Survivin Research Articles

ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance.

ObjectiveThe contribution of activating transcription factor 6α (ATF6α) in rheumatoid arthritis (RA) pathogenesis, especially on fibroblast-like synoviocytes (FLSs), has been suggested by its sensitivity to inflammatory stimulus. However, the exact role and therapeutic potential of ATF6α in RA remains to be fully elucidated.MethodsATF6α expression was determined in joint tissues and FLS, and gain-of-function and loss-of-function analyses were applied to evaluate the biological roles of ATF6α in RA FLSs. A murine collagen-induced arthritis (CIA) model, combining both gene deletion of ATF6α and treatment with the ATF6α inhibitor Ceapin-A7, was employed. Joint inflammation, tissue destruction, circulating levels of inflammatory cytokines were assessed in CIA mice. Transcriptome sequencing analysis (RNASeq), molecular biology, and biochemical approaches were performed to identify target genes of ATF6α.ResultsATF6α expression was significantly increased in synovium of RA patients and in synovium of mice subjected to CIA. ATF6α silencing or inhibition repressed RA FLSs viability and cytokine production but induced the apoptosis. CIA-model mice with ATF6α deficiency displayed decreased arthritic progression, leading to profound reductions in clinical and proinflammatory markers in the joints. Pharmacological treatment of mice with Ceapin-A7 reduced arthritis severity in CIA models. RNA-sequencing of wild-type and knockdown of ATF6α in RA FLSs revealed a transcriptional program that promotes inflammation and suppresses apoptosis, and subsequent experiments identified Baculoviral IAP Repeat Containing 3 (BIRC3) as the direct target for ATF6α.ConclusionThis study highlights the pathogenic role of ATF6α-BIRC3 axis in RA and identifies a novel pathway for new therapies against RA.

Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer.

Accurate identification of molecular targets of disease plays an important role in diagnosis, prognosis, and therapies. Breast cancer (BC) is one of the most common malignant cancers in women worldwide. Thus, the objective of this study was to accurately identify a set of molecular targets and small molecular drugs that might be effective for BC diagnosis, prognosis, and therapies, by using existing bioinformatics and network-based approaches. Nine gene expression profiles (GSE54002, GSE29431, GSE124646, GSE42568, GSE45827, GSE10810, GSE65216, GSE36295, and GSE109169) collected from the Gene Expression Omnibus (GEO) database were used for bioinformatics analysis in this study. Two packages, LIMMA and clusterProfiler, in R were used to identify overlapping differential expressed genes (oDEGs) and significant GO and KEGG enrichment terms. We constructed a PPI (protein–protein interaction) network through the STRING database and identified eight key genes (KGs) EGFR, FN1, EZH2, MET, CDK1, AURKA, TOP2A, and BIRC5 by using six topological measures, betweenness, closeness, eccentricity, degree, MCC, and MNC, in the Analyze Network tool in Cytoscape. Three online databases GSCALite, Network Analyst, and GEPIA were used to analyze drug enrichment, regulatory interaction networks, and gene expression levels of KGs. We checked the prognostic power of KGs through the prediction model using the popular machine learning algorithm support vector machine (SVM). We suggested four TFs (TP63, MYC, SOX2, and KDM5B) and four miRNAs (hsa-mir-16-5p, hsa-mir-34a-5p, hsa-mir-1-3p, and hsa-mir-23b-3p) as key transcriptional and posttranscriptional regulators of KGs. Finally, we proposed 16 candidate repurposing drugs YM201636, masitinib, SB590885, GSK1070916, GSK2126458, ZSTK474, dasatinib, fedratinib, dabrafenib, methotrexate, trametinib, tubastatin A, BIX02189, CP466722, afatinib, and belinostat for BC through molecular docking analysis. Using BC cell lines, we validated that masitinib inhibits the mTOR signaling pathway and induces apoptotic cell death. Therefore, the proposed results might play an effective role in the treatment of BC patients.

MiR-92a-3p promotes breast cancer proliferation by regulating the KLF2/BIRC5 axis.

Breast cancer remains the most common malignancy in females around the world. Recently, a growing number of studies have focused on gene dysregulation. In our previous study, Krüppel-like factors (KLFs) were found to play essential roles in breast cancer development, among which KLF2 could function as a tumor suppressor. Nevertheless, the underlying molecular mechanism remains unclear. miR-92a-3p was identified as the upstream regulator of KLF2 by starBase v.3.0. The regulation of KLF2 by miR-92a-3p was verified by a series of in vitro and in vivo assays. Further exploration revealed that Baculoviral IAP Repeat Containing 5 (BIRC5)was the target of KLF2. ChIP assay, dual-luciferase reporter analysis, quantitative real-time PCR, and western blot were performed for verification. miR-92a-3p functioned as a tumor promoter by inhibiting KLF2 by binding to its 3'-untranslated region (3'-UTR). In addition, KLF2 could transcriptionally suppress the expression of BIRC5. Collectively, our results uncovered the miR-92a-3p/KLF2/BIRC5 axis in breast cancer and provided a potential mechanism for breast cancer development, which may serve as promising strategies for breast cancer therapy.

Identification of a novel necroptosis-related classifier to predict prognosis and guide immunotherapy in breast invasive carcinoma.

BackgroundNecroptosis plays a crucial function in the progression of breast invasive carcinoma (BRCA). It may be triggered in cancer therapy to enhance anti-tumor immunity. However, the functions of necroptosis in tumors and its relationship with the tumor microenvironment (TME) remain largely unclear.MethodsNecroptosis-related genes (NRGs) were collated from high-quality literature reviews. A robust risk model was constructed to systematically evaluate the clinical value, functional status, effects exerted by the risk model on the TME, and the genomic variations based on the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) meta-cohorts.ResultsA risk model was constructed which comprised of six NRGs, including TNF receptor-associated factor 5 (TRAF5), Toll-like receptor 3 (TLR3), a riboflavin kinase (RFK), Fas ligand (FASLG), Fas-associated protein with death domain (FADD), and baculoviral IAP repeat-containing 3 (BIRC3). The stability and accuracy of the risk model were demonstrated for both the training and validation cohorts and its utility as an independent prognostic model for BRCA was verified. Patients in the low-risk group exhibited “hot” tumors having active immune and cell killing functions, while those in the high-risk group showed “cold” tumors having active tumor proliferation and immunosuppression. Moreover, patients in the high-risk group had a greater number of CNV events in their genome, while the somatic mutations were fewer. Furthermore, patients in the low-risk group showed high sensitivity toward immunotherapy and chemotherapy.ConclusionA reliable risk model based on NRGs to assess patient prognoses and guide clinical decision-making was constructed and validated. Our findings may contribute to the understanding of necroptosis and aid clinical management, along with precision treatment in BRCA.

Molecular imbalance mechanism of skin and blood leucocytes in severe burn patients at different burn times.

BackgroundSevere burns are a leading cause of injuries worldwide and are usually accompanied by considerable morbidity and mortality. The purpose of this study was to investigate the changes of gene expression in blood and skin at different times after severe burn.MethodsFirstly, the gene expression profiles of different burn time samples in GSE19743 and GSE8056 were analyzed. Secondly, the maladjusted gene network was identified by protein-protein interaction (PPI) network, and the genes in the network were enriched and analyzed. In addition, the key dysfunctional genes were identified by betweenness algorithm, and evaluated by survival analysis, Cox analysis, receiver operating characteristic (ROC) analysis. Finally, crosstalk analysis and enrichment analysis were carried out between the blood- and skin-specific differentially expressed genes (DEGs) at different burn times.ResultsThe results showed that there were common DEGs in the blood and skin at different burn times. Importantly, we screened out the key dysfunctional genes BIRC5, NCAM1, PCNA, TOP2A, and VEGFA, which were related to the course of burns. Enrichment analysis showed that these maladjusted genes were mainly involved in the immune inflammation-related signal pathway. Additionally, significant crosstalk was identified between blood- and skin-specific genes at different burn times, especially in the blood. The signal pathways involved in specific genes represent their own pathological characteristics.ConclusionsBoth blood and skin tissues express common pathological changes and unique molecular mechanisms at different times after burn injury. The results of this study provide guidance for clinical personalized treatment.

Downregulation of miR-885-5p Promotes NF-κB Pathway Activation and Immune Recruitment in Cutaneous Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) has a specific microRNA expression profile. MiR-885-5p has been found to be downregulated in the epidermis of CLE lesions; however, its biological role in the disease has not been studied. In this study, we show that miR-885-5p is markedly reduced in CLE keratinocytes (KCs) with IFN-α and UVB being strong miR-885-5p regulators invitro. Microarray expression profiling of anti‒miR-885-5p‒transfected KCs identified PSMB5 as a direct target. Specific inhibition of miR-885-5p increased epidermal proliferation by modulating keratin 16 gene K16, BIRC5, TP63, and CDK4 proliferative genes and promoted NF-κB signaling pathway in human primary KCs by increasing IκBα degradation. Silencing PSMB5 rescued the effect of miR-885-5p inhibition, indicating that miR-885-5p regulates proliferation and NF-κB activation by targeting PSMB5 in KCs. In addition, inhibition of miR-885-5p increased the ability of KCs to attract leukocytes in a PSMB5-independent manner. We identified TRAF1 as another direct target, and its silencing reduced leukocyte migration. Collectively, our findings suggest that UVB and IFN-ɑ downregulate miR-885-5p in CLE KCs, leading to epidermal inflammation by NF-κB activity enhancement and proliferation through PSMB5 and immune recruitment through TRAF1. Our data indicate that miR-885-5p is a potential therapeutic target in CLE.

Akkermansia muciniphila upregulates genes involved in maintaining the intestinal barrier function via ADP-heptose-dependent activation of the ALPK1/TIFA pathway

ABSTRACT The commensal bacteria that make up the gut microbiota impact the health of their host on multiple levels. In particular, the interactions taking place between the microbe-associated molecule patterns (MAMPs) and pattern recognition receptors (PRRs), expressed by intestinal epithelial cells (IECs), are crucial for maintaining intestinal homeostasis. While numerous studies showed that TLRs and NLRs are involved in the control of gut homeostasis by commensal bacteria, the role of additional innate immune receptors remains unclear. Here, we seek for novel MAMP-PRR interactions involved in the beneficial effect of the commensal bacterium Akkermansia muciniphila on intestinal homeostasis. We show that A. muciniphila strongly activates NF-κB in IECs by releasing one or more potent activating metabolites into the microenvironment. By using drugs, chemical and gene-editing tools, we found that the released metabolite(s) enter(s) epithelial cells and activate(s) NF-κB via an ALPK1, TIFA and TRAF6-dependent pathway. Furthermore, we show that the released molecule has the biological characteristics of the ALPK1 ligand ADP-heptose. Finally, we show that A. muciniphila induces the expression of the MUC2, BIRC3 and TNFAIP3 genes involved in the maintenance of the intestinal barrier function and that this process is dependent on TIFA. Altogether, our data strongly suggest that the commensal A. muciniphila promotes intestinal homeostasis by activating the ALPK1/TIFA/TRAF6 axis, an innate immune pathway exclusively described so far in the context of Gram-negative bacterial infections.

Expression Analysis of BIRC3 as One Target Gene of Transcription Factor NF-κB for Esophageal Cancer

Esophageal cancer (ESCA) is one of the highest lethal malignancy tumors worldwide. Baculoviral IAP repeat-containing protein 3 (BIRC3) is the main inhibitor of apoptosis in many malignancies. The aim of this study was to clarify how BIRC3 acts in ESCA cells. Through TNMplot and GEPIA2 analysis, BIRC3 was found abundantly expressed in ESCA cells. The quantitative RT-PCR assay confirmed BIRC3 was pronouncedly induced in all used ESCA cell lines. In addition, proinflammatory cytokines TNFα and IL-1β were shown to have promotion effects on BIRC3 expression in ESCA cells. These promotive effects were blocked when the function of NF-κB was inhibited by bay 11-7082, which indicates the expression of the BIRC3 gene was regulated via the NF-κB transcription pathway in ESCA. Moreover, bioinformatics analysis showed that the BIRC3 gene had many NF-κB binding cis-elements. Chromatin immunoprecipitation was then performed and it was found that NF-κB directly interacts with cis-elements of the BIRC3 gene. In conclusion, our data proved that the high expression level of BIRC3 maintained the survival of ESCA cells. BIRC3 was up-regulated by proinflammatory cytokine TNFα and IL-1β through the NF-κB signaling pathway, and this may be helpful for esophageal cancer prevention and therapy.

Anticancer activities of Brachydin C in human prostate tumor cells (DU145) grown in 2D and 3D models: Stimulation of cell death and downregulation of metalloproteinases in spheroids.

Brachydin C (BrC) has demonstrated in vitro cytotoxic and antiproliferative effects in prostate cancer cells. In the present study, we compare the anticancer effects of BrC in DU145 cells grown in common bidimensional cultures (2D) and multicellular tumor spheroids (MCTS), often denominated 3D in vitro models, that can better mimic the microenvironment of tissues. BrC IC50 values obtained in the resazurin assay after 24 h of treatment were 47.31 μM (2D) and 229.8μM (3D) and these cytotoxic effects were time-dependent only in 3D. BrC (5.0-60 μM) interfered with the growth of MCTS and reduced cell viability after 11 days of treatment, a result that is not attributable to oxidative stress evaluated using the CM-H2 DCFDA probe. BrC (6.0μM) impaired horizontal (wound-healing) and vertical cell migration and invasion (transwell assay) in 2D and BrC (5.0-60 μM) in 3D (ECM Gel®). BrC modulated the expression of genes BIRC5, TNF-α, CASP3, NKX3.1, MMP9, MMP11, CDH1, and ITGAM and downregulated proteins CASP7, BAX, and TNF-α in Western blotting analysis. In conclusion, BrC stimulated cell death and decreased epithelial-mesenchymal transition. Furthermore, DU145 MCTS displayed higher resistance to BrC-induced cell death than 2D cultures, a difference that should be considered in future approaches in prostatic cancer studies.

A double DNAzyme-loaded MnO2 versatile nanodevice for precise cancer diagnosis and Self-Sufficient synergistic gene therapy

Tumors progression is usually characterized by proliferation, migration, and angiogenesis, and it leads to uncontrolled tissue growth and blocks the mechanism of apoptosis. Therefore, targeted angiogenesis and anti-apoptosis is considered promising therapeutic strategy for cancer prevention and treatment. Herein, we report a versatile and intelligent MnO2-PEI-DNAzymes (MnPDs) nanodevice for self-sufficient anti-tumor angiogenesis and pro-apoptosis synergistic gene silencing, coupling multi-target bimodal in situ imaging. Intracellularly, the multifunctional charge-reversal MnPDs undergo reduction and lysis by the overexpressed GSH, actualizing enhanced MR imaging and sufficient DNAzyme cofactors in tumor tissue, and enabling miRNA-155 and telomerase biomarkers dual-fluorescence imaging. Under the precise multimodal imaging, the dual DNAzymes enable self-sufficient Early growth response-1 (EGR1) and Survivin (SUR) mRNAs synergistic silencing, effectively inhibiting tumor angiogenesis and anti-apoptotic. Considering that accurate and efficient therapy has become a trend in cancer therapy, our proposed self-sustaining multifunctional nanodevice is promising for broad clinical applications.

Pediatric-Type Indolent B-Cell Lymphomas With Overlapping Clinical, Pathologic, and Genetic Features.

Pediatric-type follicular lymphoma (PTFL) and pediatric nodal marginal zone lymphoma (PNMZL) are rare pediatric-type indolent B-cell lymphomas (PedIBCL) that differ clinicopathologically from their adult counterparts. Accurate diagnosis is important to avoid overtreatment but is often challenging. The mutational landscape of PTFL is known and may aid diagnosis, but the genetic features of PNMZL are not well understood. We analyzed 21 cases of PedIBCL according to their clinicopathologic findings and classified them into PTFL (n=11), PNMZL (n=2), and “mixed type” tumors (n=8) showing ambiguous histology. We also analyzed 2 cases of adult B-cell lymphomas showing features of PedIBCL. Targeted sequencing of 121 lymphoma-related genes was performed. The median age of PedIBCL patients was 16 years (range: 3 to 47), and all but 1 PTFL patient were male. All patients presented with limited-stage disease, and only 1 relapsed. There were no significant differences in clinical features among the 3 PedIBCL groups. The most frequently mutated genes were MAP2K1, TNFRSF14, KMT2C, IRF8, and NOTCH2. The genetic features of all groups were similar to the established mutational landscape of PTFL. The 2 adult B-cell lymphomas cases also had MAP2K1, TNFRSF14, and IRF8 mutations, but the clinical features were not typical of PedIBCL. In summary, this study demonstrated that PTFL and PNMZL are similar diseases with overlapping clinical, pathologic, and genetic features; mixed type tumors can also occur. Atypical adult cases with similar histologic features were also observed. Therefore, the disease spectrum of PedIBCL may be much broader than is currently believed.

Development of a cancer cells self‑activating and miR‑125a‑5p expressing poly‑pharmacological nanodrug for cancer treatment.

Cancer cells can acquire resistance to targeted therapeutic agents when the designated targets or their downstream signaling molecules develop protein conformational or activity changes. There is an increasing interest in developing poly-pharmacologic anticancer agents to target multiple oncoproteins or signaling pathways in cancer cells. The microRNA 125a-5p (miR-125a-5p) is a tumor suppressor, and its expression has frequently been downregulated in tumors. By contrast, the anti-apoptotic molecule BIRC5/SURVIVIN is highly expressed in tumors but not in the differentiated normal tissues. In the present study, the development of a BIRC5 gene promoter-driven, miR-125a-5p expressing, poly-L-lysine-conjugated magnetite iron poly-pharmacologic nanodrug (pL-MNP-pSur-125a) was reported. The cancer cells self-activating property and the anticancer effects of this nanodrug were examined in both the multidrug efflux protein ABCB1/MDR1-expressing/-non-expressing cancer cells in vitro and in vivo. It was demonstrated that pL-MNP-pSur-125a decreased the expression of ERBB2/HER2, HDAC5, BIRC5, and SP1, which are hot therapeutic targets for cancer in vitro. Notably, pL-MNP-pSur-125a also downregulated the expression of TDO2 in the human KB cervical carcinoma cells. PL-MNP-pSur-125a decreased the viability of various BIRC5-expressing cancer cells, regardless of the tissue origin or the expression of ABCB1, but not of the human BIRC5-non-expressing HMEC-1 endothelial cells. In vivo, pL-MNP-pSur-125a exhibited potent antitumor growth effects, but without inducing liver toxicity, in various zebrafish human-ABCB1-expressing and ABCB1-non-expressing tumor xenograft models. In conclusion, pL-MNP-pSur-125a is an easy-to-prepare and a promising poly-pharmacological anticancer nanodrug that has the potential to manage numerous malignancies, particularly for patients with BIRC5/ABCB1-related drug resistance after prolonged chemotherapeutic treatments.

The correlation of CD49d expression pattern with molecular genetics and hotspot gene mutants in patients with chronic lymphocytic leukemia

Objective: To explore the correlation of CD49d expression patterns with molecular genetics and hotspot gene mutants in patients with chronic lymphocytic leukemia. Methods: The expression of CD49d was detected by flow cytometry and grouped into homogeneous, bimodal, negative and positive expression. Panel fluorescence in situ hybridization (FISH) was used for molecular genetics analysis and next-generation sequencing (NGS) was conducted for gene mutation detection. Results: There were 43 patients (23.89% ) with positive CD49d expression, 137 patients (76.11% ) with negative CD49d expression, 96 patients (53.33% ) with homogeneous CD49d expression and 84 patients (46.67% ) with bimodal CD49d expression. Compared with patients in the CD49d negative group, patients in the CD49d positive group had higher Rai stage (P=0.048) and higher proportion of spleen enlargement (P=0.030) . Compared with patients with homogeneous expression of CD49d, patients with bimodal expression of CD49d had a higher proportion of spleen enlargement (P=0.009) . The expression rate of 11q22- in bimodal CD49d(-) group was significantly higher than that in homogeneous CD49d(-) group (24.29% vs 10.45% , P=0.043) . The incidence of +12 in homogeneous CD49d group was higher than that in bimodal CD49d group (16.67% vs 5.95% , P=0.035) . The incidence of +12 in homogeneous CD49d(+) group was higher than that in bimodal CD49d(-) group (17.24% vs 4.29% , P=0.045) . The incidence of +12 in homogeneous CD49d(-) group was higher than that in bimodal CD49d(-) group (16.42% vs 4.29% , P=0.024) . BIRC3 mutation rate in CD49d positive group was higher than that in CD49d negative group (11.63% vs 2.92% , P=0.037) . Conclusion: There were significant correlations between CD49d and 11q22-, +12 and BIRC3 gene mutation. Patients with bimodal CD49d were more correlated with poor prognosis indexes.

Molecular phenotypes of colorectal cancer.

e15506 Background: Despite the positive results of colorectal cancer treatment, there is a group of patients that progresses despite successful treatment for I–II stage of the disease. it may be that modern predictors in do not fully cover the entire spectrum of molecular genetic traits, especially the tumor microenvironment. Perhaps expression analysis is not only tumor tissue, but resection margin could also reach a consensus on the molecular gene phenotypes of colorectal cancer with the achievement of the goal of prognostic efficiency and therapeutic and prophylactic diagnostic tactics. Methods: The expression level of 64 genes in tumor tissue in samples obtained from 172 patients with stage I–III CRC was analyzed by real-time Polymerase chain reaction (PCR). The mean follow-up time was 28.15±14.7 months. Data analysis and predictive modeling arrays using the R 3.6.3 Computation Evaluation Framework (R Foundation for statistical computing, Vienna, Austria) using additional packages rms 5.1-4, survival 3.2-7 and pROC 1.16.2. Results: As a result of statistical analysis, data were obtained on the presence of predictors of the studied unfavorable source code among the selected sets of genes carcinogenesis in colorectal cancer. The next step revealed progression status with BIRC5, IL2, SCUBE2, MYC and P16INK4A gene expression as in tissues tumors, and in resection margin. 2 regression models were built to predict survival without progression in patients with the inclusion of the level of expression in the tumor tissue- nor, the inclusion of the level of gene expression in tumor and resection margin. Model with inclusion only tumor transcripts statistics did not differ from models without predictors. Conclusions: In this study, it was possible to identify a group of genes associated with certain favorable prognosis and responsible in one way or another for proliferation, angiogenesis, immune status of the tumor. It can be concluded that the study of the level of expression of numerical genes in tumor tissue can become a promising direction for the selection of patients in the group of poor prognosis in colorectal cancer.

Ubiquitin-specific protease 35 (USP35) mediates cisplatin-induced apoptosis by stabilizing BIRC3 in non-small cell lung cancer

AbstractUbiquitin-specific protease 35 (USP35) is a member of the ubiquitin-specific protease family (USP), which influences the progression of multiple cancers by deubiquitinating a variety of substrates. In recent years, the specific role of USP35 was begun to be understood. In this study, we investigated the role and underlying molecular mechanisms of USP35 in chemoresistance of non-small cell lung cancer (NSCLC) to cisplatin. Depletion of USP35 increased the sensitivity of NSCLC to cisplatin-induced apoptosis. We screened and identified a potential substrate of USP35, baculoviral IAP repeat containing 3 (BIRC3). Overexpression of USP35 in H460 cells increased the abundance of BIRC3, while USP35 knockdown in Anip973 cells decreased BIRC3 abundance. Notably, USP35 directly interacted with and stabilized BIRC3 through lys48-mediated polyubiquitination via its deubiquitinating enzyme activity. USP35 alleviated cisplatin-induced cell apoptosis by regulating BIRC3 levels in NSCLC cells. Moreover, a significant positive correlation between USP35 and BIRC3 protein expression levels was observed in human NSCLC tissues. Taken together, USP35 plays a vital role in resistance to cisplatin-induced cell death through the overexpression of BIRC3. USP35 might be a potentially novel therapeutic target in human NSCLC.The authors illustrate that ubiquitin-specific protease 35 (USP35) alleviates cisplatin-induced cell apoptosis by directly interacting with and stabilizing BIRC3. A significant positive correlation was observed between USP35 and BIRC3 in human NSCLC tissues. They hypothesize that USP35 plays a vital role in resistance to cisplatin-induced cell death through the overexpression of BIRC3, and might be a potentially novel therapeutic target in human NSCLC.

Abstract 388: Role Of The Antiapoptotic C-iap2 On The Generation Of An Endothelial Memory In Schistosomiasis-associated Pulmonary Arterial Hypertension

Introduction: Schistosomiasis-associated Pulmonary Arterial Hypertension (Sch-PAH) is a life-threatening complication of chronic S. mansoni infection, which can evolve to heart failure and death. During PAH, hyperproliferation of apoptosis-resistant endothelial cells (ECs) has been extensively reported, but therapeutic approaches to reverse this pathological phenotype remain clinically challenging. Hypothesis: Thus, our hypothesis is that antigenic molecules from S. mansoni eggs amplify the secretion of inhibitor of apoptosis protein 2 (c-IAP2), leading to generation of an abnormal EC memory of survival and the development of PAH. Methods/Results: Previously, we showed that depletion of the anti-apoptotic protein Caveolin-1 (Cav-1) via shedding of extracellular vesicles (EVs) leads to the survival of an abnormal EC phenotype through an unclear mechanism. Analysis of survival-associated genes in isolated murine lung ECs from Flk1 +/GFP ;Cav1 -/- mice, revealed high expression of the anti-apoptotic genes BIRC3 and BIRC5 (which encodes cIAP2 and survivin, respectively) when compared to control ECs. Interesting, exposure to 1 μg/mL of the major S. mansoni egg antigen Sm-p40 induced time-dependent phosphorylation of Cav-1 at residue Tyr14 in human lung microvascular EC (HMVEC-L: 228.2 +/- 38.28% of control; p<0.05; n=4), culminating in c-IAP2 expression with no difference on the constitutive expression of c-IAP1. Furthermore, Sm-p40 treatment of HMVEC-L in the presence of pro-inflammatory mediators IL-6, TNF-α, and ATP induced a significant release of EVs containing c-IAP2. Finally, in vivo analysis of lungs from S. mansoni -infected mice confirmed a significant decrease in Cav-1 expression unique to the egg-dependent granuloma area, indicating that local inflammatory response due to egg-derived antigenic molecules is essential for reprogramming and survival of an abnormal EC phenotype during Sch-PAH. Conclusions: Our data suggest that S. mansoni -induced Cav-1 depletion promotes the secretion of the anti-apoptotic c-IAP2 protein, which may be critical for prolonged survival of a pathogenic EC phenotype during the development of Sch-PAH.

Analysis of polymorphic variants of the survivin promoter and p53 transcription factor in patients with genital endometriosis, type 1 diabetes mellitus and their combination

AIM: The aim of this study was to analyze the association between the SNP surviving, the p53 gene polymorphisms and the risk of developing genital endometriosis and type 1 diabetes mellitus.
 MATERIALS AND METHODS: The frequency of allelic variants of the BIRC5 and TP53 genes was studied by PCR-RFLP analysis in 243 women, including 84 patients with genital endometriosis (stages IIV), 85 patients with type 1 diabetes mellitus, 47 women with diabetes mellitus type 1 and endometriosis and 27 women of the control group represented by the population sample.
 RESULTS: It was found that the frequency of the allele C polymorphic variant of rs9904341 in the BIRC5 gene was significantly higher in the group of patients with diseases compared to the population sample (p 0.05). Significant differences for the C / C genotype in patients with genital endometriosis relative to the control group (p = 0.01) According to the odds ratio, the risk of developing genital endometriosis was 56 times higher for this genotype (ОR 56.31, CI 2.521258.7). Significant differences for the ins/ins genotype of TP53(p16) gene in patients with genital endometriosis relative to the control group (p = 0.005). According to the odds ratio, the risk of developing genital endometriosis was 94 times higher for this genotype (ОR 94.29, CI 3.882288.81). In addition, the frequency of the allele ins polymorphic variant of p16 in the TP53 gene was significantly higher in the group of patients with diseases compared to the control group (p 0.05). The same results for the P allele of the rs1042522 polymorphism in the TP53 gene (p 0.05). According to the odds ratio, the risk of developing genital endometriosis with diabetes mellitus type 1 was 3 times higher for G/A genotype of rs9930232 (p6) than for other genotypes (ОR 3.1, CI 2.521258.7)
 CONCLUSIONS: The investigated factors can be considered as risk markers for the development of genital endometriosis and diabetes mellitus type one.

Transcriptional Activity of Some Genes Involved in Apoptosis in Patients with Vulvar Lichen Sclerosus.

Lichen sclerosus of the vulva is a common, but poorly studied disease. We assessed the level of transcriptional activity of APAF1, BAX, BCL2, BIRC5, CCND1, DAPK1, MCL1, and MYC genes encoding products that control apoptosis in the samples of tissues affected by vulvar lichen sclerosus and adjacent control tissues (n=24). Analysis of transcriptional activity was performed by real-time PCR using specific primers and SYBR Green intercalating dye. After the total group was divided by the presence of the concomitant gynecological diseases, a significant increase in the transcriptional activity of the CCND1 gene was revealed in patients with concomitant uterine fibroids. This may indicate the possible role of the activation of mitosis during tumor initiation.

Pan-cancer analysis identifies BIRC5 as a prognostic biomarker

BackgroundThe BIRC5 gene encodes for the Survivin protein, which is a member of the inhibitor of apoptosis family. Survivin is found in humans during fetal development, but generally not in adult cells thereafter. Previous studies have shown that Survivin is abundant in most cancer cells, thereby making it a promising target for anti-cancer drugs and a potential prognostic tool.MethodsTo assess genetic alterations and mutations in the BIRC5 gene as well as BIRC5 co-expression with other genes, genomic and transcriptomic data were downloaded via cBioPortal for approximately 9000 samples from The Cancer Genome Atlas (TCGA) representing 33 different cancer types and 11 pan-cancer organ systems, and validated using the ICGC Data Portal and COSMIC. TCGA BIRC5 RNA sequencing data from 33 different cancer types and matching normal tissue samples for 16 cancer types were downloaded from Broad GDAC Firehose and validated using breast cancer microarray data from our previous work and data sets from the GENT2 web-based tool. Survival data were analyzed with multivariable Cox proportional hazards regression analysis and validated using KM plotter for breast-, ovarian-, lung- and gastric cancer.ResultsAlthough genetic alterations in BIRC5 were not common in cancer, BIRC5 expression was significantly higher in cancer tissue compared to normal tissue in the 16 different cancer types. For 14/33 cancer types, higher BIRC5 expression was linked to worse overall survival (OS, 4/14 after adjusting for both age and tumor grade and 10/14 after adjusting only for age). Interestingly, higher BIRC5 expression was associated with better OS in lung squamous cell carcinoma and ovarian serous cystadenocarcinoma. Higher BIRC5 expression was also linked to shorter progressive-free interval (PFI) for 14/33 cancer types (4/14 after adjusting for both age and tumor grade and 10/14 after adjusting only for age). External validation showed that high BIRC5 expression was significantly associated with worse OS for breast-, lung-, and gastric cancer.ConclusionsOur findings suggest that BIRC5 overexpression is associated with the initiation and progression of several cancer types, and thereby a promising prognostic biomarker.

Expression pattern and prognostic significance of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) in breast cancer: A comprehensive analysis

BackgroundBaculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, member of the inhibitor of apoptosis (IAP), is a multitasking protein and among the top 100 deregulated genes in breast cancer patients. It negatively regulates apoptosis of tumor cells by inducing gene expression of anti-apoptotic proteins, promoting tumor cell proliferation, and modulates response to chemotherapeutics. ObjectiveThe main objective of the study was to analyze the expression pattern, prognostic significance and functional role of BIRC5 in breast cancer (BC). MethodsIn the present study, we utilized a bioinformatic approach, to analyze the expression pattern and prognostic significance of BIRC5 in BC and explore the interactions of BIRC5 in promoting breast tumorigenicity. ResultsBIRC5 mRNA levels were augmented in breast carcinoma & over-expression of BIRC5 was found associated with poor overall survival (OS) and relapse-free survival (RFS). The KEGG pathway and gene ontology analysis of BIRC5 indicate that BIRC5 is highly enriched in mitotic pathways and cancer pathways. The PPI and correlation analysis further revealed that BIRC5 showed high with oncogenic proteins. Moreover, BIRC5 showed high correlation with infiltration of myeloid derived suppressor cells (MDSCs) in the breast tumor stroma. ConclusionsCumulatively, this study signifies that BIRC5 promotes tumor progression, & targeting BIRC5 in combination with conventional therapies will significantly enhance the response of BC patients to therapy.