associated with the histological grades (G1–2 vs. G3) (odds ratio (OR) = 0.53, 95% CI: 0.34–0.83, p = 0.01) and: International Federation Gynecology and Obstetrics (FIGO) stage (I–II vs. III–IV) (OR = 0.22, 95% CI: 0.09–0.55, p = 0.00), but it was not significantly correlated with the histological subtype (OR = 1.14, 95% CI: 0.83–1.58, p = 0.42). Conclusions: Our meta-analysis suggests that survivin expression may be a marker of poor prognosis in ovarian cancer. Survivin expression was associated with parameters of greater aggressiveness of ovarian cancer. Prospective studies are needed to confirm our results indicating that survivin expression can be used as an ovarian cancer biomarker.

Prognostic significance of survivin expression in diffuse large B-cell lymphomas

AbstractSurvivin is an inhibitor of apoptosis overexpressed in various human cancers but undetectable in normal differentiated tissues. A potential expression and prognostic significance of survivin was studied in 222 patients with diffuse large B-cell lymphomas (centroblastic, 96%; immunoblastic, 4%). All patients were enrolled between 1987 and 1993 (median follow-up, 7 years) in the LNH87 protocol of the Groupe d'Etudes des Lymphomes de l'Adulte (GELA) and treated either with the reference ACVBP arm (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone)[AU3A] (n = 79) or other experimental anthracycline-containing regimens (n = 143). The characteristics of these patients were median age of 56 years; serum lactate dehydrogenase (LDH) greater than 1N, 60%; stage III-IV, 55%; performance status, according to the Eastern Cooperative Oncology Group (ECOG) scale, more than 1, 23%; extranodal sites more than 1, 29%; mass more than 10 cm, 44%; bone marrow involvement, 15%. Of the 222 patients studied, 134 (60%) revealed survivin expression in virtually all tumor cells by immunohistochemistry. The overall 5-year survival rate was significantly lower in patients with survivin expression than in those without (40% vs 54%, P = .02). Multivariate analysis incorporating prognostic factors from the International Prognostic Index (IPI) identified survivin expression as an independent predictive parameter on survival (P = .03, relative risk [RR] = 1.6) in addition to LDH (P = .02, RR = 1.6), stage (P = .03, RR = 1.7), and ECOG scale (P = .05, RR = 1.6). A second analysis incorporating IPI as a unique parameter demonstrated that survivin expression (P = .02, RR = 1.6) remained a prognostic factor for survival independently of IPI (P = .001, RR = 1.5). Survivin expression may be considered a new unfavorable prognostic factor of diffuse large B-cell lymphoma.

Prognostic Significance of Survivin Expression and Combined Analysis with Cancer Stem Cell and Epithelial-Mesenchymal Transition-related Markers in Patients with Rectal Cancer Undergoing Preoperative Chemoradiotherapy.

To identify the candidate marker predicting treatment response and survival outcome in rectal cancer patients who received preoperative chemoradiotherapy (CRT). Between 2000 and 2015, 159 patients with histologically-confirmed rectal adenocarcinoma underwent preoperative CRT followed by surgery. Among them, 70 patients were enrolled and the expression of survivin, cancer stem cell markers (CD44 and CD133) and epithelial-mesenchymal transition markers (E-cadherin and TWIST1) in pretreatment biopsy specimens were evaluated by immunohistochemistry. Associations between the expression of markers and clinical outcomes were evaluated. The median follow-up period of all patients was 71 (range=15-203) months. Five-year overall (OS), disease-free (DFS), locoregional recurrence-free (LRRFS) and distant metastasis-free (DMFS) survival were 80.5%, 60.2% 90.1% and 76.5%, respectively. A significant association between survivin overexpression and worse treatment outcome was shown on univariate analyses for OS, DFS and DMFS (p=0.022, 0.002, and 0.005, respectively). On multivariate analysis, survivin overexpression was an adverse prognosticator for DFS and DMFS (p=0.007 and 0.015, respectively), with a borderline significant trend towards a shorter OS (p=0.069). Four other single biomarkers were not associated with survival outcomes. However, overexpression of both survivin and CD44 was significantly associated with worse OS on multivariate analysis (p=0.003). Survivin combined with CD44 might be a candidate biomarker for the prediction of recurrence and survival in patients who received preoperative CRT for rectal cancer. Further research with a larger population is needed to validate these results.

Clinicalpathological and prognostic significance of survivin expression in renal cell carcinoma: a meta-analysis.

BackgroundIn recent years, survivin expression had been investigated as a prognostic biomarker for renal cell carcinoma (RCC), however, the results were conflicting. This study was aimed to explore the association between survivin expression and clinicalpathological features and the prognostic value for cancer-specific survival (CSS) and overall survival (OS) in RCC.ResultsEleven studies with 1,697 subjects were included in this meta-analysis. The results showed that survivin expression was associated with higher tumor grade (OR=4.25, 95%CI: 3.04-5.95, p<0.001), advanced tumor stage (OR=3.83, 95%CI: 2.01-7.3, p<0.001) and lymph node metastasis (OR=4.19, 95%CI: 2.34-7.52, p<0.001), but had no association with age, gender or distant metastasis. In addition, survivin expression was also correlated with poor CSS (HR=2.08, 95%CI: 1.07-4.05, p=0.032) and poor OS (HR=2.28, 95%CI: 1.57-3.33, p<0.001).Materials and MethodsLiterature was searched by PubMed, Embase and Web of Science. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were extracted from eligible studies. Fixed or random effects model were used to calculate pooled HRs and 95%CIs according to heterogeneity.ConclusionsThis study demonstrated that survivin expression was associated with more aggressive clinical features and predicted poor CSS and OS in patients with RCC.

Clinicopathological and prognostic significance of survivin expression in renal cancer patients: a meta-analysis

BackgroundSurvivin has been reported to play a role in the diagnosis and prognosis of renal cell carcinoma (RCC); however, published data on this subject are conflicting.AimTo conduct a meta-analysis to...

The prognostic significance of survivin expression in gallbladder carcinoma.

Gallbladder cancers (GBC) are characterized by rapid progression, early metastasis, and poor prognosis; the molecular mechanisms of the various signaling pathways involved should be elucidated to develop effective therapies. Survivin, an apoptosis inhibitor protein expressed in the G2/M phase of the cell cycle, plays a role in cell division and affects both cell survival and proliferation. Survivin has been investigated in many types of cancer, and this study aims to examine the relationship of survivin expression in gallbladder cancer patients with clinicopathological features and prognosis. We evaluated demographic characteristics (age, gender), tumor characteristics (histopathological type, differentiation, perineural, and lymphovascular invasion; serosal invasion, surgical margin positivity and lymphocytic response), and Survivin expression immunohistochemically, and we analysed the relationship between these characteristics and prognosis in 47 gallbladder carcinoma cases from 2000 to 2011. Immunohistochemically, while survivin expression was observed in 36 cases, it was absent in 11 cases. Follow-up data were obtained from 32 patients. Two (8.7%) of 23 cases with a Survivin-positive tumor were alive at 74th and 35th months, whereas 5 (%55.6) of nine cases with Survivin-negative tumor were alive at 50th, 89th, 124th, 126th, 131th months. Survivin expression was correlated with short survival (p = 0.043), and the univariate analysis showed that reduced overall survival was associated with age (p = 0.043), male gender (p = 0.038), infiltrative pattern (p = 0.019), lymphovascular invasion (p = 0.004), perineural invasion (p = 0.009), serosal invasion (p = 0.027), ulcer (p = 0.033), and surgical margin positivity (p = 0.022). Despite the low number of patients in our study, the analysis results suggest that survivin positivity might actually be a significant prognostic factor. This finding could be a reference point for targeted treatment studies. However, further studies involving broader series and longer follow-up are still required for highly lethal gallbladder cancers.

The prognostic significance of survivin expression in gallbladder carcinoma.

e15589Background: Gallbladder cancers (GBC) have poor prognosis and the molecular mechanisms of GBC should be elucidated to develop effective therapies.Survivin, an apoptosis inhibitor protein, pla...

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of >25%, associated with an International Prognostic Index score of >2 (P=0.015), disease in ≥2 extranodal sites (P=0.011), and a high Ki-67 index (P<0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivin-negative patients (P=0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P=0.035 and P=0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an independent prognostic factor for poor outcome in patients with activated B cell-like disease treated with the R-CHOP regimen, and patients with survivin-positive activated B cell-like diffuse large B-cell lymphoma seem to benefit less from this treatment and may require additional novel agents.

Prognostic Significance of Survivin Expression in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Therapy: A Report from the International DLBCL Rituximab-CHOP Consortium Program

502 Prognostic Significance of Survivin Expression in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Therapy: A Report from the International DLBCL Rituximab-CHOP Consortium Program Zhiyu Liu, Zijun Y. Xu-Monette, Xin Cao, Carlo Visco, Alexander Tzankov, Santiago Montes-Moreno, Karen Dybkaer, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W.L. Choi, J. Han van Krieken, Jooryung Huh, Weiyun Ai, Maurilio Ponzoni, Andres J.M. Ferreri, John P. Farnen, Michael B. Moller, Jane N. Winter, Miguel A. Piris, L. Jeffrey Medeiros, Ken H. Young Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; San Bartolo Hospital, Vicenza, Italy; University Hospital, Basel, Switzerland; Hospital Universitario Marques de Valdecilla, Santander, Spain; Aalborg University Hospital, Aalborg, Denmark; Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA; The Methodist Hospital, Houston, TX, USA; Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; University of North Carolina School of Medicine, Chapel Hill, NC, USA; Cleveland Clinic, Cleveland, OH, USA; University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China; Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea; University of California San Francisco School of Medicine, San Francisco, CA, USA; San Raffaele H. Scientific Institute, Milan, Italy; Gundersen Lutheran Health System, La Crosse, WI, USA; Odense University Hospital, Odense, Denmark; Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Survivin expression in canine lymphomas in relation with proliferative markers.

Survivin is a member of apoptosis inhibiting proteins family. Apart from its antiapoptotic activity it plays a critical role in regulating the cell cycle and mitosis. It is overexpressed in most human malignancies. While the prognostic significance of survivin expression is widely investigated in human non-Hodgkin's lymphomas, little is known about its expression in canine lymphomas. The aim of the study was to evaluate the expression of survivin in canine lymphomas in relation to proliferation markers (mitotic index and percentage of Ki67-positive cells). Survivin was found in all examined lymphomas belonging to 6 different morphological subtypes with nuclear immunoreactivity. In most of lymphomas (18/25) survivin expression ranged 10%-25% of positive cells. Only single cases had lower (0-10% positive cells, 1/25) or higher (25-50% and > 50% positive cells, 5/25 and 1/25, respectively) index of survivin. Neither mitotic index nor proliferative index correlated with survivin expression when the values quantified randomly in whole specimens were compared. However, when survivin expression were quantified in selected tumor areas of low and high proliferation activity the high correlations between survivin expression and proliferation index were found. The results indicated that survivin is commonly expressed in canine lymphomas. Nuclear labelling together with the relation of its expression and proliferative activity in highly proliferative areas of neoplastic tissue suggest a potential role of survivin in cell cycle activation in canine lymphoma cells. However, further studies of the relation between expression of survivin and other proteins involved in cell cycle regulation are needed. Moreover, the results suggest that survivin may pose the therapeutic target in canine lymphomas.

Clinicopathological and prognostic significance of survivin expression in patients with oral squamous cell carcinoma: evidence from a meta-analysis.

BackgroundSurvivin has been proposed as a promising prognostic marker in oral squamous cell carcinoma (OSCC), but the published data on survivin expression in patients with this condition are controversial. To address this we performed a meta-analysis systematically to assess the clinicopathological and prognostic significance of survivin expression in OSCC.MethodsWe searched PubMed, Embase, Web of Science and Ovid databases for papers investigating the clinicopathological and prognostic significance of survivin expression in OSCC. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to determine the relevance of survivin.ResultsA total of 15 papers, including 1040 cases in which survivin expression was detected by immunohistochemistry (IHC) or reverse transcription polymerase chain reaction (RT-PCR), were included. A meta-analysis of clinicopathological variables revealed a correlation between survivin expression and lymph node metastasis (OR = 0.62, 95% CI = 0.44–0.88, p < 0.05) and clinical stage (OR = 0.63, 95% CI = 0.41–0.96, p < 0.05). However, no significant associations were found between survivin expression and tumor differentiation grade (OR = 0.72, 95%CI = 0.26–1.11, p > 0.05), depth of invasion (OR = 0.76, 95% CI = 0.50–1.14, p > 0.05), age (OR = 0.78, 95% CI = 0.48–1.29, p > 0.05) or gender (OR = 1.31, 95% CI = 0.86–2.01, p > 0.05). Subgroup analysis using stratified detection methods showed no significant associations between the expression of survivin protein and clinicopathological variables in OSCC. A correlation between survivin expression and poor prognosis of patients with OSCC (HR = 1.62, 95% CI = 1.23–2.01, p < 0.05) was demonstrated.ConclusionSurvivin is a potential prognostic marker of OSCC. Future studies with larger sample sizes and well-designed inclusion criteria will be needed to dissect the role of survivin expression in determining the clinicopathological features and/or prognosis of OSCC.

661P - Prognostic Significance of Survivin Expression in Patients with Gastric Cancer

ABSTRACT Aim: Detection of circulating tumor cells (CTC) in peripheral blood is thought to be a promising method for predicting tumor recurrence and for monitoring treatment efficacy. However, unlike in breast or lung cancer, little information is available in gastric cancer. Recently, survivin, a member of the inhibitor of apoptosis (IAP) family, had been reported to be associated with tumor progression and prognosis in gastric cancer. In addition, survivin expression in peripheral blood appears to be a promising prognostic marker. In order to evaluate the clinical significance of surviving expression in peripheral blood, we performed real-time RT-PCR analysis using whole blood obtained from healthy volunteers and patients with gastric cancer. Methods: A total of 26 healthy volunteers and 129 patients with gastric cancer treated at our cancer center between Nov. 2009 and March 2014 were enrolled in this study. Peripheral blood samples were collected using PAXgene and RNA was isolated using Boom method. After cDNA synthesis, quantitative real-time PCR targeting survivin gene (BIRC5) was performed and the relative expression level of survivin mRNA was calculated. Correlation between survivin expression and clinicopathologic factors and survival was investigated. Results: Median survivin mRNA expression level in peripheral blood were 171 (46 to 538) in healthy volunteers and 440 (35 to 4932) in gastric cancer, respectively. There was a significant difference between healthy volunteers and gastric cancer (p Conclusions: Survivin expression in peripheral blood was significantly higher in gastric cancer. In addition, survivin was selected as an independent prognostic factor. Survivin is considered to be a promising CTC marker in gastric cancer. Disclosure: All authors have declared no conflicts of interest.

Survivin expression in patients with newly diagnosed nodal diffuse large B cell lymphoma (DLBCL)

Survivin is one of the inhibitors of apoptosis proteins (IAP) that might play an important role in the pathogenesis of diffuse large B cell lymphoma (DLBCL). The present study was designed to investigate the clinical and prognostic significance of survivin expression in nodal DLBCL. We analyzed lymph node biopsy specimens obtained from 56 patients with newly diagnosed nodal DLBCL, treated with immunochemotherapy (R-CHOP). The expression of survivin was analyzed using the standard immunohistochemical method on formalin-fixed and routinely processed paraffin-embedded lymph node specimens and evaluated semiquantitatively as a percentage of tumor cells. Survivin immunoexpression (>45 % positive tumor cells) was found in 22 (39.28 %) and observed as cytoplasmic staining in 15 patients, or mixed (cytoplasmic and nuclear) staining in 7 patients. A significant difference in survivin immunoexpression was noticed between the GCB and the non-GCB subtypes of DLBCL (p = 0.031). However, survivin immunoexpression had no significant association with IPI, “bulky” disease, extranodal localization, hemoglobin, Ki-67 immunoexpression or other clinicopathological parameters. A univariate analysis showed that survivin positivity was an unfavorable factor for therapy response and a predictor of shorter survival in patients with DLBCL (p = 0.048 and p = 0.034, respectively). Patients with survivin overexpression experienced a relapse more often than patients without expression of this apoptotic protein (27.3 vs. 11.8 %), but this difference did not reach statistical significance (p = 0.131). The results of this study showed that disregulation of survivin expression had an important role in the determination of the course of the disease in patients with nodal DLBCL treated with R-CHOP. Therefore, survivin represents a potential target for therapeutic intervention in DLBCL.

Survivin in Multiple Myeloma: Prognostic and Therapeutic Implications

Abstract 137The IAP (inhibitor-of-apoptosis) family member, survivin, is one of the most significantly over-expressed genes in malignant cells. Survivin has been reported to inhibit apoptosis and regulate mitosis as well as cytokinesis. We therefore first determined the expression of survivin in CD138-purified multiple myeloma (MM) cells from previously untreated patients at our centers’ trial group (TG) (n=246) and the UAMS Arkansas (n=345) validation group (VG). Using the PANP algorithm, survivin is aberrantly expressed in 27% (TG) of MM cell samples. It is not expressed in normal bone marrow plasma cell samples (n=7) while expression increases significantly from MM stage I-III (P<.001). Survivin expression correlates with proliferation as assessed by gene expression- (r=.8, P<.001) or propidium iodide (r=.7, P<.001). Presence of survivin expression correlates with inferior event-free and overall survival in patients undergoing high-dose chemotherapy in the TG (22.6 vs. 35.4 months, P<.001, 52.9 vs. n.r., P=.002) as well as in the VG (12.3 vs. 54.1 months, P<.001, and 17.4 vs. n.r., respectively). These results support the further evaluation of survivin as a therapeutic target in MM. We next assessed the effects of siRNA-mediated knock-down of survivin in vitro. Suppression of survivin by siRNA induced cell cycle arrest and apoptosis in MM cell lines. The small molecule suppressant of survivin, YM155, is currently in clinical development for the treatment of solid tumors. Here, we investigated YM155 for its anti-MM activity. YM155 abrogated proliferation and induced apoptosis in a panel of 10 human MM cell lines and MM cells isolated from multidrug-resistant patients at an IC50 of 4–50nM while the IC50 was not reached in primary bone marrow stromal cells up to 500nM. YM155 was also able to overcome the protective effect of IL-6, IGF-1 and the presence of bone marrow stromal cells, respectively. The induction of apoptosis by YM155 closely correlated with down-regulation of intracellular survivin protein expression within 24 to 36h of treatment with 50–100nM of YM155. However, inhibition of cell proliferation is already detectable at 12h at 5–10nM, suggesting two different dose- and time-dependent mechanisms of action. We therefore performed gene expression and protein profiling on YM155-treated MM cells. Strikingly, these data revealed early up-regulation of the ER stress response (PERK, phospho-eIF2a, ATF4, ATF3) followed by increased CHOP expression and a profound abrogation of proliferation. This appeared to be independent of cellular survivin levels, indicating that the early proliferation arrest at very low nanomolar concentrations is mediated primarily by the ER stress response. Moreover, gene signatures regulated by the IL-6/STAT pathway (CCND1, BCL2L1, MCL1, BIRC5A) were markedly altered upon YM155 treatment. Importantly, IL-6 profoundly sensitized IL-6 responsive MM cell lines to treatment with YM155. We therefore hypothesized that YM155 might abrogate upstream regulatory signaling pathways of survivin expression. Indeed, YM155 abrogated constitutive as well as IL-6 induced phosphorylation of STAT3, an important transcription factor for survivin expression in MM cells. In contrast, phosphorylation of ERK1/2 and AKT remained unchanged. Dephosphorylation of STAT3 closely correlated with the loss of intracellular survivin. In conclusion, we have demonstrated the prognostic significance of survivin expression and a potential therapeutic role for the small molecule suppressant of survivin YM155 in MM. Disclosures:No relevant conflicts of interest to declare.

Prognostic significance of survivin expression in renal cell cancer and its correlation with radioresistance

Survivin, an important inhibitor of apoptosis, has been found to play an important role in the initiation, progression, and chemoradioresistance of human malignancies. Previously, we have reported that upregulation of survivin in oral squamous cell carcinoma correlates with poor prognosis and chemoresistance. The aim of this study was to assess prognostic significance of survivin protein expression in RCC and analyze its correlation with radiosensitivity of RCC cells. RT-PCR and Western blot assays were performed to detect survivin mRNA and protein expression in normal human kidney epithelial cell line (HKEC) or RCC cell lines. The expression of survivin mRNA in RCC and corresponding nontumor kidney tissues was also detected by RT-PCR. Immunohistochemistry was performed to determine survivin protein expression in 75 cases of RCC tissue samples. Moreover, the association of survivin protein expression with clinicopathogical factors and prognosis of RCC patients was statistically analyzed. Small interfering RNA was used to knockdown the endogenous survivin expression in RCC cell line (ACHN) and evaluate the effects of survivin knockdown on proliferation, apoptosis, and radiosensitivity of RCC cell line. RCC cells showed sufficient expression of survivin mRNA and protein, but the expression of survivin gene was not detected in normal HKEC. Moreover, the expression level of survivin mRNA in RCC tissues was significantly higher than that in corresponding nontumor kidney tissues. The immunostaining of survivin protein was mainly located in cytoplasm of RCC tumor cells. Tumor pathological stage (P = 0.028), grade (P = 0.004), and lymph node metastasis (P = 0.017) of RCC patients were significantly correlated with survivin protein expression. In addition, patients with high survivin levels had a significantly shorter overall survival than those with low levels (P < 0.001), and the expression of survivin protein was an independent prognostic factor for RCC patients (P = 0.008). The expression of survivin gene could be reduced in RCC cell line and survivin knockdown could inhibit growth and enhance in vivo radiosensitivity of RCC cell line by inducing apoptosis enhancement. Taken together, the status of survivin protein expression may be an independent factor for predicting the prognosis of RCC patients and tumor-specific survivin knockdown combined with radiotherapy will be a potential strategy for RCC therapy.

Evaluation of survivin as a prognostic marker in oral squamous cell carcinoma

Poor prognosis of oral squamous cell carcinoma (OSCC) is partly attributed to the lack of significant tumor marker for accurate staging and prognostication. We have evaluated survivin, which is a member of the inhibitor of apoptosis family as a cancer marker associated with proliferation, angiogenesis, oral carcinogenesis, and OSCC patient survival, as we reported a prognostic significance of survivin expression in lymph node previously. To evaluate survivin expression in six OSCC cell lines, Western blotting was performed. Hamster oral carcinogenesis model was used to observe changes of survivin expression in oral carcinogenesis. Finally, we assessed the diagnostic and prognostic significance of survivin in a series of 38 primary OSCC through immunohistochemistry (CD31, PCNA) and Kaplan-Meier's test. Survivin expression was detected in all OSCC cell lines at a varying level but not observed in normal gingival keratinocyte cells. In hamster model, survivin expression was observed from 8 weeks through 16 weeks and the intensity of expression became strong until 16 weeks. Clinicopathological analysis revealed a significant correlation between survivin expression and lymph node metastasis (P = 0.006) and proliferation (P < 0.001). However, there was no significant relationship with differentiation, micro vessel density, and cancer stage based on TNM. Survivin overexpression had a significant negative effect on survival of patients. These results demonstrate the significant relationship between survivin expression and oral carcinogenesis and aggressiveness of OSCC including survival rate of patient. Survivin therefore may be used as a significant cancer marker to gain prognostic information of OSCC.

The Prognostic Significance of Survivin Expression in Breast Cancer

Purpose: Survivin is a member of the inhibitors of apoptosis family. It has recently comes into the limelight as a promising tumor marker, but many previous reports have shown controversial results regarding the significance and prognostic value of a survivin expression. In this study we determined the correlation between the survivin expression and the conventional prognostic markers and we also investigated the outcomes according to the localization of the survivin expression. Methods: Tissue microarray (TMA) blocks were made with formalin-fixed paraffin-embedded tissues from 185 breast cancer patients and the immunohistochemical staining was done using an anti-survivin antibody. Among these, 157 patients were available for a survivin expression. The conventional clinicopathologic features and overall survival were correlated with the localization of the survivin expression. Results: Survivin was expressed in 101 breast cancers (64.3%). A higher cytoplasmic survivin expression were noted in the older group (p=0.003), in the node-negative cancers (p= 0.012), in the earlier tumor stages (p=0.012) and in the cancers that had not been treated with adjuvant chemotherapy (p=0.014). On the contrary, a higher nuclear survivin expression was inversely correlated with an estrogen expression (p=0.006) and a progesterone receptor (p=0.043) expression. In terms of survival, a cytoplasmic expression was associated with improved overall survival (p=0.01) but a nuclear survivin expression was correlated with unfavorable overall survival (p=0.002). A high cytoplasmic to nuclear ratio of survivin was associated with improved overall survival (p=0.001) conversely, increased nuclear to cytoplasmic survivin ratio was correlated with unfavorable overall survival (p<0.0001). Multivariate analysis revealed that nuclear survivin expression (p= 0.001) and high nuclear to cytoplasmic survivin ratio (p=0.012) were independent predictor of overall survival. Conclusion: Survivin is frequently expressed in primary breast cancer. A cytoplasmic survivin expression is a good prognostic predictor for patients with axillary node negative early breast cancers and a nuclear survivin expression is a worse independent predictor of overall survival for patients with axillary node positive breast cancers.