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Pathology Oncology Research : POR 2021Epithelioid mesothelioma (EM) is the commonest subtype of malignant pleural mesothelioma. Its histopathological discrimination from reactive mesothelial hyperplasia...
Epithelioid mesothelioma (EM) is the commonest subtype of malignant pleural mesothelioma. Its histopathological discrimination from reactive mesothelial hyperplasia (RMH) could be challenging. Thus, an immunohistochemical panel is mandatory for better discrimination. BAP1 is a newly identified diagnostic marker whose loss is specific to malignant mesothelioma. EZH2 overexpression is reported in different cancers, but its relation to BAP1 in malignant mesothelioma has not been fully understood. Survivin expression is said to be significantly higher in EM than in non-neoplastic pleural tissue, but its diagnostic utility as an immunohistochemical marker has not been thoroughly investigated in this field. To the best of our knowledge, no previous studies have been conducted to assess the diagnostic accuracy of the combined use of these three nuclear markers (BAP1, EZH2 and Survivin) in discriminating pleural EM from RMH. This retrospective study includes two groups: 81 cases of pleural EM and 67 cases of RMH, retrieved from the archives of Pathology Department of Ain Shams University Hospitals and Ain-Shams University Specialized Hospital during the period from January 2016 to December 2019. An immunohistochemical study was performed using BAP1, EZH2 and Survivin antibodies. There were highly statistically significant relations between study groups as regards the studied markers ( = 0.001 for each). The specificity was 100% for all combinations of immunohistochemical markers. Sensitivity of any combination of the immunohistochemical markers used in this study was found to be higher than the sensitivity of any of these markers used individually. The combination of all three markers showed the highest diagnostic accuracy (95.9%) and the highest sensitivity (92.6%). However, the combination of Survivin and EZH2 yielded the same diagnostic accuracy and sensitivity. Adding EZH2, Survivin and BAP1 to the diagnostic IHC panel for differentiating pleural EM and RMH could enhance diagnostic sensitivity. Moreover, Survivin is a potentially promising marker in this context, especially when combined with EZH2.
Topics: Aged; Biomarkers, Tumor; Diagnosis, Differential; Enhancer of Zeste Homolog 2 Protein; Female; Follow-Up Studies; Humans; Hyperplasia; Male; Mesothelioma, Malignant; Middle Aged; Pleural Neoplasms; Prognosis; Retrospective Studies; Survivin; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 34257556
DOI: 10.3389/pore.2021.600073 -
Proceedings of the National Academy of... Mar 2021The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective...
The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) cascade plays a critical role in the regulation of mutant , in which FOS acts as a transcriptional factor for to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 () and inactivation of two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of up-regulating its expression. Thus, this study identifies a therapeutic strategy for promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.
Topics: Apoptosis; Benzophenones; Carcinogenesis; Cell Line, Tumor; GA-Binding Protein Transcription Factor; Gene Expression Regulation, Neoplastic; Humans; Isoxazoles; Mutation; Neoplasms; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; Survivin; Telomerase
PubMed: 33836600
DOI: 10.1073/pnas.2022779118 -
The American Journal of Pathology Jul 2006Although the roles of survivin in control of cancer cell division and apoptosis as well as targeting survivin for cancer therapeutics have been extensively explored and... (Review)
Review
Although the roles of survivin in control of cancer cell division and apoptosis as well as targeting survivin for cancer therapeutics have been extensively explored and reviewed, the pathophysiological role of survivin in normal human cells/organs has not been deeply investigated or sufficiently reviewed. Studies in the latter area, however, appear to be important for the identification of different mechanisms of regulation and function of survivin in normal versus abnormal cells and tissues (including cancer), which might ultimately provide the basis for novel approaches for disease treatment with low toxicity. This Review is intended to summarize current observations in the literature related to the physiological and/or pathological roles for survivin in various normal human cells or organs. Our view of potential future research directions for survivin pertinent to potential therapeutic applications will also be discussed.
Topics: Animals; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Survivin
PubMed: 16816356
DOI: 10.2353/ajpath.2006.060121 -
Oncogene Oct 2008A little over 10 years after its discovery in 1997, the small inhibitor of apoptosis (IAP) protein, survivin, continues to generate intense interest and keen attention... (Review)
Review
A little over 10 years after its discovery in 1997, the small inhibitor of apoptosis (IAP) protein, survivin, continues to generate intense interest and keen attention from disparate segments of basic and disease-related research. Part of this interest reflects the intricate biology of this multifunctional protein that intersects fundamental networks of cellular homeostasis. Part is because of the role of survivin as a cancer gene, which touches nearly every aspect of the disease, from onset to outcome. And part is due to the potential value of survivin for novel cancer diagnostics and therapeutics, which have already reached the clinic, and with some promise. Grappling with emerging new signaling circuits in survivin biology, and their implications in cancer, will further our understanding of this nodal protein, and open fresh opportunities for translational oncology research.
Topics: Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Neoplasms; Signal Transduction; Subcellular Fractions; Survivin
PubMed: 18931693
DOI: 10.1038/onc.2008.303 -
Molecular Therapy : the Journal of the... Nov 2022Survivin is a component of the chromosomal passenger complex, which includes Aurora B, INCENP, and Borealin, and is required for chromosome segregation and cytokinesis....
Survivin is a component of the chromosomal passenger complex, which includes Aurora B, INCENP, and Borealin, and is required for chromosome segregation and cytokinesis. We performed a genome-wide screen of deubiquitinating enzymes for survivin. For the first time, we report that USP19 has a dual role in the modulation of mitosis and tumorigenesis by regulating survivin expression. Our results found that USP19 stabilizes and interacts with survivin in HCT116 cells. USP19 deubiquitinates survivin protein and extends its half-life. We also found that USP19 functions as a mitotic regulator by controlling the downstream signaling of survivin protein. Targeted genome knockout verified that USP19 depletion leads to several mitotic defects, including cytokinesis failure. In addition, USP19 depletion results in significant enrichment of apoptosis and reduces the growth of tumors in the mouse xenograft. We envision that simultaneous targeting of USP19 and survivin in oncologic drug development would increase therapeutic value and minimize redundancy.
Topics: Animals; Humans; Mice; Carcinogenesis; Deubiquitinating Enzymes; Endopeptidases; Survivin; Mitosis
PubMed: 35918893
DOI: 10.1016/j.ymthe.2022.07.019 -
Asian Pacific Journal of Cancer... Sep 2023This study aimed to evaluate the expression of class III β-tubulin (TUBB3), ribonucleoside-diphosphate reductase 1 (RRM1), apurinic/apyrimidinic endonuclease 1 (APE1),...
BACKGROUND
This study aimed to evaluate the expression of class III β-tubulin (TUBB3), ribonucleoside-diphosphate reductase 1 (RRM1), apurinic/apyrimidinic endonuclease 1 (APE1), and survivin in patients with advanced non-small cell lung cancer (NSCLC) to predict response to chemotherapy.
METHODS
TUBB3, RRM1, APE1, and survivin expression levels were determined using immunohistochemistry. Protein expression was validated in Car/Pac-resistant human H1792 and A549 cells. This study included 86 patients, among whom 34 received cisplatin (Cis)/gemcitabine (Gem) and 52 received carboplatin (Car)/paclitaxel (Pac).
RESULTS
Patients with low TUBB3 expression and high RRM1 and survivin expression had higher response rates than those with low RRM1 and survivin expression and high TUBB3 expression in the Car/Pac regimen. The multivariate analysis indicated that TUBB3 and RRM1 were significant independent predictive biomarkers for the Car/Pac regimen; however, there was no association between any protein and overall response in patients treated with this regimen. In the Cis/Gem regimen, only high TUBB3 expression was associated with poor overall survival; however, it did not exhibit a prognostic ability.
CONCLUSION
The expression levels of TUBB3 and RRM1 in NSCLC cells are potential predictive biomarkers, but not prognostic factors, of response to chemotherapy in patients with NSCLC receiving the Car/Pac regimen.
Topics: Humans; Biomarkers, Tumor; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; DNA-Binding Proteins; Endonucleases; Lung Neoplasms; Paclitaxel; Prognosis; Ribonucleoside Diphosphate Reductase; Survivin; Tubulin; Tumor Suppressor Proteins
PubMed: 37774051
DOI: 10.31557/APJCP.2023.24.9.3003 -
Journal of Biomedical Science Feb 2020X-linked inhibitor of apoptosis protein (XIAP), survivin, and BRUCE are members of the inhibitor-of-apoptosis protein (IAP) family known for their inhibitory effects on... (Review)
Review
X-linked inhibitor of apoptosis protein (XIAP), survivin, and BRUCE are members of the inhibitor-of-apoptosis protein (IAP) family known for their inhibitory effects on caspase activity and dysregulation of these molecules has widely been shown to cause embryonic defects and to promote tumorigenesis in human. Besides the anti-apoptotic functions, recent discoveries have revealed that XIAP, survivin, and BRUCE also exhibit regulatory functions for autophagy in cells. As the role of autophagy in human diseases has already been discussed extensively in different reviews; in this review, we will discuss the emerging autophagic role of XIAP, survivin, and BRUCE in cancer cells. We also provide an update on the anti-apoptotic functions and the roles in maintaining DNA integrity of these molecules. Second mitochondria-derived activator of caspases (Smac) is a pro-apoptotic protein and IAPs are the molecular targets of various Smac mimetics currently under clinical trials. Better understanding on the functions of XIAP, survivin, and BRUCE can enable us to predict possible side effects of these drugs and to design a more "patient-specific" clinical trial for Smac mimetics in the future.
Topics: Apoptosis; Autophagy; Humans; Inhibitor of Apoptosis Proteins; Survivin; Tumor Cells, Cultured; X-Linked Inhibitor of Apoptosis Protein
PubMed: 32019552
DOI: 10.1186/s12929-020-0627-5 -
Ovarian Primary and Metastatic Tumors Suppressed by Survivin Knockout or a Novel Survivin Inhibitor.Molecular Cancer Therapeutics Dec 2019Survivin, a member of the inhibitor of apoptosis family, is upregulated in multiple cancers including ovarian cancer, but is rarely detectable in normal tissues. We...
Survivin, a member of the inhibitor of apoptosis family, is upregulated in multiple cancers including ovarian cancer, but is rarely detectable in normal tissues. We previously reported that survivin promoted epithelial-to-mesenchymal transition (EMT) in ovarian cancer cells, suggesting that survivin may contribute to ovarian tumor metastasis and chemoresistance. In this study, we tested whether knockout or pharmacologic inhibition of survivin overcomes chemoresistance and suppresses tumor metastasis. The genetic loss of survivin suppressed tumor metastasis in an orthotopic ovarian cancer mouse model. To pharmacologically test the role of survivin on ovarian tumor metastasis, we treated chemo-resistant ovarian cancer cells with a selective survivin inhibitor, MX106, and found that MX106 effectively overcame chemoresistance MX106 inhibited cell migration and invasion by attenuating the TGFβ pathway and inhibiting EMT in ovarian cancer cells. To evaluate the efficacy of MX106 in inhibiting ovarian tumor metastasis, we treated an orthotopic ovarian cancer mouse model with MX106, and found that MX106 efficiently inhibited primary tumor growth in ovaries and metastasis in multiple peritoneal organs as compared with vehicle-treated control mice. Our data demonstrate that inhibition of survivin using either genetic knockout or a novel inhibitor MX106 suppresses primary ovarian tumor growth and metastasis, supporting that targeting survivin could be an effective therapeutic approach in ovarian cancer.
Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Mice; Mice, Knockout; Neoplasm Metastasis; Ovarian Neoplasms; Survivin
PubMed: 31515295
DOI: 10.1158/1535-7163.MCT-19-0118 -
Journal of Colloid and Interface Science Sep 2023In recent years, small interfering RNA (siRNA) has been widely used in the treatment of human diseases, especially tumors, and has shown great appeal. However, the...
In recent years, small interfering RNA (siRNA) has been widely used in the treatment of human diseases, especially tumors, and has shown great appeal. However, the clinical application of siRNA faces several challenges. Insufficient efficacy, poor bioavailability, poor stability, and lack of responsiveness to a single therapy are the main problems affecting tumor therapy. Here, we designed a cell-penetrating peptide (CPP)-modified metal organic framework nanoplatform (named PEG-CPP33@ORI@survivin siRNA@ZIF-90, PEG-CPP33@NPs) for targeted co-delivery of oridonin (ORI), a natural anti-tumor active ingredient) and survivin siRNA in vivo. This can improve the stability and bioavailability of siRNA and the efficacy of siRNA monotherapy. The high drug-loading capacity and pH-sensitive properties of zeolite imidazolides endowed the PEG-CPP33@NPs with lysosomal escape abilities. The Polyethylene glycol (PEG)-conjugated CPP (PEG-CPP33) coating significantly improved the uptake in the PEG-CPP33@NPs in vitro and in vivo. The results showed that the co-delivery of ORI and survivin siRNA greatly enhanced the anti-tumor effect of PEG-CPP33@NPs, demonstrating the synergistic effect between ORI and survivin siRNA. In summary, the novel targeted nanobiological platform loaded with ORI and survivin siRNA presented herein showed great advantages in cancer therapy, and provides an attractive strategy for the synergistic application of chemotherapy and gene therapy.
Topics: Humans; Survivin; RNA, Small Interfering; Cell-Penetrating Peptides; Metal-Organic Frameworks; Neoplasms; Lysosomes; Nanoparticles; Cell Line, Tumor
PubMed: 37207419
DOI: 10.1016/j.jcis.2023.04.126 -
Ear, Nose, & Throat Journal Jan 2021The objective of this study was to evaluate the expression of survivin and p16 in laryngeal squamous cell carcinoma (LSCC) in order to analyze their pathogenesis and...
The objective of this study was to evaluate the expression of survivin and p16 in laryngeal squamous cell carcinoma (LSCC) in order to analyze their pathogenesis and prognostic significance in Tunisian patients. A total of 70 patients with LSCC collected at the Salah Azaiez Cancer Institute of Tunis were retrospectively evaluated. Expression of survivin and p16 was examined using immunohistochemistry, and the correlations with clinicopathological parameters, overall survival (OS), and disease-free survival (DFS) were statistically evaluated. The positive expression of survivin and p16 were found in 58.6% and 51.43% of LSCC cases, respectively. The p16 expression was not associated with either clinical parameters or patient survival, whereas there was a strong correlation of survivin expression and lymph node metastases ( = .002), alcohol consumption ( = .024), and therapeutic protocol (with or without chemotherapy; = .001). Kaplan-Meier survival curves showed that patients with LSCC having positive survivin expression have shorter OS ( = .026) and shorter DFS ( = .01) than those with negative expression. Positive survivin expression was also correlated with high recurrence rate ( = .014). Therefore, survivin is a poor prognostic marker for LSCC but the therapeutic protocol remains, in multivariate study, the most decisive for the OS and DFS of our patients with < .01. Our data indicated that, in Tunisian laryngeal squamous cell carcinoma, survivin expression is associated with unfavorable outcomes and represents a predictor marker of recurrence and chemoresistance. However, p16 expression has no prognosis value.
Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Gene Expression; Genes, p16; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Laryngeal Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Multivariate Analysis; Prognosis; Retrospective Studies; Survival Rate; Survivin; Tunisia
PubMed: 31159573
DOI: 10.1177/0145561319855644