High Survivin Research Articles

Abstract 2598: siRNA silencing of survivin enhances activity of mitomycin C in human bladder RT4 xenografts

Abstract For intravesical therapy of nonmuscle-invading bladder cancer, maximizing the mitomycin (MMC) exposure by pharmacokinetic interventions yielded 43% 5-year recurrence-free survival (Au et al., JNCI, 2001). Further improvement requires enhancing chemosensitivity, such as silencing of survivin, an inhibitor of apoptosis and indicator of bladder cancer aggressiveness and recurrence. Survivin is induced by chemotherapy, and its in vitro knockdown by si/shRNA enhances sensitivity to chemotherapy including MMC. As the utility of siRNA has been impeded by lack of activity in vivo, we developed a siRNA carrier that enhances its intracellular bioavailability and in vivo transfection. This carrier uses a fusogenic lipid to destabilize the endosomal membrane plus paclitaxel to perturb the endosomal siRNA transport (PPCat). The present study investigated if survivin siRNA-loaded PPCat (PPCat-siSurvivin) produces in vivo survivin knockdown and enhances MMC activity in human bladder RT4 tumors. Table shows the results. In vitro studies showed that MMC at 50% cytotoxic concentration induced survivin expression, which was reversed by PPCat-siSurvivin. A separate experiment evaluated if a modified PPCat-siSurvivin (i.e., PCat, without paclitaxel) enhanced the MMC activity; the results showed (a) lower clonogenicity for the combination compared to either agents (p<0.05, n=3 experiments), and (b) PCat comprising non-target siRNA had no effects. Taken together, these data indicate the enhanced activity was due to survivin knockdown and not the paclitaxel contained in PPCat. In mice bearing subcutaneous RT4 tumors, single agent MMC delayed tumor growth, with the residual tumors showing higher survivin expression. PPCat-siSurvivin significantly enhanced the MMC activity, which appeared to correlate with reduced survivin level. As single agent PPCat-siSurvivin was inactive in vivo, the enhanced activity for the combination indicates synergy. Supported in part by R43TR000356 and RO1CA158300, DHHS. GroupIn VitroIn VivoSurvivin expression (3 experiments, 3 samples each)Time for 50% size increase, Median (Range), daysRelative survivin protein levelmRNAProteinControl1.00 ± 0.101.00 ± 0.098 (8-12, n=4)1.00 (0.94-1.06, n=2)PPCat-NT siRNA Control1.08 ± 0.050.99 ± 0.2512 (8-12, n=4)Not donePPCat-siSurvivin0.82 ± 0.02*0.58 ± 0.10*12 (8-12, n=4)Not doneMMC1.47 ±0.34*1.52 ± 0.08*37 (23-44, n=8)*2.60 (2.56-2.72, n=2)MMC + PPCat-NT siRNA1.53 ± 0.24*1.33 ± 0.06*Not doneNot doneMMC + PPCat-siSurvivin1.13 ± 0.17**0.90 ± 0.04**44 (37-58, n=8)***1.06 (0.94-1.18, n=2)* p<0.05 vs. control groups. ** p<0.05 vs. MMC and MMC+PPCat-NT siRNA, but not different from the two control groups. *** p<0.05 vs. all other groups. Citation Format: Minjain Cui, M. Guillaume Wientjes, Jessie L.-S. Au, Michael O'Donnell, Kevin Loughlin, Ze Lu. siRNA silencing of survivin enhances activity of mitomycin C in human bladder RT4 xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2598. doi:10.1158/1538-7445.AM2014-2598

The combination of strong immunohistochemical mtTFA expression and a high survivin index predicts a shorter disease-specific survival in pancreatic ductal adenocarcinoma.

Mitochondrial transcription factor A (mtTFA) plays a crucial role in both the transcription and maintenance of mitochondrial DNA. A high expression of mtTFA has been demonstrated in several solid tumors, and is closely associated with cancer cell survival/apoptosis and growth. However, its expression pattern in pancreatic ductal adenocarcinoma (PAC) remains to be elucidated. Additionally, our groups have recently revealed that a subset of apoptosis-related genes is strongly regulated by mtTFA, and that two putative mtTFA binding sites are present in the promoter region of the survivin gene, which is a member of the inhibitor-of-apoptosis protein family. We therefore investigated the correlation of the immunohistochemical mtTFA expression and the survivin index with various clinicopathological variables and the prognosis, using 70 paraffin-embedded tumor samples from patients with surgically-resected PAC. The mtTFA expression or survivin index was considered to be strong or high when ≥30% or 10% of the PAC cells showed positive staining, respectively. Strong mtTFA expression and/or a high survivin index was revealed to have a significant relationship to a pathologically high tumor grading and advanced tumor stage. Moreover, mtTFA showed significantly high co-expression with survivin. Univariate and multivariate analyses demonstrated that both the strong mtTFA expression and high survivin index groups had significantly shorter survival rates, especially within the first two years postoperatively. The combination of strong mtTFA expression and a high survivin index may predict a poor prognosis in patients with PAC, and these new biomarkers might offer useful information for the early clinical management.

Variation in Sp1 binding sites correlates with expression of survivin in breast cancer

Survivin is the smallest member of the inhibitor of apoptosis (IAP) family and is deregulated in breast cancer, where it is associated with a poor overall prognosis. It is well established that survivin overexpression predominately occurs at the transcriptional level. Numerous transcription factors bind to specific sequences in the promoter regions of genes and are involved in transcriptional regulation. Specificity protein (Sp) 1 binding sites have been found in the promoter region of the survivin gene. The present study aimed to investigate whether variations in Sp1 binding sites affect survivin expression. Nested polymerase chain reaction followed by DNA sequencing were performed to analyze the survivin gene promoter region in 42 breast cancer tissue samples. Furthermore, survivin expression was assessed using immunohistochemistry. High survivin protein expression was found in 66.7% (28/42) of breast cancer tissue samples. In addition, 15 variations in seven Sp1 binding sites were detected in 12 samples and Sp1 binding site variation was found to be associated with low survivin expression in the 42 samples. These findings suggested that variations in Sp1 binding sites may be associated with survivin expression.

Survivin mRNA Level in Blood Predict the Efficacy of Neoadjuvant Chemotherapy in Patients with Stage IIIA-N2 Non-Small Cell Lung Cancer.

In a previous study, survivin mRNA expression in non-small cell lung cancer (NSCLC) tissue had been demonstrated to be associated with unfavorable prognosis of patients treated with chemotherapy. In this study, we investigated the survivin mRNA levels in blood of patients with stage IIIA-N2 NSCLC and their association with the efficacy of neoadjuvant chemotherapy (NCT) and disease-free survival (DFS) and overall survival (OS). Blood specimens were collected from 56 patients with stage IIIA-N2 NSCLC before (N0) and after the complete of NCT (N1). Survivin mRNA was measured by real-time quantitative-PCR assay. Receiver operating characteristics curve analysis was undertaken to determine the best cutoff value for survivin mRNA. Results showed that high blood survivin mRNA levels at N0 and N1 were significantly associated with clinical (P = 0.01 and P = 0.008, respectively) and pathologic response (both P = 0.004, respectively). Moreover, the change of blood survivin mRNA levels in these NSCLC patients is associated with the clinical and pathologic response to NCT. Patients with high survivin mRNA levels at N0 and N1 had significantly shorter DFS and OS than those with low survivin mRNA levels (P = 0.021 and P = 0.014, respectively for DFS; P = 0.009 and P = 0.005, respectively for OS). Multivariate analysis demonstrated that high blood survivin mRNA level was an independent predictor for worse DFS and OS in the NSCLC patients receiving NCT. In conclusion, survivin mRNA level in blood from stage IIIA-N2 NSCLC patients receiving NCT is predictive of cancer outcome.

Nanoformulated cell-penetrating survivin mutant and its dual actions.

In this study, we investigated the differential actions of a dominant-negative survivin mutant (SurR9-C84A) against cancerous SK-N-SH neuroblastoma cell lines and differentiated SK-N-SH neurons. In both the cases, the mutant protein displayed dual actions, where its effects were cytotoxic toward cancerous cells and proliferative toward the differentiated neurons. This can be explained by the fact that tumorous (undifferentiated SK-N-SH) cells have a high endogenous survivin pool and upon treatment with mutant SuR9-C84A causes forceful survivin expression. These events significantly lowered the microtubule dynamics and stability, eventually leading to apoptosis. In the case of differentiated SK-N-SH neurons that express negligible levels of wild-type survivin, the mutant indistinguishably behaved in a wild-type fashion. It also favored cell-cycle progression, forming the chromosome-passenger complex, and stabilized the microtubule-organizing center. Therefore, mutant SurR9-C84A represents a novel therapeutic with its dual actions (cytotoxic toward tumor cells and protective and proliferative toward neuronal cells), and hence finds potential applications against a variety of neurological disorders. In this study, we also developed a novel poly(lactic-co-glycolic acid) nanoparticulate formulation to surmount the hurdles associated with the delivery of SurR9-C84A, thus enhancing its effective therapeutic outcome.

AB0033 Intracellular Expression of Survivin and Bcl-6 is Decreased in CD4+ T-Cells of Rheumatoid Arthritis Patients with High Serum Survivin

BackgroundSurvivin is recognized as a marker of persistently active and erosive RA. The findings in experimental arthritis suggested that survivin co-ordinates the antigen-dependent leukocyte maturation and function by regulating transcriptional...

Survivin protein as predictor of pathologic response in patients with locally advanced cervical cancer treated with chemoradiation followed by radical surgery

We investigated the correlation of pathologic response and immunohistochemically assessed expression of survivin protein in 71 patients with locally advanced cervical cancer treated with chemoradiation (CT/RT) followed by radical surgery. The prognostic role of survivin expression was also evaluated. Immunohistochemical analysis of survivin expression was carried out using the polyclonal rabbit antisurvivin antibody. Cytoplasmic survivin immunoreaction was observed in 69 (97.2%) of 71 cases and nuclear staining in 7 (9.8%) of 71 women. Median cytoplasmic survivin expression was 160 (range, 0-280), and higher levels were observed in patients with residual disease (≥3 mm) in the cervix (survivin level, 160 versus 120; P = .016) and in women with metastatic lymph nodes (survivin levels, 160 versus 150; P = .032). No differences were documented in the distribution of patients with positive nuclear staining, according to clinicopathological variables. In multivariate analysis, cytoplasmic survivin expression emerged as an independent predictor of residual cervical disease and lymph node status after CT/RT. During a follow-up period of 83 months (range, 8-175 months), recurrences occurred in 24 (33.8%) women, and all patients died of disease. Women with high cytoplasmic survivin experienced shorter disease-free survival compared with patients with low levels (5-year disease-free survival, 80.8% versus 55.3%; P = .033). Only a trend was observed for greater overall survival in patients with high expression (5-year overall survival, 81.0% versus 55.3%; P = .069). No survival differences were documented for nuclear survivin status. The immunohistochemically assessed survivin cytoplasmic levels at diagnosis represent a reliable and easily assessable tool to predict response to CT/RT in patients with locally advanced cervical cancer.

Significance of intracellular localization of survivin in cervical squamous cell lesions: Correlation with disease progression.

Survivin is a member of the inhibitor of apoptosis protein family. Under normal circumstances, survivin is expressed in embryonic and fetal tissues, but is completely downregulated in normal adult tissues. Notably, this protein has been found to be prominently expressed in a variety of human malignant tumors. The present study was designed to evaluate the possible role of survivin in the tumorigenesis of cervical intraepithelial neoplasia and invasive squamous cell carcinoma (SCC) of the uterine cervix. In addition, it was investigated whether the nuclear or cytoplasmic expression of survivin is associated with tumor progression. In total, 71 samples of cervical squamous tissue were obtained, including 15 normal squamous epithelia, 25 high-grade squamous intraepithelial lesions (HSILs) and 31 SCCs, from cone biopsy and hysterectomy specimens and stained for survivin expression by immunohistochemistry. The intensity of survivin expression tended to increase with tumor progression (60.0% of normal mucosa, 76.0% of HSIL and 80.6% of SCC samples demonstrated high intensity survivin expression), but this correlation was not found to be statistically significant. However, a statistically significant difference was identified in the intracellular localization of survivin among the normal mucosa, HSIL and SCC samples (P<0.001). In total, 72% (18/25) of HSIL and 54.8% (17/31) of SCC cases expressed cytoplasmic staining in contrast to the nuclear staining of the normal mucosa. In addition, 64% (16/25) of HSIL and 42% (13/31) of SCC cases showed coexpression in the nucleus and cytoplasm. An inverse correlation was identified between the decrement of nuclear survivin expression and tumor progression, but was not statistically significant (P=0.08). These results indicated that analysis of the intracellular expression of survivin (particularly cytoplasmic expression) is a marker for predicting disease progression in the uterine cervix.

Livin, Survivin and Caspase 3 as early recurrence markers in non-muscle-invasive bladder cancer

To explore the potential correlation and prognostic value of Livin, Survivin and Caspase 3 expression in non-muscle-invasive bladder cancer (NMIBC). We prospectively examined the simultaneous expression of Livin, Survivin and Caspase 3 with immunohistochemistry in the paraffin blocks of 138 patients who underwent transurethral resection, and ten cases of normal bladder specimens were studied as the control group. During a 48-month follow-up, clinical pathologic factors including gender, age, pathology stage, histology grade, adjuvant therapy and recurrence time were recorded. The curves for recurrence-free survival (RFS) were estimated by the Kaplan-Meier method, and the relationship between these proteins' expression and clinical pathologic factors was analyzed with the Cox regression model. Livin and Survivin showed a high expression (H-exp) level of 65.22 and 71.01 % in NMIBC, respectively, whereas Caspase 3 expression level was 50.72 %, and H-exp level of Livin and Survivin were 72.7 and 80.0 % in pT1 stage, respectively, which were proved to be higher than that in pTa/Tis ratio (P < 0.05). The relation between the H-exp and low-expression (L-exp) groups of Livin and Survivin and RFS were found statistically significant (P < 0.05). Conversely, there was better RFS in H-exp Caspase 3 group than in L-exp group (P < 0.05). A risk score was developed on the basis of all three biomarkers to estimate the prognosis of NMIBC patients, and those expressing high Survivin and Livin and low Caspase 3 had a significant shorter RFS time (P < 0.05). Livin, Survivin and Caspase 3 may be valuable as promising indicators of early recurrence in NMIBC.

Clinical Significance of Survivin Expression in Patients with Urothelial Carcinoma

Background. Survivin is a member of the inhibitors of apoptosis protein family that plays an important role in carcinogenesis. Here, we examined the association between survivin expression and clinical outcome in urothelial carcinoma of the bladder (UCB). Methods. A total of 56 histopathologically confirmed UCB patients were recruited from the Department of Urology of Chiayi Christian Hospital from August 2007 to May 2009. Immunohistochemistry (IHC) was used to detect the survivin expression in tumor tissues. The –31 C/G polymorphism in survivin promoter region was determined by polymerase chain reaction-restricted fragment length polymorphism. Results. The frequency of high survivin expression was significantly higher in muscle-invasive tumors (66.6%) than in non-muscle-invasive tumors (34.2%) (P = 0.042) and in poorly differentiated (85.7%) tumors than in moderately differentiated tumors (30.8%) (P = 0.0014). The higher frequency of risk genotypes (C/C and C/G) was found in the median (72.7%) and high (68.0%) survivin expression groups. The multivariate analysis showed that a high survivin expression level was a potential predictive biomarker of poor overall survival (P = 0.02). Conclusion. Our results suggest that the high survivin expression was associated with tumor stage and grade and may present a predictive marker of overall survival in UCB.

Prognostic utility of apoptosis index, Ki-67 and survivin expression in dogs with nasal carcinoma treated with orthovoltage radiation therapy.

ABSTRACTApoptosis, Ki-67 and survivin expression have been reported as prognostic values in human cancer treated with radiation therapy. The aim of this study was to evaluate the correlation between the outcome of canine nasal carcinomas treated with radiation therapy and these cancer markers. The apoptotic index (AI) was evaluated with TUNEL assays, and an immunohistochemical evaluation was performed on Ki-67 and survivin in 33 biopsy samples taken before treatment. Median survival times were estimated using Kaplan-Meier curves and the log-rank method. The AI ranged from 0 to 0.7%, and the percentage of Ki-67-positive cells defined as the proliferative index (PI) ranged from 0.8 to 77% in all samples. Neither the AI nor the PI had a significant relationship with survival time (P=0.056 and 0.211). Survivin expression was detected in 84.9% of samples of canine nasal carcinoma. Dogs with high survivin expression were associated with poorer response to treatment and had shorter survival times (P=0.017 and 0.031). Advanced-stage tumors were also significantly associated with a high level of survivin (P=0.026). Overexpression of survivin was shown to be an unfavorable prognostic factor in dogs with nasal carcinomas treated with radiation therapy.

Clinical significance of Smac and survivin expression in breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy

The second mitochondria‑derived activator of caspases (Smac), an antagonist of the inhibitor of apoptosis protein (IAP), increases chemosensitivity in vitro. Survivin, an IAP family member, mediates cancer cell survival and chemoresistance. The present study investigated the correlation between Smac and survivin expression in primary breast cancer, and the sensitivity to anthracycline during neoadjuvant chemotherapy (NAC). Pre‑treatment biopsies and post‑anthracycline treatment tumor sections were analyzed from 98 cases. Biomarker expression was evaluated by immunohistochemistry in tumor samples from clinical stage II and III anthracycline‑based NAC‑treated breast cancer. A univariate analysis indicated that the estrogen receptor (ER), Smac and survivin were significantly predictive of a pathological complete response (pCR) (P=0.004, 0.001 and 0.037, respectively) in pre‑chemotherapy samples. ER, Smac and survivin expression was also significant for pCR on the multivariate analysis (P=0.001, 0.031 and 0.012, respectively). An inverse association was identified between survivin and Smac expression (r=‑0.217, P=0.032; and r=‑0.335, P=0.003, respectively) prior to and following NAC. The patients with low survivin expression or high Smac expression had significantly longer disease‑free survival (DFS; P=0.012 and P=0.020, respectively) and overall survival (OS; P=0.01 and P=0.033, respectively) compared with the patients with high survivin or low Smac expression. Cox regression analyses demonstrated that survivin, Smac and clinical stage were independent predictors for DFS and OS. The present study indicated the significance of Smac and survivin in determining the breast cancer response to anthracycline‑based chemotherapy, and may permit further stratifying of pre‑chemotherapy patients to undertake more tailored treatments.

Expression of nuclear survivin in normal skin and squamous cell carcinoma: a possible role in tumour invasion

Background:Survivin is detected in few adult normal cells and it is highly expressed in cancer. Nuclear survivin facilitates cell cycle entry, whereas the mitochondrial pool protects cells from apoptosis. Survivin is overexpressed in keratinocyte stem cells (KSCs) and protects them from apoptosis.Methods:As KSCs are at the origin of squamous cell carcinoma (SCC), we evaluated survivin expression in normal and cancerous skin in vivo by immunohistochemistry and western blotting. HaCaT cells overexpressing survivin and wound-healing assay are used. Analysis of variance and Student's T-tests are used for statistical analysis.Results:Survivin is localised in both the cytoplasm and nucleus of normal adult and young keratinocytes. Nuclear survivin is detected in one every 10 of 11 basal keratinocytes. When present in suprabasal cells, nuclear survivin is coexpressed with K10 but not with K15 or p75-neurotrophin receptor (p75NTR), a transit amplifying cell marker. Nuclear, but not cytoplasmic, survivin expression markedly increases in actinic keratosis and in SCC in situ, as compared with normal epidermis, and it is highest in poorly differentiated SCC. In SCC tumours, nuclear survivin-positive cells are mainly K10/p75NTR-negative and K15-positive. In poorly differentiated tumours, survivin mostly localises in the deep infiltrating areas. When overexpressed in keratinocytes, survivin increases cell migration.Conclusion:High survivin expression and the subcellular localisation of survivin correlate with keratinocyte differentiation and are associated with undifferentiated and more invasive SCC phenotype.

Evaluation of survivin expression and its prognostic value in papillary thyroid carcinoma

Overexpression of survivin, an inhibitor of apoptosis protein, has been found in a variety of human cancers, and is associated with tumor aggressiveness. In this study, we analyzed the expression of survivin in papillary thyroid carcinoma (PTC) and evaluated its clinical significance for predicting an aggressive course of disease at the time of diagnosis. Survivin expression was determined by immunohistochemistry in 104 tissue specimens of PTC, confirmed by Western blot and correlated with clinicopathological parameters. Of the tumors examined, 74 (71.15%) showed high cytoplasmic survivin expression. There was no association between high survivin expression and age, gender or tumor size. On the other hand, it was closely correlated with the presence of lymph node metastasis (P=0.009), and there was a tendency for correlation with extrathyroidal invasion (P=0.062). The high risk PTC group (TNM stage III–IV) was associated with high levels of survivin (P=0.027). These results indicate that survivin is an unfavorable molecule for PTC prognosis, and that its high expression may indicate a subset of PTC patients with a more aggressive disease course. Evaluation of its expression in fine needle aspiration samples could be a useful tool for the identification of those PTC patients who require more extensive surgery, careful follow-up and therapeutic strategy.

Role of survivin in acute lung injury: epithelial cells of mice and humans

Survivin, an inhibitor of apoptosis, regulates cell division and is a potential target for anticancer drugs because many cancers express high survivin levels. However, whether survivin would be toxic to human lung cells and tissues has not been determined. This report clarified the involvement of survivin in acute lung injury. We used immunohistochemical analysis, immunoelectron microscopy, and real-time reverse transcription-quantitative polymerase chain reaction to study survivin expression and localization in injured mouse and human lungs. We also used cultured human lung epithelial cells (BEAS-2B and A549) to study survivin cytoprotection. Nuclei and cytoplasm of epithelial cells in day 3 and day 7 models of bleomycin-injured lung showed survivin-positive results, which is consistent with upregulated survivin mRNA expression. These nuclei also evidenced double positive findings for proliferating cell nuclear antigen and survivin. Day 7 models had similar Smac/DIABLO-positive and survivin-positive cell distributions. The cytoplasm and nuclei of epithelial cells in lesions with diffuse alveolar damage manifested strong survivin-positive findings. Bleomycin stimulation in both epithelial cell lines upregulated expression of survivin and apoptosis-related molecules. Suppression of survivin expression with small interfering RNA rendered human lung epithelial cells susceptible to bleomycin-induced damage, with markedly upregulated activation of caspase-3, caspase-7, poly (ADP-ribose) polymerase, and lactate dehydrogenase activity and an increased number of dead cells compared with mock small interfering RNA-treated cells. Overexpression of survivin via transfection resulted in these epithelial cells being resistant to bleomycin-induced cell damage, with reduced activation of apoptosis-related molecules and lactate dehydrogenase activity and fewer dead cells compared with results for mock-transfected cells. Survivin, acting at the epithelial cell level that depends partly on apoptosis inhibition, is therefore a key mediator of cytoprotection in acute lung injury. Understanding the precise role of survivin in normal lung cells is required for the development of therapeutic survivin.

Survivin expression is an independent poor prognostic marker in lung adenocarcinoma but not in squamous cell carcinoma

Survivin is a member of the inhibitors of apoptosis and frequently overexpressed in various cancer cells. Overexpression of survivin in lung cancer cells attenuates antitumor effect of tyrosine kinase inhibitors. However, data from the previous studies on the clinicopathologic implication of survivin in non-small-cell lung carcinoma (NSCLC) are inconsistent. We investigated the expression of survivin in 373 cases of surgically resected NSCLC. Correlations between the expression of survivin and clinicopathologic, molecular features and prognostic significance were analyzed. In adenocarcinoma, the increased expression of survivin was associated with the presence of vascular invasion, lymph node metastasis, and tumor recurrences, but we didn't find any correlation with survivin expression and clinicopathological parameters in squamous cell carcinoma. Patients with high survivin expression had significantly shorter disease-free survival (DFS; 42.2 vs. 58.8 months; p = 0.001) and shorter overall survival (OS; 60.8 vs. 71.5 months; p = 0.009) than those with low survivin expression group in adenocarcinoma. In squamous cell carcinoma, the expression of survivin was not associated with prognosis of the patients (DFS; 48.9 vs. 48.7 months; p = 0.837, OS; 61.0 vs. 62.4 months; p = 0.771). Multivariate analysis confirmed that survivin was an independent poor prognostic factor in adenocarcinoma (DFS: hazard ratio (HR), 1.687; 95 % confidence interval (CI), 1.123-2.532; p = 0.012; OS: HR, 1.965; 95 % CI, 1.108-3.486; p = 0.021). There was no statistically significant difference in the expression of survivin among different molecular subgroups (p > 0.05). Our results suggest that survivin is an independent negative prognostic factor in adenocarcinoma, but not in squamous cell carcinoma. The different prognostic roles played by survivin in adenocarcinoma and squamous cell carcinoma highlights the biological differences between these two histologic types.

Comparison of the Efficiency of Complexes Based on S413-PV Cell-Penetrating Peptides in Plasmid DNA and siRNA Delivery

The successful application of gene therapy approaches is highly dependent on the efficient delivery of nucleic acids into target cells. In the present study, new peptide-based nonviral systems were developed to enhance plasmid DNA and siRNA delivery, aiming at generating appropriate gene delivery and gene silencing tools for preclinical and clinical application. For this purpose, a new cell-penetrating peptide derived from the wild-type S4(13)-PV peptide was synthesized through the addition of a five-histidine tail to its N-terminus (H5-S4(13)-PV), and its ability to mediate gene expression and gene silencing was evaluated and compared to that of the wild-type peptide. The histidine-enriched peptide, H5-S4(13)-PV, proved to be generally more efficient and less toxic than the wild-type peptide in the delivery of plasmid DNA. In addition, complexes of H5-S4(13)-PV with siRNAs, but not of S4(13)-PV, were efficiently internalized by cells and presented high knockdown activity (63%). Interestingly, systems containing the S4(13)-PV or the H5-S4(13)-PV peptide exhibited superior biological activity when compared to those containing the reverse NLS or scrambled peptides, suggesting that both the cell-penetrating sequence and the NLS of the S4(13)-PV peptide influence the competence of binary and ternary complexes to accomplish nucleic acid delivery. In order to unravel the cancer therapeutic potential of formulations with the histidine-enriched peptide, their efficiency to mediate silencing of the oncogenic protein survivin was evaluated. As opposed to complexes with the wild-type peptide, H5-S4(13)-PV complexes showed the ability to promote a high survivin knockdown at the level of both protein (44%) and mRNA (73%), in HT1080 cells.

Immunoprofiling of oral squamous cell carcinomas reveals high p63 and survivin expression

Cancer is a multifactorial disease composed of cells that show somatic mutations and epigenetic changes. The aim of this study was to investigate the expression of proteins involved in the development and maintenance of epithelia, cell cycle regulation, and apoptosis in human oral squamous cell carcinoma (OSCC) tissue samples. A tissue microarray containing 65 primary human OSCC specimens was immunolabeled for bcl-2, survivin, epidermal growth factor receptor (EGFR), p21, p53, p63, and cleaved caspase-3. Samples were scored for percentage of positively stained tumor cells and staining intensity. A total immunostaining score was also calculated, using the product of percentage and intensity scores. All specimens showed high scores, > 75%, for p63 and survivin, and 75.4% of the specimens also presented high EGFR expression. All cases showed p53-positive cells. p21 showed a diffuse staining pattern. The percentage of cells positive for cleaved caspase-3 and bcl-2 was low. The high frequency of tumor cells expressing p63 and survivin highlights the role of these proteins in the malignant transformation of oral epithelium. Collectively, our results suggest that p63 and survivin may constitute attractive targets for cancer therapy in patients with OSCC.

Prognostic value of survivin expression in breast cancer patients: a meta-analysis

The prognostic role of survivin expression in breast cancer patients has been widely reported. However, controversy still remains. Thus, a meta-analysis was conducted to obtain a more precise estimation of the relationship between survivin expression and overall survival (OS) in breast cancer patients. Relevant articles were selected for further assessment by online search in PubMed, EMBASE, and China National Knowledge Infrastructure. Pooled hazard ratios (HR) with 95 % confidence interval (95 % CI) were used to estimate the strength of the association between survivin expression and OS in breast cancer patients. Funnel plots of Begger's and Egger's linear regression test were used to evaluate the publication bias. Heterogeneity and sensitivity analysis were also assessed. Fifteen studies were included in the final analysis with the total number of 2,202 patients. There was a significant association between positive survivin expression and a poor OS consequence in patients with breast cancer (pooled HR 1.80, 95 % CI 1.55-2.09). No significant heterogeneity was observed among all the eligible studies (x (2) = 21.87, p = 0.081, I (2) = 36.0 %). Publication bias was absent. Sensitivity analysis revealed that the results of this meta-analysis were robust. Our results suggested that high survivin expression had an unfavorable prognostic role for patients with breast cancer.

Adenoid cystic carcinoma of the lacrimal gland: role of nuclear survivin (BIRC5) as a prognostic marker

This study aimed to evaluate the expression of nuclear survivin in adenoid cystic carcinoma (ACC) of the lacrimal gland and to determine if this expression is associated with histopathological features, markers of apoptosis and proliferation or clinical outcomes. Immunohistochemical staining for survivin, p53, Ki-67 and Bcl-2 was analyzed in 55 cases of ACC of lacrimal gland. Thirty-one cases (56.3%) expressed nuclear survivin. All cases expressed p53, Ki-67 and Bcl-2. Eleven cases (35.5%) had a high nuclear survivin score (NS-SCORE) and 20 cases (64.5%) had a low NS-SCORE. Cases with a high NS-SCORE had a shorter progression-free survival (PFS) (P < 0.0001), higher expression of Ki-67 (P < 0.005) and a solid tumour pattern >30% (P < 0.005). Nuclear expression of survivin impacts prognosis significantly and is thus a promising prognostic marker in ACC of the lacrimal gland.