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Chuwa AH, Mvunta DH. Prognostic and clinicopathological significance of survivin in gynecological cancer. Oncol Rev 2024; 18:1444008. [PMID: 39687493 PMCID: PMC11646728 DOI: 10.3389/or.2024.1444008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Survivin belongs to the inhibitor of apoptosis protein (IAP) family and is encoded by the baculoviral inhibitor of apoptosis repeat-containing, or BIRC5, gene. It is preferentially expressed in cancers with functional complexity in cell signaling cascades such as extracellular signal-regulated kinases (ERK), mitogen-activated protein kinases (MAPK), heat shock protein-90 (HSP90), epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription (STAT), hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), and others. Survivin plays a role in cell division and cell death, properties that have attracted a large body of research to decipher its therapeutic and prognostic significance in cancer. Survivin has tumor-promoting effects in endometrial (EC) and ovarian (OC) cancers, and its upregulation in endometrial cancer has been associated with poor overall survival (OS). While survivin protein is abundantly expressed in OC, it is barely detectable in normal ovarian tissue or benign ovarian tumors. Survivin expression is also a marker for cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus, and a predictor of viral clearance and prognosis in uterine cervical cancer (UCC). Furthermore, nuclear survivin expression is very low in normal vulvar squamous epithelium and increases to become abundant in vulvar invasive squamous cell carcinoma (ISCC), conferring resistance to apoptosis in vulvar carcinogenesis. In this review, we discuss in detail the impact of survivin signaling on gynecological cancers and provide insight on its therapeutic and diagnostic potential, existing research gaps, and areas for future research.
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Affiliation(s)
- Agapiti H. Chuwa
- Department of Physiology, Mbeya College of Health and Allied Sciences, University of Dar es Salaam, Mbeya, Tanzania
| | - David H. Mvunta
- Department of Obstetrics and Gynecology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
- Department of Surgical Oncology, Ocean Road Cancer Institute, Dar es Salaam, Tanzania
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2
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Kefas J, Flynn M. Unlocking the potential of immunotherapy in platinum-resistant ovarian cancer: rationale, challenges, and novel strategies. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:39. [PMID: 39534871 PMCID: PMC11555186 DOI: 10.20517/cdr.2024.67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024]
Abstract
Ovarian cancer is a significant global health challenge, with cytoreductive surgery and platinum-based chemotherapy serving as established primary treatments. Unfortunately, most patients relapse and ultimately become platinum-resistant, at which point there are limited effective treatment options. Given the success of immunotherapy in inducing durable treatment responses in several other cancers, its potential in platinum-resistant ovarian cancer (PROC) is currently being investigated. However, in unselected advanced ovarian cancer populations, researchers have reported low response rates to immune checkpoint inhibition, and thus far, no validated biomarkers are predictive of response. Understanding the intricate interplay between platinum resistance, immune recognition, and the tumour microenvironment (TME) is crucial. In this review, we examine the research challenges encountered thus far, the biological rationale for immunotherapy, the underlying mechanisms of immune resistance, and new strategies to overcome resistance.
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Affiliation(s)
| | - Michael Flynn
- Medical Oncology, University College London Hospitals NHS Foundation Trust, London NW1 2PG, UK
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3
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Wang Q, Greene MI. Survivin as a Therapeutic Target for the Treatment of Human Cancer. Cancers (Basel) 2024; 16:1705. [PMID: 38730657 PMCID: PMC11083197 DOI: 10.3390/cancers16091705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/17/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis. More recent studies showed that survivin is a component of the chromosome passenger complex and acts as an essential mediator of mitotic progression. Other potential functions of survivin, such as mitochondrial function and autophagy, have also been proposed. Survivin has emerged as an attractive target for cancer therapy because its overexpression has been found in most human cancers and is frequently associated with chemotherapy resistance, recurrence, and poor survival rates in cancer patients. In this review, we discuss our current understanding of how survivin mediates various aspects of malignant transformation and drug resistance, as well as the efforts that have been made to develop therapeutics targeting survivin for the treatment of cancer.
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Affiliation(s)
- Qiang Wang
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mark I. Greene
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Danziger M, Xu F, Noble H, Yang P, Roque DM. Tubulin Complexity in Cancer and Metastasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1452:21-35. [PMID: 38805123 DOI: 10.1007/978-3-031-58311-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Tubulin plays a fundamental role in cellular function and as the subject for microtubule-active agents in the treatment of ovarian cancer. Microtubule-binding proteins (e.g., tau, MAP1/2/4, EB1, CLIP, TOG, survivin, stathmin) and posttranslational modifications (e.g., tyrosination, deglutamylation, acetylation, glycation, phosphorylation, polyamination) further diversify tubulin functionality and may permit additional opportunities to understand microtubule behavior in disease and to develop microtubule-modifying approaches to combat ovarian cancer. Tubulin-based structures that project from suspended ovarian cancer cells known as microtentacles may contribute to metastatic potential of ovarian cancer cells and could represent an exciting novel therapeutic target.
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Affiliation(s)
- Michael Danziger
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Fuhua Xu
- Division of Gynecologic Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Helen Noble
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Peixin Yang
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Dana M Roque
- Division of Gynecologic Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
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Danziger M, Noble H, Roque DM, Xu F, Rao GG, Santin AD. Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1452:1-19. [PMID: 38805122 DOI: 10.1007/978-3-031-58311-7_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Microtubules are dynamic polymers composed of α- and β-tubulin heterodimers. Microtubules are universally conserved among eukaryotes and participate in nearly every cellular process, including intracellular trafficking, replication, polarity, cytoskeletal shape, and motility. Due to their fundamental role in mitosis, they represent a classic target of anti-cancer therapy. Microtubule-stabilizing agents currently constitute a component of the most effective regimens for ovarian cancer therapy in both primary and recurrent settings. Unfortunately, the development of resistance continues to present a therapeutic challenge. An understanding of the underlying mechanisms of resistance to microtubule-active agents may facilitate the development of novel and improved approaches to this disease.
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Affiliation(s)
- Michael Danziger
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Helen Noble
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Dana M Roque
- Division of Gynecologic Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Fuhua Xu
- Division of Gynecologic Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Gautam G Rao
- Division of Gynecologic Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
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Mehrotra M, Phadte P, Shenoy P, Chakraborty S, Gupta S, Ray P. Drug-Resistant Epithelial Ovarian Cancer: Current and Future Perspectives. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1452:65-96. [PMID: 38805125 DOI: 10.1007/978-3-031-58311-7_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Epithelial ovarian cancer (EOC) is a complex disease with diverse histological subtypes, which, based on the aggressiveness and course of disease progression, have recently been broadly grouped into type I (low-grade serous, endometrioid, clear cell, and mucinous) and type II (high-grade serous, high-grade endometrioid, and undifferentiated carcinomas) categories. Despite substantial differences in pathogenesis, genetics, prognosis, and treatment response, clinical diagnosis and management of EOC remain similar across the subtypes. Debulking surgery combined with platinum-taxol-based chemotherapy serves as the initial treatment for High Grade Serous Ovarian Carcinoma (HGSOC), the most prevalent one, and for other subtypes, but most patients exhibit intrinsic or acquired resistance and recur in short duration. Targeted therapies, such as anti-angiogenics (e.g., bevacizumab) and PARP inhibitors (for BRCA-mutated cancers), offer some success, but therapy resistance, through various mechanisms, poses a significant challenge. This comprehensive chapter delves into emerging strategies to address these challenges, highlighting factors like aberrant miRNAs, metabolism, apoptosis evasion, cancer stem cells, and autophagy, which play pivotal roles in mediating resistance and disease relapse in EOC. Beyond standard treatments, the focus of this study extends to alternate targeted agents, including immunotherapies like checkpoint inhibitors, CAR T cells, and vaccines, as well as inhibitors targeting key oncogenic pathways in EOC. Additionally, this chapter covers disease classification, diagnosis, resistance pathways, standard treatments, and clinical data on various emerging approaches, and advocates for a nuanced and personalized approach tailored to individual subtypes and resistance mechanisms, aiming to enhance therapeutic outcomes across the spectrum of EOC subtypes.
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Affiliation(s)
- Megha Mehrotra
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer-Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Pratham Phadte
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer-Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Priti Shenoy
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer-Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Sourav Chakraborty
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer-Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Sudeep Gupta
- Homi Bhabha National Institute, Mumbai, India
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Pritha Ray
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer-Tata Memorial Centre, Navi Mumbai, India.
- Homi Bhabha National Institute, Mumbai, India.
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Yesupatham ST, Dayanand CD, Azeem Mohiyuddin SM, Harendra Kumar ML. An Insight into Survivin in Relevance to Hematological, Biochemical and Genetic Characteristics in Tobacco Chewers with Oral Squamous Cell Carcinoma. Cells 2023; 12:1444. [PMID: 37408277 PMCID: PMC10217417 DOI: 10.3390/cells12101444] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Survivin is an inhibitor of apoptosis protein (IAP), encoded by the Baculoviral IAP Repeat Containing 5 (BIRC5) gene located on q arm (25.3) on chromosome 17. It is expressed in various human cancers and involved in tumor resistance to radiation and chemotherapy. The genetic analysis of the BIRC5 gene and its protein survivin levels in buccal tissue related to oral squamous cell carcinoma (OSCC) in South Indian tobacco chewers has not been studied. Hence, the study was designed to quantify survivin in buccal tissue and its association with pretreatment hematological parameters and to analyze the BIRC5 gene sequence. METHOD In a single centric case control study, buccal tissue survivin levels were measured by ELISA. A total of 189 study subjects were categorized into Group 1 (n = 63) habitual tobacco chewers with OSCC, Group 2 (n = 63) habitual tobacco chewers without OSCC, and Group 3 (n = 63) healthy subjects as control. Retrospective hematological data were collected from Group 1 subjects and statistically analyzed. The BIRC5 gene was sequenced and data were analyzed using a bioinformatics tool. RESULTS Survivin protein mean ± SD in Group 1 was (1670.9 ± 796.21 pg/mL), in Group 2 it was (1096.02 ± 346.17 pg/mL), and in Group 3 it was (397.5 ± 96.1 pg/mL) with significance (p < 0.001). Survivin levels showed significance with cut-off levels of absolute monocyte count (AMC), neutrophil/lymphocyte ratio (NLR), and lymphocyte/monocyte ratio (LMR) at (p = 0.001). The unique variants found only in OSCC patients were T → G in the promoter region, G → C in exon 3, C → A, A → G, G → T, T → G, A → C, G → A in exon 4, C → A, G → T, G → C in the exon 5 region. CONCLUSIONS The tissue survivin level increased in OSCC patients compared to controls; pretreatment AMC, LMR, and NLR may serve as add-on markers along with survivin to measure the progression of OSCC. Unique mutations in the promoter and exons 3-5 were observed in sequence analysis and were associated with survivin concentrations.
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Affiliation(s)
- Susanna Theophilus Yesupatham
- Department of Biochemistry, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar 563103, Karnataka, India;
| | - C. D. Dayanand
- Allied Health and Basic Sciences, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar 563103, Karnataka, India
| | - S. M. Azeem Mohiyuddin
- Department of Otorhinolaryngology and Head and Neck Surgery, Sri Devaraj Urs Academy of Higher Education and Research, Tamaka, Kolar 563103, Karnataka, India
| | - M. L. Harendra Kumar
- Department of Pathology, Shridevi Institute of Medical Sciences and Research Hospital, Sira Road, Tumakuru 572106, Karnataka, India
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Mechanisms of Drug Resistance in Ovarian Cancer and Associated Gene Targets. Cancers (Basel) 2022; 14:cancers14246246. [PMID: 36551731 PMCID: PMC9777152 DOI: 10.3390/cancers14246246] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/30/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022] Open
Abstract
In the United States, over 100,000 women are diagnosed with a gynecologic malignancy every year, with ovarian cancer being the most lethal. One of the hallmark characteristics of ovarian cancer is the development of resistance to chemotherapeutics. While the exact mechanisms of chemoresistance are poorly understood, it is known that changes at the cellular and molecular level make chemoresistance challenging to treat. Improved therapeutic options are needed to target these changes at the molecular level. Using a precision medicine approach, such as gene therapy, genes can be specifically exploited to resensitize tumors to therapeutics. This review highlights traditional and novel gene targets that can be used to develop new and improved targeted therapies, from drug efflux proteins to ovarian cancer stem cells. The review also addresses the clinical relevance and landscape of the discussed gene targets.
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Zhang Q, Wang X, Zhang X, Zhan J, Zhang B, Jia J, Chen J. TMEM14A aggravates the progression of human ovarian cancer cells by enhancing the activity of glycolysis. Exp Ther Med 2022; 24:614. [PMID: 36160886 PMCID: PMC9468797 DOI: 10.3892/etm.2022.11551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 07/06/2022] [Indexed: 12/09/2022] Open
Affiliation(s)
- Qingmei Zhang
- Department of Gynecology, The People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350004, P.R. China
| | - Xiaohong Wang
- Department of Gynecology, The People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350004, P.R. China
| | - Xuan Zhang
- Department of Gynecology, The People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350004, P.R. China
| | - Jingfen Zhan
- Department of Gynecology, The People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350004, P.R. China
| | - Binbin Zhang
- Department of Gynecology, The People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350004, P.R. China
| | - Jin Jia
- Department of Gynecology, The People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350004, P.R. China
| | - Jie Chen
- Department of Gynecology, The People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350004, P.R. China
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Mohamed AA, Yassin AS, Gomaa BS, Darwish H, Mohamed RS, Makled S, Ramdan A, Abd-Elsalam S, Raafat MM. Association of Polymorphism in Survivin Gene and the Risk of Liver Cancer Resulting from Hepatitis C Virus Among Egyptian Patients. Curr Cancer Drug Targets 2021; 21:536-543. [PMID: 33653251 DOI: 10.2174/1568009621666210302090917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 12/06/2020] [Accepted: 12/26/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND This study aims to investigate the relation between Survivin gene polymorphisms and the risk of Hepatocellular carcinoma (HCC) resulting from hepatitis C infection among the Egyptian population. METHODS This prospective study was conducted on 164 patients, 57 patients were diagnosed with hepatitis C, where 57 were diagnosed with HCC in addition to 50 healthy volunteers as controls. Genotyping for Survivin rs1042489 and rs8073069 single nucleotide polymorphisms was carried out by the allelic discrimination Real-Time Polymerase Chain Reaction Single Nucleotide Polymorphisms genotyping technology. RESULTS The results of Survivin rs1042489 polymorphism revealed that the TC and CC genotypes were significantly different between hepatocellular carcinoma patients (OR=15.5, 95%CI: 3.299-72.825,P<0.001), and controls (OR=44, 95%CI: 8.025-241.254, P<0.001). Furthermore, CC genotype was significantly different between cirrhotic and hepatocellular carcinoma patients (OR=19.2, 95%CI: 3.097-119.049, P=0.002). Moreover, the TC genotype shows a significant difference between controls and cirrhotic patients (OR=5.5, 95%CI: 2.111-14.328, P<0.001). However, when comparing TT genotypes, CC+TC genotypes results showed a significant association with increasing the risk of cirrhosis and hepatocellular carcinoma (OR=4.812, 95%CI: 1.893-12.233, P=0.001), (OR=21.607, 95%CI: 4.738-98.532, P<0.01), respectively. On the other hand, there was no significant difference among all studied groups for all genotypes regarding Survivin rs8073069. Also, the CC+GC genotype showed no significant association with increased risk of hepatocellular carcinoma (P=0.999) compared with the GG genotypes. CONCLUSION The study indicates that functional Survivin rs1042489 polymorphism may contribute to the risk of hepatocellular carcinoma while Survivin rs8073069 polymorphism has no significant association with increased risk of hepatocellular carcinoma among the studied groups.
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Affiliation(s)
- Amal A Mohamed
- Biochemistry Department, National Hepatology and Tropical Medicine Research Institution, Cairo, Egypt
| | - Aymen S Yassin
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Basma S Gomaa
- Microbiology and Immunology Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
| | - Hossam Darwish
- Oncology Department, Ismailia Teaching Hospital, Ismailia, Egypt
| | - Rasha S Mohamed
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sahar Makled
- Tropical Department, National Hepatology and Tropical Medicine Research Institute Cairo, Egypt
| | - Ahmed Ramdan
- Department of Tropical, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sherief Abd-Elsalam
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Marwa M Raafat
- Microbiology and Immunology Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
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Prognostic Significance of Survivin Expression in Patients with Ovarian Carcinoma: A Meta-Analysis. J Clin Med 2021; 10:jcm10040879. [PMID: 33669912 PMCID: PMC7924601 DOI: 10.3390/jcm10040879] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/06/2021] [Accepted: 02/16/2021] [Indexed: 12/24/2022] Open
Abstract
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.
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Wu H, Zhou WJ, Liu L, Fan Z, Tang H, Yu RQ, Jiang JH. In vivo mRNA imaging based on tripartite DNA probe mediated catalyzed hairpin assembly. Chem Commun (Camb) 2021; 56:8782-8785. [PMID: 32618290 DOI: 10.1039/d0cc03596c] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Herein, we develop a novel tripartite DNA probe to transport phosphorothioated substrate hairpins and an aptamer for the intramolecular CHA circuit, which achieves detection of a low amount of specific mRNA in living cells and mice. Our study provides an improved strategy to promote in vivo fluorescence imaging applications in early-stage clinical diagnosis.
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Affiliation(s)
- Han Wu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
| | - Wen-Jing Zhou
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
| | - Lan Liu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
| | - Ze Fan
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
| | - Hao Tang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
| | - Ru-Qin Yu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
| | - Jian-Hui Jiang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
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13
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Majera D, Mistrik M. Effect of Sepatronium Bromide (YM-155) on DNA Double-Strand Breaks Repair in Cancer Cells. Int J Mol Sci 2020; 21:ijms21249431. [PMID: 33322336 PMCID: PMC7763167 DOI: 10.3390/ijms21249431] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/04/2020] [Accepted: 12/09/2020] [Indexed: 12/19/2022] Open
Abstract
Survivin, as an antiapoptotic protein often overexpressed in cancer cells, is a logical target for potential cancer treatment. By overexpressing survivin, cancer cells can avoid apoptotic cell death and often become resistant to treatments, representing a significant obstacle in modern oncology. A survivin suppressor, an imidazolium-based compound known as YM-155, is nowadays studied as an attractive anticancer agent. Although survivin suppression by YM-155 is evident, researchers started to report that YM-155 is also an inducer of DNA damage introducing yet another anticancer mechanism of this drug. Moreover, the concentrations of YM-155 for DNA damage induction seems to be far lower than those needed for survivin inhibition. Understanding the molecular mechanism of action of YM-155 is of vital importance for modern personalized medicine involving the selection of responsive patients and possible treatment combinations. This review focuses mainly on the documented effects of YM-155 on DNA damage signaling pathways. It summarizes up to date literature, and it outlines the molecular mechanism of YM-155 action in the context of the DNA damage field.
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14
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Garrido MP, Salvatierra R, Valenzuela-Valderrama M, Vallejos C, Bruneau N, Hernández A, Vega M, Selman A, Quest AFG, Romero C. Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells. Pharmaceuticals (Basel) 2020; 13:E315. [PMID: 33081077 PMCID: PMC7602813 DOI: 10.3390/ph13100315] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/22/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780/SKOV3) cells were stimulated with NGF and/or metformin to assess the expression of c-MYC, β-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.
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Affiliation(s)
- Maritza P. Garrido
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
- Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
| | - Renato Salvatierra
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
| | - Manuel Valenzuela-Valderrama
- Laboratorio de Microbiología Celular, Instituto de Investigación e Innovación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8320000, Chile;
| | - Christopher Vallejos
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
| | - Nicole Bruneau
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
| | - Andrea Hernández
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
| | - Margarita Vega
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
- Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
| | - Alberto Selman
- Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
- Instituto Nacional del Cáncer, Santiago 8380455, Chile
| | - Andrew F. G. Quest
- Laboratorio de Comunicaciones Celulares, Centro de estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas (ICBM), Facultad De Medicina, Universidad de Chile, Santiago 8380453, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380000, Chile
| | - Carmen Romero
- Laboratorio de Endocrinología y Biología de la Reproducción, Hospital Clínico Universidad de Chile, Santiago 8380456, Chile; (M.P.G.); (R.S.); (C.V.); (N.B.); (A.H.); (M.V.)
- Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
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15
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Göbel A, Zinna VM, Dell'Endice S, Jaschke N, Kuhlmann JD, Wimberger P, Rachner TD. Anti-tumor effects of mevalonate pathway inhibition in ovarian cancer. BMC Cancer 2020; 20:703. [PMID: 32727400 PMCID: PMC7388525 DOI: 10.1186/s12885-020-07164-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 07/10/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Ovarian cancer remains the most fatal gynecological malignancy. Current therapeutic options are limited due to late diagnosis in the majority of the cases, metastatic spread to the peritoneal cavity and the onset of chemo-resistance. Thus, novel therapeutic approaches are required. Statins and amino-bisphosphonates are inhibitors of the mevalonate pathway, which is a fundamental pathway of cellular metabolism, essential for cholesterol production and posttranslational protein farnesylation and geranylgeranylation. While this pathway has emerged as a promising treatment target in several human malignancies, its potential as a therapeutic approach in ovarian cancer is still not fully understood. METHODS Human ovarian cancer cell lines (IGROV-1, A2780, A2780cis) were treated with increasing concentrations (0.5-100 μM) of statins (simvastatin, atorvastatin, rosuvastatin) and zoledronic acid. Effects on cell vitality and apoptosis were assessed using Cell Titer Blue®, Caspase 3/7 Glo®, clonogenic assays as well as cleaved poly (ADP-ribose) polymerase (cPARP) detection. The inhibition of the mevalonate pathway was confirmed using Western Blot of unprenylated Ras and Rap1a proteins. Quantitative real-time PCR and ELISA were used to analyze modulations on several key regulators of ovarian cancer tumorigenesis. RESULTS The treatment of IGROV-1 and A2780 cells with statins and zoledronic acid reduced vitality (by up to 80%; p < 0.001) and induced apoptosis by up to 8-folds (p < 0.001) in a dose-dependent fashion. Rescue experiments using farnesyl pyrophosphate or geranylgeranyl pyrophosphate evidenced that blocked geranylgeranylation is the major underlying mechanism of the pro-apoptotic effects. Gene expression of the tumor-promoting cytokines and mediators, such as transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), interleukin (IL)-8, and IL-6 were significantly suppressed by statins and zoledronic acid by up to 90% (p < 0.001). For all readouts, simvastatin was most potent of all agents used. Cisplatin-resistant A2780cis cells showed a relative resistance to statins and zoledronic acid. However, similar to the effects in A2780 cells, simvastatin and zoledronic acid significantly induced caspase 3/7 activation (6-folds; p < 0.001). CONCLUSION Our in vitro findings point to promising anti-tumor effects of statins and zoledronic acid in ovarian cancer and warrant additional validation in preclinical and clinical settings.
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Affiliation(s)
- Andy Göbel
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität, Fetscherstraße 74, 01307, Dresden, Germany.
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Valentina M Zinna
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Stefania Dell'Endice
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität, Fetscherstraße 74, 01307, Dresden, Germany
| | - Nikolai Jaschke
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität, Fetscherstraße 74, 01307, Dresden, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Jan Dominik Kuhlmann
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Pauline Wimberger
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Tilman D Rachner
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität, Fetscherstraße 74, 01307, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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16
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Stavropoulos A, Varras M, Vasilakaki T, Varra VK, Varra FN, Tsavari A, Nonni A, Kavantzas N, Lazaris AC. Expression of anti-apoptotic protein survivin in human endometrial carcinoma: Clinical and pathological associations as a separate factor and in combination with concomitant PTEN and p53 expression. Oncol Lett 2020; 20:1033-1054. [PMID: 32724342 PMCID: PMC7377108 DOI: 10.3892/ol.2020.11690] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Endometrial carcinoma is one of the most common types of gynecological cancer. A total of 99 cases of primary endometrial carcinoma were investigated for survivin expression by immunohistochemistry. Furthermore, the association between concomitant survivin, PTEN and p53 expression, and clinicopathological parameters was examined. Immunopositivity for survivin was identified in 88% of cases. Concomitant survivin, PTEN and p53 expression (staining scores and intensity) was observed in 60% of endometrial adenocarcinomas. A significant association was identified between the sum of staining intensity and scores of survivin immunopositive cells, and patient age (P=0.028), histological grade (P<0.001), clinical stage (P=0.018) and fallopian tube and/or ovarian invasion (P=0.039). A negative tendency for correlation was observed between surivin and PTEN immunostaining scores (P=0.062; ρ=−0.238). Specimens with high scores of survivin expression tended to show decreased scores of PTEN immunostaining, and vice versa. However, in circumstances with an increased co-expression of survivin and PTEN, a statistically significant association with histological types was observed (P=0.020). A statistically significant positive correlation was identified between survivin and p53 sum co-expression (P=0.008; ρ=0.300). Furthermore, a significant association was identified between survivin and p53 concomitant sum expression and age of patients (P=0.001), histological type (P=0.020), clinical stage (P=0.037), histological differentiation (P=0.001) and presence of fallopian tube and/or ovarian invasion (P=0.026). The present findings suggested that survivin may be an indicator of unfavorable outcome in older patients with endometrial carcinoma, in specific circumstances that are dependent on different concomitant genetic alterations and different combinations of molecular signaling pathways. Increased expression levels of survivin and PTEN may serve a role in the development of more aggressive endometrial carcinoma during their interaction. In addition, protein expression levels of survivin and p53 are positively correlated and may share a common molecular pathway to promote endometrial carcinogenesis. These findings provided evidence that survivin and p53 combined may be useful markers for the prediction of tumor behavior and prognosis.
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Affiliation(s)
- Aggelis Stavropoulos
- Forth Obstetrics and Gynecology Department, 'Elena Venizelou' General Hospital, Athens 11521, Greece
| | - Michail Varras
- Fifth Obstetrics and Gynecology Department, 'Elena Venizelou' General Hospital, Athens 11521, Greece
| | - Thivi Vasilakaki
- Department of Pathology, 'Tzaneio' General Hospital, Piraeus 18536, Greece
| | | | - Fani-Niki Varra
- Department of Pharmacy, Frederick University, Nicosia 1036, Cyprus
| | - Aikaterini Tsavari
- Department of Pathology, 'Tzaneio' General Hospital, Piraeus 18536, Greece
| | - Aphrodite Nonni
- First Pathology Department, Medical School, National Kapodistrian University, Athens 11527, Greece
| | - Nikolaos Kavantzas
- First Pathology Department, Medical School, National Kapodistrian University, Athens 11527, Greece
| | - Andreas C Lazaris
- First Pathology Department, Medical School, National Kapodistrian University, Athens 11527, Greece
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17
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Büscheck F, Sulimankhil M, Melling N, Höflmayer D, Hube-Magg C, Simon R, Göbel C, Hinsch A, Weidemann S, Izbicki JR, Jacobsen F, Mandelkow T, Blessin NC, Möller-Koop C, Lutz F, Viehweger F, Möller K, Sauter G, Lennartz M, Burandt E, Lebok P, Minner S, Bonk S, Huland H, Graefen M, Schlomm T, Fraune C. Loss of cytoplasmic survivin expression is an independent predictor of poor prognosis in radically operated prostate cancer patients. Cancer Med 2020; 9:1409-1418. [PMID: 31893572 PMCID: PMC7013067 DOI: 10.1002/cam4.2773] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/27/2019] [Accepted: 11/27/2019] [Indexed: 12/14/2022] Open
Abstract
Survivin is an inhibitor of apoptosis. Aberrant survivin expression occurs in malignant tumors and has often been linked to unfavorable patient outcome. Here we analyzed 12 432 prostate cancers by immunohistochemistry. Survivin immunostaining was regularly expressed at high levels in normal prostate epithelium but expression was often reduced in prostate cancers. Among 9492 evaluable prostate cancers, 9% expressed survivin strongly, 19% moderately, 28% weakly, and 44% lacked it. Loss of cytoplasmic survivin was seen in advanced tumor stage, higher Gleason score, preoperative PSA levels, and Ki‐67 labeling index, and associated with earlier PSA recurrence (P < .0001). Survivin loss was significantly more common in cancers carrying TMPRSS2:ERG fusions (61% survivin negative) than in ERG wild‐type cancers (32% survivin negative; P < .0001). Multivariate analysis revealed that reduced cytoplasmic survivin expression predicted poor prognosis independent from Gleason score, pT, pN, and serum PSA level. This was valid for ERG‐positive and ERG‐negative cancers. Survivin expression loss even retained its prognostic impact in 1020 PTEN deleted cancers, a group that is already characterized by dismal patient prognosis. In conclusion, reduced survivin expression is associated with more aggressive tumors and inferior prognosis in prostate cancer.
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Affiliation(s)
- Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mariam Sulimankhil
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nathaniel Melling
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cosima Göbel
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jacob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tim Mandelkow
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Niclas C Blessin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Möller-Koop
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Lutz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maximillian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Bonk
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hartwig Huland
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Graefen
- Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thorsten Schlomm
- Department of Urology, Charité-University Medical Center Berlin, Berlin, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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18
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Nan XW, Gong LH, Chen X, Zhou HH, Ye PP, Yang Y, Xing ZH, Wei MN, Li Y, Wang ST, Liu K, Shi Z, Yan XJ. Survivin Promotes Piperlongumine Resistance in Ovarian Cancer. Front Oncol 2019; 9:1345. [PMID: 31850227 PMCID: PMC6895030 DOI: 10.3389/fonc.2019.01345] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 11/15/2019] [Indexed: 12/20/2022] Open
Abstract
Ovarian cancer is one of the most fatal female malignancies while targeting apoptosis is critical for improving ovarian cancer patients' lives. Survivin is regarded as the most robust anti-apoptosis protein, and its overexpression in ovarian cancer is related to poor survival and apoptosis resistance. Piperlongumine (PL) extracted from peppers is defined as an active alkaloid/amide and exhibits a broad spectrum of antitumor effects. Here, we demonstrate that PL induces the rapid depletion of survivin protein levels via reactive oxygen species (ROS)-mediated proteasome-dependent pathway in vitro, while exerting a remarkable inhibitory influence on the proliferation of ovarian cancer cells. Overexpression of survivin raises the survival rate of ovarian cancer cells to PL. Moreover, PL inhibits ovarian cancer cells xenograft tumor growth and downregulates survivin in vivo. Our findings reveal a previously unrecognized mechanism of PL in suppressing survivin expression as well as survivin promotes piperlongumine resistance in ovarian cancer and suggest that ROS-mediated proteasome-dependent pathway can be exploited to overcome apoptosis resistance triggered by aberrant expression of survivin.
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Affiliation(s)
- Xing-Wei Nan
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Li-Hua Gong
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xu Chen
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hai-Hong Zhou
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Piao-Piao Ye
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yang Yang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zi-Hao Xing
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Meng-Ning Wei
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yao Li
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Sheng-Te Wang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Kun Liu
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zhi Shi
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xiao-Jian Yan
- Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
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19
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Inhibition of bromodomain and extraterminal domain reduces growth and invasive characteristics of chemoresistant ovarian carcinoma cells. Anticancer Drugs 2019; 29:1011-1020. [PMID: 30096128 DOI: 10.1097/cad.0000000000000681] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination are the major reasons for low survival rate in the patients. The bromodomain and extraterminal domain (BET) proteins are known as epigenetic 'readers,' and their inhibitors are novel epigenetic strategies for cancer treatment. Accumulating body of evidence indicates that epigenetic modifications have critical roles in development of EOC, and overexpression of the BET family is a key step in the induction of important oncogenes. Here, we examined the mechanistic activity of I-BET151, a pan-inhibitor of the BET family, in therapy-resistant EOC cells. Our findings showed that I-BET151 diminished cell growth, clonogenic potential, and induced apoptosis. I-BET151 inhibited cell proliferation through down-modulation of FOXM1 and its targets aurora kinase B and cyclin B1. I-BET151 attenuated migration and invasion of the EOC cells by down-regulation of epithelial-mesenchymal transition markers fibronectin, ZEB2, and N-cadherin. I-BET151 synergistically enhanced cisplatin chemosensitivity by down-regulation of survivin and Bcl-2. Our data provide insights into the mechanistic activity of I-BET151 and suggest that BET inhibition has potential as a therapeutic strategy in therapy-resistant EOC. Further in vivo investigations on the therapeutic potential of I-BET151 in EOC are warranted.
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20
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Role of Survivin and p53 Expression in Response of Primary Culture of Ovarian Cancer Cells to Treatment With Chemotherapeutic Agents. Int J Gynecol Cancer 2019; 28:1239-1246. [PMID: 29727353 DOI: 10.1097/igc.0000000000001281] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Ovarian cancer is associated with a high relapse rate and is the fifth leading cause of cancer deaths in women. The genetic profile of a tumor is responsible for deciding response to chemotherapeutic agents. In this study, we investigate the relation between survivin and p53 expression and response to chemotherapeutic agents of primary cultures of ovarian cancer cells established from ascitic fluid. MATERIALS AND METHOD Ascitic fluid and Dulbecco's modified Eagle medium was mixed in equal proportion in culture flasks and incubated to establish primary culture. The cells were treated with different combinations of carboplatin and paclitaxel with and without survivin small interfering RNA transfection. Cell survival was estimated by MTT assay. Survivin and p53 expression was quantified by real-time polymerase chain reaction. RESULTS Out of 19 ascitic fluid samples, 13 primary cultures of ovarian cancer cells were established. The half maximal inhibitory concentration doses of carboplatin (≥70 μg/mL) and paclitaxel (≥18 μg/mL) were high for 10/13 and 5/13 patients, respectively. Survivin messenger RNA expression was significantly downregulated on treatment with carboplatin (100 μg/mL), paclitaxel (12.5 μg/mL), and a combination of carboplatin (50 μg/mL) and paclitaxel (6.25 μg/mL). Only paclitaxel-treated ovarian cancer cells showed decrease in expression of p53. Survivin small interfering RNA increased sensitivity of the primary cultures to chemotherapeutic agents. CONCLUSIONS The present study highlights the fact that establishing primary cultures from ascitic fluid may help to develop personalized treatment regime for individual patients based on their molecular profile. Our study also shows that supplementing taxols drugs with survivin inhibitors may prove to be beneficial in the treatment of ovarian cancer patients.
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21
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Xiang SD, Wilson KL, Goubier A, Heyerick A, Plebanski M. Design of Peptide-Based Nanovaccines Targeting Leading Antigens From Gynecological Cancers to Induce HLA-A2.1 Restricted CD8 + T Cell Responses. Front Immunol 2018; 9:2968. [PMID: 30631324 PMCID: PMC6315164 DOI: 10.3389/fimmu.2018.02968] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 12/03/2018] [Indexed: 01/02/2023] Open
Abstract
Gynecological cancers are a leading cause of mortality in women. CD8+ T cell immunity largely correlates with enhanced survival, whereas inflammation is associated with poor prognosis. Previous studies have shown polystyrene nanoparticles (PSNPs) are biocompatible, do not induce inflammation and when used as vaccine carriers for model peptides induce CD8+ T cell responses. Herein we test the immunogenicity of 24 different peptides, from three leading vaccine target proteins in gynecological cancers: the E7 protein of human papilloma virus (HPV); Wilms Tumor antigen 1 (WT1) and survivin (SV), in PSNP conjugate vaccines. Of relevance to vaccine development was the finding that a minimal CD8+ T cell peptide epitope from HPV was not able to induce HLA-A2.1 specific CD8+ T cell responses in transgenic humanized mice using conventional adjuvants such as CpG, but was nevertheless able to generate strong immunity when delivered as part of a specific longer peptide conjugated to PSNPs vaccines. Conversely, in most cases, when the minimal CD8+ T cell epitopes were able to induce immune responses (with WT1 or SV super agonists) in CpG, they also induced responses when conjugated to PSNPs. In this case, extending the sequence around the CD8+ T cell epitope, using the natural protein context, or engineering linker sequences proposed to enhance antigen processing, had minimal effects in enhancing or changing the cross-reactivity pattern induced by the super agonists. Nanoparticle approaches, such as PSNPs, therefore may offer an alternative vaccination strategy when conventional adjuvants are unable to elicit the desired CD8+ T cell specificity. The findings herein also offer sequence specific insights into peptide vaccine design for nanoparticle-based vaccine carriers.
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Affiliation(s)
- Sue D Xiang
- Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia.,PX Biosolutions Pty Ltd., South Melbourne, VIC, Australia.,Ovarian Cancer Biomarker Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Kirsty L Wilson
- Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Anne Goubier
- PX Biosolutions Pty Ltd., South Melbourne, VIC, Australia
| | - Arne Heyerick
- PX Biosolutions Pty Ltd., South Melbourne, VIC, Australia
| | - Magdalena Plebanski
- Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia.,PX Biosolutions Pty Ltd., South Melbourne, VIC, Australia.,School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
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22
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Rasool I, Afroze D, Wani KA, Yousuf A, Bhat IA, Rah B, Nazir SU, Hussain S, Dubey S. Role of the Functional Polymorphism of Survivin Gene (-31G/C) and Risk of Breast Cancer in a North Indian Population. Clin Breast Cancer 2018; 18:e671-e676. [DOI: 10.1016/j.clbc.2017.11.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 11/07/2017] [Accepted: 11/17/2017] [Indexed: 12/29/2022]
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Bassaro L, Russell SJ, Pastwa E, Somiari SA, Somiari RI. Screening for Multiple Autoantibodies in Plasma of Patients with Breast Cancer. Cancer Genomics Proteomics 2018; 14:427-435. [PMID: 29109092 DOI: 10.21873/cgp.20052] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Revised: 09/20/2017] [Accepted: 09/22/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIM Autoantibodies have potential as circulating biomarkers for early cancer detection. This study aimed to screen for known autoantibodies in human plasma using an Autoantibody Profiling System (APS) and quantify the levels in plasma of donors with/without breast cancer. MATERIALS AND METHODS Plasma from nine female donors diagnosed with breast cancer (test group) and nine matched donors with no personal history of cancer (reference group) were screened with an APS containing probes for 30 autoantibodies. Autoantibody levels ≥1.5 times the mean concentration of the group were considered elevated, and test/reference ratios ≥1.3 were considered higher in the test group compared to the reference group. RESULTS Twenty percent of the probes detected elevated levels of autoantibodies against proteins involved in different cancer mechanisms. Amongst these, the levels of autoantibodies against interleukin 29 (IL29), osteoprotegerin (OPG), survivin (SUR), growth hormone (GRH) and resistin (RES) were significantly higher in the cancer group compared to the reference group (p<0.05), whereas the level of autoantibody against cytotoxic T-lymphocyte associated antigen-4 (CTLA4) was not significantly different between the two groups (p=0.38). CONCLUSION Disease-relevant autoantibodies were detected in the plasma of patients with breast cancer and donors without breast cancer. This means that identifying the type and level of autoantibodies in samples will be important in determining their significance in the disease process. A microtiter plate-based array system could be a fast and inexpensive screening method for identifying and quantifying autoantibodies in human plasma.
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Affiliation(s)
- Lauren Bassaro
- Functional Genomics & Proteomics Unit, ITSI-Biosciences, Johnstown, PA, U.S.A
| | - Stephen J Russell
- Functional Genomics & Proteomics Unit, ITSI-Biosciences, Johnstown, PA, U.S.A
| | - Elzbieta Pastwa
- Functional Genomics & Proteomics Unit, ITSI-Biosciences, Johnstown, PA, U.S.A
| | - Stella A Somiari
- Biobanking & Biospecimen Science Research Unit, Windber Research Institute, Windber, PA, U.S.A
| | - Richard I Somiari
- Functional Genomics & Proteomics Unit, ITSI-Biosciences, Johnstown, PA, U.S.A.
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Functional pharmacogenomics and toxicity of PolyPurine Reverse Hoogsteen hairpins directed against survivin in human cells. Biochem Pharmacol 2018; 155:8-20. [PMID: 29940174 DOI: 10.1016/j.bcp.2018.06.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Accepted: 06/14/2018] [Indexed: 01/27/2023]
Abstract
PolyPurine Reverse Hoogsteen (PPRH) hairpins constitute a relatively new pharmacological agent for gene silencing that has been applied for a growing number of gene targets. Previously we reported that specific PPRHs against the antiapoptotic gene survivin were able to decrease viability of PC3 prostate cancer cells by increasing apoptosis, while not acting on HUVEC non-tumoral cells. These PPRHs were efficient both in vitro and in vivo. In the present work, we performed a functional pharmacogenomics study on the effects of specific and unspecific hairpins against survivin. Incubation of PC3 cells with the specific HpsPr-C-WT led to 244 differentially expressed genes when applying the p < 0.05, FC > 2, Benjamini-Hochberg filtering. Importantly, the unspecific or control Hp-WC did not originate differentially expressed genes using the same settings. Gene Set Enrichment Analysis (GSEA) revealed that the differentially expressed genes clustered very significantly within the gene sets of Regulation of cell proliferation, Cellular response to stress, Apoptosis and Prostate cancer. Network analyses using STRING identified important interacting gene-nodes within the response of PC3 cells to treatment with the PPRH against survivin, mainly POLR2G, PAK1IP1, SMC3, SF3A1, PPARGC1A, NCOA6, UGT2B7, ALG5, VAMP7 and HIST1H2BE, the former six present in the Gene Sets detected in the GSEA. Additionally, HepG2 and 786-O cell lines were used to carry out in vitro experiments of hepatotoxicity and nephrotoxicity, respectively. The unspecific hairpin did not cause toxicity in cell survival assays (MTT) and produced minor changes in gene expression for selected genes in RT-qPCR arrays specifically developed for hepatic and renal toxicity screening.
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25
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Davis JB, Calvert V, Roberts S, Bracero S, Petricoin E, Couch R. Induction of nerve growth factor by phorbol 12-myristate 13-acetate is dependent upon the mitogen activated protein kinase pathway. Heliyon 2018; 4:e00617. [PMID: 29872754 PMCID: PMC5986306 DOI: 10.1016/j.heliyon.2018.e00617] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 01/23/2018] [Accepted: 04/27/2018] [Indexed: 01/20/2023] Open
Abstract
Several small molecules have been identified that induce glial cells to synthesize and secrete nerve growth factor (NGF), a critical neurotrophin that supports neuronal growth and survival, and as such show promise in the development of drugs for the chemoprevention of Alzheimer's disease. To map the signal transduction cascade leading to NGF synthesis and secretion, cultured human glial cells were stimulated by phorbol 12-myristate 13-acetate (PMA), an agonist of Protein Kinase C. Changes in intracellular protein phosphorylation states were evaluated by reverse phase protein microarrays (RPPA), selectively screening over 130 protein endpoints. Of these, 55 proteins showed statistically significant changes in phosphorylation state due to cellular exposure to PMA. A critical signal transduction pathway was identified, and subsequent validation by ELISA and qPCR revealed that the signaling proteins Raf, MEK, ERK, and the signal transduction factor CREB are all essential to the upregulation of NGF gene expression by PMA. Additionally, members of the RSK family of kinases appear to be involved in glial secretion (exocytosis) of the NGF protein. Furthermore, through RPPA, the effects of PMA on apoptosis signaling events and cell proliferation were differentiated from the pathway to NGF upregulation. Overall, this study reveals potential protein targets for the rational design of Alzheimer's therapeutics.
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26
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Li XJ, Pang JS, Li YM, Ahmed FA, He RQ, Ma J, Ma FC, Chen G. Clinical value of survivin and its underlying mechanism in ovarian cancer: A bioinformatics study based on GEO and TCGA data mining. Pathol Res Pract 2018; 214:385-401. [PMID: 29499854 DOI: 10.1016/j.prp.2017.12.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 12/10/2017] [Accepted: 12/31/2017] [Indexed: 12/16/2022]
Abstract
OBJECTIVE An increasing number of studies have confirmed that survivin (BIRC5) plays essential roles in ovarian cancer. Nevertheless, inconsistent or controversial results exist in some studies. In the present study, we sought to determine the clinical significance of survivin and its potential molecular pathways. METHODS The correlation between survivin (BIRC5) expression and diagnostic value, prognostic value and clinicopathological features was assessed by meta-analysis with more than 4000 patients from literature, GEO and TCGA. In addition, the potential molecular mechanism of survivin in ovarian cancer was also determined. RESULTS The pooled sensitivity and specificity were 0.71 (95%CI: 0.68-0.74) and 0.97 (95%CI: 0.94-0.98), respectively. The AUC of sROC was 0.8765. The results showed that there was also a significant relationship between survivin expression and poor overall survival (HR: 1.24, 95%CI: 1.14-1.35, p < 0.001), disease-free survival (HR: 1.53, 95%CI: 0.57-4.09, p < 0.001), as well as higher recurrence rate (HR: 1.11, 95%CI: 0.97-1.27). Moreover, survivin expression was also associated with tumor progression (cancerous vs. benign, OR: 11.29, 95%CI: 8.96-14.24, p < 0.001), TNM stage (III + IV vs. I + II, OR: 5.38, 95%CI: 4.16-6.97, p < 0.001), histological grades (G3 vs. G1 ∼ G2, OR: 4.36, 95%CI: 3.29-5.77, p < 0.001), and lymphatic metastasis (metastasis vs. non-metastasis, 3.35, 95%CI 2.36-4.75, p < 0.001). Bioinformatics analysis revealed the 50 most frequently altered neighboring genes of survivin in OC, and then Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted. GO analysis showed that these genes were related to signal conduction, cell cycle, apoptosis, and metabolism. KEGG pathways analysis indicated that these genes were primarily enriched in mitotic prometaphase, PLK1 signaling events and the regulation of glucokinase by the glucokinase regulatory protein. CONCLUSION Survivin (BIRC5) expression might become a specific but low-sensitivity biomarker in ovarian cancer patients, and its presence indicated poor prognosis and worse TNM stages. This protein might function as an oncoprotein by influencing specific pathways involving the 50 genes identified herein. Additional studies are needed to confirm these results.
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Affiliation(s)
- Xiao-Jiao Li
- Department of PET-CT, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China.
| | - Jin-Shu Pang
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China
| | - Yao-Mei Li
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China
| | - Farah Abdirahman Ahmed
- Department of PET-CT, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China; Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China; Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China
| | - Rong-Quan He
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China
| | - Jie Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China
| | - Fu-Chao Ma
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China.
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China
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Peery RC, Liu JY, Zhang JT. Targeting survivin for therapeutic discovery: past, present, and future promises. Drug Discov Today 2017; 22:1466-1477. [PMID: 28577912 DOI: 10.1016/j.drudis.2017.05.009] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 05/12/2017] [Accepted: 05/23/2017] [Indexed: 12/11/2022]
Abstract
Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is overexpressed in cells of almost all cancers but not in most normal tissues in adults. Survivin expression is required for cancer cell survival and knocking down its expression or inhibiting its function using molecular approaches results in spontaneous apoptosis. Thus, survivin is an attractive and perhaps ideal target for cancer drug discovery. However, a US Food and Drug Administration (FDA)-approved drug targeting survivin has yet to emerge. In this Foundation Review, we examine and evaluate various strategies that have been used to target survivin and the stages of each survivin inhibitor to help understand this lack of success. We also provide future perspectives moving forward in targeting survivin for drug discovery.
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Affiliation(s)
- Robert C Peery
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jing-Yuan Liu
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Computer and Information Science, Indiana University Purdue University, Indianapolis, IN 46202, USA
| | - Jian-Ting Zhang
- Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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29
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Waligórska-Stachura J, Sawicka-Gutaj N, Zabel M, Andrusiewicz M, Gut P, Czarnywojtek A, Ruchała M. Survivin DEx3 as a biomarker of thyroid cancers: A study at the mRNA and protein level. Oncol Lett 2017; 13:2437-2441. [PMID: 28454416 DOI: 10.3892/ol.2017.5713] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 11/23/2016] [Indexed: 12/31/2022] Open
Abstract
Survivin and its splice variants DEx3 and 2B are involved in pathogenesis of numerous types of cancer. Proliferating cell nuclear antigen (PCNA) level correlates with cellular proliferation. The present study aimed to analyze the potential utility of survivin and its splice variants DEx3 and 2B as biomarkers for thyroid cancer. PCNA, survivin and its splice variants DEx3 and 2B expressions were analyzed in 22 tissue samples (15 thyroid cancers and 7 benign lesions) by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry (IHC). There was significantly higher staining for survivin (P=0.019), survivin DEx3 (P=0.001), survivin 2B (P=0.0149) and PCNA (P=0.0237) in thyroid malignant tumors when compared with benign lesions. The receiver operating characteristics curve analysis has shown that the cut-off points of survivin IHC expression >2 [sensitivity 46.7%; specificity 100%; area under curve (AUC) 0.810; P=0.0005] and survivin DEx3 IHC expression >0 (sensitivity 86.7%; specificity 100%; AUC 0.933; P<0.0001) were the best predictors of thyroid malignancy. Additionally, PCNA staining >1 (sensitivity 93.3%; specificity 71.4%; AUC 0.790; P=0.0243) and survivin 2B >2 (sensitivity 46.7%; specificity 100%; AUC 0.824; P=0.0002) were the best predictors of thyroid cancer. In conclusion, the present study exhibited that survivin DEx3 expression has high specificity and sensitivity for discrimination between benign thyroid lesions and cancers. Survivin DEx3 may be considered a biological marker of thyroid malignancy and therefore applied in clinical practice.
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Affiliation(s)
- Joanna Waligórska-Stachura
- Department of Endocrinology, Metabolism and Internal Medicine, Poznań University of Medical Sciences, 60-355 Poznań, Poland
| | - Nadia Sawicka-Gutaj
- Department of Endocrinology, Metabolism and Internal Medicine, Poznań University of Medical Sciences, 60-355 Poznań, Poland
| | - Maciej Zabel
- Department of Histology and Embryology, Poznań University of Medical Sciences, 60-781 Poznań, Poland
| | - Mirosław Andrusiewicz
- Department of Cell Biology, Poznań University of Medical Sciences, 60-806 Poznań, Poland
| | - Paweł Gut
- Department of Endocrinology, Metabolism and Internal Medicine, Poznań University of Medical Sciences, 60-355 Poznań, Poland
| | - Agata Czarnywojtek
- Department of Endocrinology, Metabolism and Internal Medicine, Poznań University of Medical Sciences, 60-355 Poznań, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznań University of Medical Sciences, 60-355 Poznań, Poland
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30
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Sankpal UT, Ingersoll SB, Ahmad S, Holloway RW, Bhat VB, Simecka JW, Daniel L, Kariali E, Vishwanatha JK, Basha R. Association of Sp1 and survivin in epithelial ovarian cancer: Sp1 inhibitor and cisplatin, a novel combination for inhibiting epithelial ovarian cancer cell proliferation. Tumour Biol 2016; 37:14259-14269. [PMID: 27581819 DOI: 10.1007/s13277-016-5290-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 08/14/2016] [Indexed: 10/21/2022] Open
Abstract
The expression of specificity protein 1 (Sp1) and survivin was evaluated in clinical specimens of epithelial ovarian cancer (EOC) patients. When compared to normal tissue, EOC samples showed high expression of Sp1 and survivin using qPCR (Sp1: ∼2-fold; survivin: ∼5-fold) and Western blot (Sp1: >2.6-fold; survivin: >100-fold). The Sp1 inhibitor, and anti-cancer small molecule, tolfenamic acid (TA), was tested to enhance the response of Cisplatin (Cis) in EOC cell lines. Cell viability (CellTiter-Glo), combination index (CalcuSyn software), apoptosis (Annexin-V staining), cell cycle analyses (flow cytometry), and reactive oxygen species (flow cytometry) were determined. Cell migration and invasion was assessed using matrigel coated transwell chambers. Agilent Technologies proteomics analysis identified potential signaling pathways involved. The combination of TA (50 μM) and Cis (5 μM) synergistically increased the growth inhibition in ES2 (∼80 %, p < 0.001) and OVCAR-3 (60 %, p < 0.001) cells. TA or TA + Cis treatment in ES2 cells caused cell cycle arrest in G1 Phase (TA) or S-Phase (TA + Cis) and unregulated reactive oxygen species. Invasion and migration was decreased in ES2 cells. Global proteomic profiling showed modulation of proteins associated with oxidative phosphorylation, apoptosis, electron transport chain, DNA damage, and cell cycle proteins. These results demonstrate an association of Sp1 and survivin in EOC and confirm targeting these candidates with TA potentially sensitizes EOC cells to cisplatin.
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MESH Headings
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Blotting, Western
- Carcinoma, Ovarian Epithelial
- Cell Cycle/drug effects
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Cisplatin/pharmacology
- Drug Therapy, Combination
- Female
- Humans
- Inhibitor of Apoptosis Proteins/genetics
- Inhibitor of Apoptosis Proteins/metabolism
- Neoplasms, Glandular and Epithelial/drug therapy
- Neoplasms, Glandular and Epithelial/metabolism
- Neoplasms, Glandular and Epithelial/pathology
- Ovarian Neoplasms/drug therapy
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
- Proteomics/methods
- RNA, Messenger/genetics
- Reactive Oxygen Species/metabolism
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Sp1 Transcription Factor/antagonists & inhibitors
- Sp1 Transcription Factor/genetics
- Sp1 Transcription Factor/metabolism
- Survivin
- Tumor Cells, Cultured
- ortho-Aminobenzoates/pharmacology
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Affiliation(s)
- Umesh T Sankpal
- Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
| | - Susan B Ingersoll
- Department of Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, 32804, USA
| | - Sarfraz Ahmad
- Department of Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, 32804, USA
| | - Robert W Holloway
- Department of Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, 32804, USA
| | | | - Jerry W Simecka
- Pre-clinical Services, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
- Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
| | - Liz Daniel
- MD Anderson Cancer Center Orlando, Orlando, FL, 32806, USA
| | - Ekamber Kariali
- Department of Biotechnology, Sambalpur University, Jyoti Vihar, Sambalpur, Odisha, 768019, India
| | - Jamboor K Vishwanatha
- Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
- Molecular and Medical Genetics, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
| | - Riyaz Basha
- Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
- Pre-clinical Services, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
- Molecular and Medical Genetics, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
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31
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Abstract
Survivin, a member of the inhibitor of apoptosis (IAP) protein family that inhibits caspases and blocks cell death, is highly expressed in most cancers and is associated with a poor clinical outcome. Survivin has consistently been identified by molecular profiling analysis to be associated with high tumour grade cancers, different disease survival and recurrence. Polymorphisms in the survivin gene are emerging as powerful tools to study the biology of the disease and have the potential to be used in disease prognosis and diagnosis. The survivin gene polymorphisms have also been reported to influence tumour aggressiveness as well as survival of cancer patients. The differential expression of survivin in cancer cells compared to normal tissues and its role as a nodal protein in a number of cellular pathways make it a high target for different therapeutics. This review discusses the complex circuitry of survivin in human cancers and gene variants of survivin, and highlights novel therapy that targets this important protein.
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Affiliation(s)
| | | | - R D Mittal
- Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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Dziegielewska B, Casarez EV, Yang WZ, Gray LS, Dziegielewski J, Slack-Davis JK. T-Type Ca2+ Channel Inhibition Sensitizes Ovarian Cancer to Carboplatin. Mol Cancer Ther 2016; 15:460-70. [PMID: 26832797 DOI: 10.1158/1535-7163.mct-15-0456] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 12/23/2015] [Indexed: 12/14/2022]
Abstract
Ovarian cancer is the deadliest gynecologic cancer, due in large part to the diagnosis of advanced stage disease, the development of platinum resistance, and inadequate treatment alternatives. Recent studies by our group and others have shown that T-type calcium (Ca(2+)) channels play a reinforcing role in cancer cell proliferation, cell-cycle progression, and apoptosis evasion. Therefore, we investigated whether T-type Ca(2+) channels affect ovarian tumor growth and response to platinum agents. Inhibition of T-type Ca(2+) channels with mibefradil or by silencing expression resulted in growth suppression in ovarian cancer cells with a simultaneous increase in apoptosis, which was accompanied by decreased expression of the antiapoptotic gene survivin (BIRC5). Analysis of intracellular signaling revealed mibefradil reduced AKT phosphorylation, increased the levels and nuclear retention of FOXO transcription factors that repress BIRC5 expression, and decreased the expression of FOXM1, which promotes BIRC5 expression. Combining carboplatin with mibefradil synergistically increased apoptosis in vitro. Importantly, mibefradil rendered platinum-resistant ovarian tumors sensitive to carboplatin in a mouse model of peritoneal metastasis. Together, the data provide rationale for future use of T-type channel antagonists together with platinum agents for the treatment of ovarian cancer.
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Affiliation(s)
| | - Eli V Casarez
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Wesley Z Yang
- Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia
| | | | - Jaroslaw Dziegielewski
- Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia. Cancer Center, University of Virginia, Charlottesville, Virginia
| | - Jill K Slack-Davis
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia. Cancer Center, University of Virginia, Charlottesville, Virginia.
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Survivin and cycline D1 expressions are associated with malignant potential in mucinous ovarian neoplasms. J Mol Histol 2016; 47:145-52. [PMID: 26815661 DOI: 10.1007/s10735-016-9661-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 01/22/2016] [Indexed: 10/22/2022]
Abstract
The most prevalent malignant ovarian neoplasms are epithelial ovarian cancers which is the most common cause of death among all gynecologic malignancies and a result of complex interaction of multiple oncogenes and tumor suppressor genes. The aim of this study was to evaluate expression of survivin and cycline D1 biomarkers in mucinous ovarian neoplasms and their correlations with clinicopathological variables in mucinous ovarian cancers. We analyzed pathological specimens of 98 patients with benign (n = 34), borderline (n = 22) and malignant (n = 42) mucinous ovarian neoplasms. Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded specimens. Immunohistochemical analysis revealed that survivin and cyclin D1 expressions were located primarily in the nucleus of ovarian tumor cells and relatively weaker cytoplasmic staining. Survivin expression was significantly higher in malignant tumors (88.1 %) than those found in borderline (18.2 %) and benign tumors (8.8 %) (p < 0.001). Similarly, higher cyclin D1 expression was observed in malignant tumors (100 %) compared to borderline (36.4 %) and benign tumors (5.9 %) (p < 0.001). Expression of all biomarkers analyzed significantly and gradually increased from benign to borderline and borderline to malignant mucinous tumors. In terms of clinicopathological variables, tumor grade, FIGO stage and lymph node methastasis were associated with the expression of both biomarkers. Whereas age exhibited no different correlations in mucinous ovarian cancers. The expressions of survivin and cycline D1 are positively correlated with the malignant potential of mucinous ovarian neoplasms.
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Lin JY, Ke YM, Lai JS, Ho TF. Tanshinone IIA enhances the effects of TRAIL by downregulating survivin in human ovarian carcinoma cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2015; 22:929-938. [PMID: 26321742 DOI: 10.1016/j.phymed.2015.06.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 06/20/2015] [Accepted: 06/23/2015] [Indexed: 06/04/2023]
Abstract
BACKGROUND Tanshinone IIA (TIIA), a diterpene quinone from the medicinal plant Salvia miltiorrhiza Bunge (Lamiaceae) was shown to possess apoptotic and TRAIL-sensitizing effects. Still, the molecular mechanisms whereby TIIA induces apoptosis remain largely unknown. PURPOSE The role of survivin, an inhibitor of apoptosis protein, in TIIA-induced apoptosis has never been addressed before and hence was the primary goal of this study. METHODS In this study, we explored the anticancer effect of TIIA in TOV-21G, SKOV3, and OVCAR3 ovarian carcinoma cells. Cytotoxicity was determined by MTS assay. Real-time RT-PCR and Western blotting were used to assess the mRNA and protein expression of related signaling proteins. RESULTS Our results illustrated that TIIA's cytotoxic effect was caused by apoptosis with the involvement of caspases activity. Moreover, TIIA downregulated survivin in a concentration-dependent manner without affecting the expression of Bcl-2, Bcl-xL, and Bax. TIIA-induced survivin downregulation is regulated by both transcriptional processes and proteasomal degradation. Using TOV-21G cells as our cellular model, we demonstrated that TIIA-induced survivin downregulation requires p38 MAPK activation. Importantly, genetic overexpression of survivin rendered cells more resistant to TIIA, indicating an essential role of survivin downregulation in TIIA-induced apoptosis. This TRAIL sensitization effect of TIIA is ascribed to survivin downregulation because the effect was abrogated in cells that overexpressed survivin. CONCLUSION Our findings provide new insights into the action modes of TIIA-mediated anticancer effects and further implicate a rational design for cancer therapeutic regimens by combining TIIA-sensitized TRAIL via downregulating survivin to elicit ovarian cancer cell death.
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Affiliation(s)
- Jyun-Yi Lin
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Yu-Min Ke
- Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Jui-Sheng Lai
- Division of Biotechnology, Taiwan Agricultural Research Institute, Taichung, Taiwan
| | - Tsing-Fen Ho
- Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan.
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Du J, Li B, Fang Y, Liu Y, Wang Y, Li J, Zhou W, Wang X. Overexpression of Class III β-tubulin, Sox2, and nuclear Survivin is predictive of taxane resistance in patients with stage III ovarian epithelial cancer. BMC Cancer 2015. [PMID: 26198101 PMCID: PMC4511538 DOI: 10.1186/s12885-015-1553-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Class III β-tubulin, Sox2, and Survivin play important roles in tumor survival and proliferation. However, the association of these three factors with clinicopathological characteristics, chemoresistance, and survival in patients with ovarian cancer remains controversial. METHODS We investigated the predictive value and correlation among the expression levels of Class III β-tubulin, Sox2, and Survivin in 110 patients with stage III ovarian epithelial cancer, including 58 patients who received taxane-based chemotherapy and 52 patients who received non-taxane-based chemotherapy. Expression of these three factors was immunohistochemically examined in 110 ovarian tumor tissues obtained from patients before chemotherapy. RESULTS The positive expression rates for Class III β-tubulin, Sox2, and Survivin in ovarian tumor tissues were 59.09 %, 61.82 % and 52.73 %, respectively. The expression of nuclear Survivin and Class III β-tubulin was consistent with that of Sox2 (p = 0.005 and 0.020, respectively). Positive expression of Class III β-tubulin, Sox2, and nuclear Survivin was significantly associated with chemoresistance to taxane-based chemotherapy (p = 0.006, 0.007, and 0.009, respectively), but not to non-taxane-based chemotherapy. Additionally, overexpression of Class III β-tubulin, Sox2, and nuclear Survivin predicted poor progression-free survival in patients receiving taxane-based chemotherapy (p = 0.032, 0.005, and 0.004, respectively). CONCLUSIONS These findings suggest that overexpression of Class III β-tubulin, Sox2, and nuclear Survivin might be predictive of taxane resistance and poor progression-free survival in patients with stage III ovarian epithelial cancer. Expression of these three factors may show positive correlations in these patients.
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Affiliation(s)
- Jintong Du
- Department of Chemotherapy, Qilu Hospital of Shandong University, No. 107 Wenhuaxi road, Ji'nan, Shandong, 250012, China. .,Shandong Cancer Hospital, Shandong Academy of Medical Science, Ji'nan, Shandong, 250012, China.
| | - Bei Li
- Department of Chemotherapy, Qilu Hospital of Shandong University, No. 107 Wenhuaxi road, Ji'nan, Shandong, 250012, China.
| | - Yingli Fang
- Department of Chemotherapy, Qilu Hospital of Shandong University, No. 107 Wenhuaxi road, Ji'nan, Shandong, 250012, China.
| | - Yanguo Liu
- Department of Chemotherapy, Qilu Hospital of Shandong University, No. 107 Wenhuaxi road, Ji'nan, Shandong, 250012, China.
| | - Yang Wang
- Department of Chemotherapy, Qilu Hospital of Shandong University, No. 107 Wenhuaxi road, Ji'nan, Shandong, 250012, China.
| | - Jisheng Li
- Department of Chemotherapy, Qilu Hospital of Shandong University, No. 107 Wenhuaxi road, Ji'nan, Shandong, 250012, China.
| | - Wen Zhou
- Department of Chemotherapy, Qilu Hospital of Shandong University, No. 107 Wenhuaxi road, Ji'nan, Shandong, 250012, China.
| | - Xiuwen Wang
- Department of Chemotherapy, Qilu Hospital of Shandong University, No. 107 Wenhuaxi road, Ji'nan, Shandong, 250012, China.
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Wu Z, Liu GQ, Yang XL, Jiang JH. Electrostatic nucleic acid nanoassembly enables hybridization chain reaction in living cells for ultrasensitive mRNA imaging. J Am Chem Soc 2015; 137:6829-36. [PMID: 25969953 DOI: 10.1021/jacs.5b01778] [Citation(s) in RCA: 266] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Efficient approaches for intracellular delivery of nucleic acid reagents to achieve sensitive detection and regulation of gene and protein expressions are essential for chemistry and biology. We develop a novel electrostatic DNA nanoassembly that, for the first time, realizes hybridization chain reaction (HCR), a target-initiated alternating hybridization reaction between two hairpin probes, for signal amplification in living cells. The DNA nanoassembly has a designed structure with a core gold nanoparticle, a cationic peptide interlayer, and an electrostatically assembled outer layer of fluorophore-labeled hairpin DNA probes. It is shown to have high efficiency for cellular delivery of DNA probes via a unique endocytosis-independent mechanism that confers a significant advantage of overcoming endosomal entrapment. Moreover, electrostatic assembly of DNA probes enables target-initialized release of the probes from the nanoassembly via HCR. This intracellular HCR offers efficient signal amplification and enables ultrasensitive fluorescence activation imaging of mRNA expression with a picomolar detection limit. The results imply that the developed nanoassembly may provide an invaluable platform in low-abundance biomarker discovery and regulation for cell biology and theranostics.
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Affiliation(s)
- Zhan Wu
- State Key Laboratory of Chemeo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, P. R. China
| | - Gao-Qin Liu
- State Key Laboratory of Chemeo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, P. R. China
| | - Xiao-Li Yang
- State Key Laboratory of Chemeo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, P. R. China
| | - Jian-Hui Jiang
- State Key Laboratory of Chemeo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, P. R. China
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Survivin expression as a prognostic factor in patients with epithelial ovarian cancer or primary peritoneal cancer treated with neoadjuvant chemotherapy. Int J Gynecol Cancer 2015; 24:687-96. [PMID: 24662134 DOI: 10.1097/igc.0000000000000108] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND The aim of this study was to evaluate association of expression of survivin and p53 with the effects of neoadjuvant chemotherapy (NAC) in patients with advanced ovarian cancer (AOC). METHODS We retrospectively evaluated 60 consecutive patients with AOC (International Federation of Gynecology and Obstetrics stage IIIC-IV) treated with NAC. The expression of p53 and survivin was assessed immunohistochemically. The median of expression total score survivin equals 2 was adopted to dichotomize the group. The positive and negative expression of p53 was used to dichotomize the group. RESULTS The expression of survivin in tumor tissue taken before and after NAC was a significant difference in the percentage of stained nuclei (P = 0.0002), the intensity of staining (P = 0.0003), and total score (P = 0.0001). There was a significant difference in p53 expression in tumor tissue before and after NAC in the percentage of stained nuclei (P = 0.0424). Survivin expression, in contrast to p53 expression, was a prognostic factor in patients with AOC treated with NAC (P = 0.0484). The expression of survivin and p53 was not a predictive factor. Independent adverse predictor factors were as follows: lack of optimal interval debulking surgery and the lack of an objective response (the respective hazard ratio was 3.93 [95% confidence interval, 2.07-7.46; P < 0.0001] and 2.36 [95% confidence interval,1.25-4.47; P = 0.0080]). The suboptimal range of interval debulking surgery, resistance to platinum, and the lack of paclitaxel in the NAC were adverse prognostic factors (the respective hazard ratio was 2.61 [95% confidence interval, 1.17-5.83], 2.72 [95% confidence interval, 1.07-6.89], and 2.56 [95% confidence interval, 1.06-6.18]; P < 0.05]). CONCLUSIONS High expression of survivin could be a prognostic factor in patients treated with NAC for AOC.
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Waligórska-Stachura J, Andrusiewicz M, Sawicka-Gutaj N, Biczysko M, Jankowska A, Kubiczak M, Czarnywojtek A, Wrotkowska E, Ruchała M. Survivin delta Ex3 overexpression in thyroid malignancies. PLoS One 2014; 9:e100534. [PMID: 24945990 PMCID: PMC4063961 DOI: 10.1371/journal.pone.0100534] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 05/23/2014] [Indexed: 11/20/2022] Open
Abstract
Context Thyroid cancer incidence has increased significantly during the past decades and is the most common type of endocrine malignancy. Many factors in thyroid cancers were studied as independent predictors of a poor prognosis. Objective The objective of the study was to evaluate survivin expression – BIRC5 and its splice variants: survivin delta Ex3 and survivin 2B in benign and malignant thyroid nodules. Design Thyroid tissues samples from a group of 50 patients consisting of: 29 patients with thyroid cancers (including medullary, papillary, follicular and undifferentiated types), as well as from 21 patients with non-cancerous thyroid tissues (including: 11 benign thyroid lesions and 10 healthy thyroid samples). Main Outcome Measures The analysis of the survivin gene expression and evaluation of the level of splice variants were performed using quantitative RT-PCR. Results A statistically significant higher level of expression of survivin gene – BIRC5 was detected in thyroid malignant nodules, when compared with benign lesions and healthy thyroid samples. Moreover, the comparison of survivin relative expression in different staged tumors (pT1, pT3, and pT4) revealed a much higher amount of BIRC5 transcripts in tumor tissues of pT3/pT4. The comparison of survivin expression between benign thyroid nodules and healthy thyroid did not reveal significant differences. Importantly, high expression rate of the survivin delta Ex3 splice variant characterized thyroid carcinomas. Conclusion The results suggest that survivin, especially survivin delta Ex3 splice variant being overexpress, is a characteristic feature of thyroid malignancy.
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Affiliation(s)
- Joanna Waligórska-Stachura
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznań, Poland
| | | | - Nadia Sawicka-Gutaj
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznań, Poland
| | - Maciej Biczysko
- Department of General, Gastroenterological and Endocrine Surgery, Poznan University of Medical Sciences, Poznań, Poland
| | - Anna Jankowska
- Department of Cell Biology, Poznan University of Medical Sciences, Poznań, Poland
| | - Marta Kubiczak
- Department of Cell Biology, Poznan University of Medical Sciences, Poznań, Poland
| | - Agata Czarnywojtek
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznań, Poland
| | - Elżbieta Wrotkowska
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznań, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznań, Poland
- * E-mail:
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Mir R, Stanzani E, Martinez-Soler F, Villanueva A, Vidal A, Condom E, Ponce J, Gil J, Tortosa A, Giménez-Bonafé P. YM155 sensitizes ovarian cancer cells to cisplatin inducing apoptosis and tumor regression. Gynecol Oncol 2013; 132:211-20. [PMID: 24262875 DOI: 10.1016/j.ygyno.2013.11.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 11/05/2013] [Accepted: 11/11/2013] [Indexed: 11/29/2022]
Abstract
OBJECTIVE The objective of this study is to chemosensitize ovarian cancer (OVCa) cells to cisplatin (CDDP) using an inhibitor of Survivin, YM155. The efficacy of YM155 in combination with CDDP was determined in vitro, ex vivo and in vivo. METHODS Human OVCa cell lines A2780p and their cisplatin-resistant derivative A2780cis, were treated with CDDP, YM155, and the combined treatment (YM155+CDDP), and cell viability, mRNA and protein expression levels, cell-cycle distribution, and DNA damage were then evaluated. Furthermore, the efficacy of YM155 combined with CDDP was further examined in established primary cell cultures and xenograft models. RESULTS The combination of YM155 with CDDP induced G2/M cell cycle arrest and apoptosis, increased DNA damage, and decreased Survivin levels, especially in A2780cis CDDP-resistant cells. Additionally, YM155 in combination with CDDP sensitized primary cell cultures to CDDP. Studies in vivo showed how this combination significantly decreased the tumor size of OVCa xenografts. CONCLUSIONS Our results demonstrate that in OVCa cells the expression of Survivin did not affect their sensitivity to YM155, suggesting that Survivin was not the only target of YM155. The combination of YM155 with CDDP could be a good option for therapy of CDDP-resistant OVCa, independently of p53 status.
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Affiliation(s)
- Roser Mir
- Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain
| | - Elisabetta Stanzani
- Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain
| | - Fina Martinez-Soler
- Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain; Department of Basic Nursing, School of Nursing of the Health Campus of Bellvitge, Universitat de Barcelona, IDIBELL, Spain
| | - Alberto Villanueva
- Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, IDIBELL, Spain
| | - August Vidal
- Department of Pathology, Hospital de Bellvitge, Department of Pathology and Experimental Therapeutics, Universitat de Barcelona, IDIBELL, Spain
| | - Enric Condom
- Department of Pathology, Hospital de Bellvitge, Department of Pathology and Experimental Therapeutics, Universitat de Barcelona, IDIBELL, Spain
| | - Jordi Ponce
- Department of Gynecology, Hospital de Bellvitge, Barcelona, Spain
| | - Joan Gil
- Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain
| | - Avelina Tortosa
- Department of Basic Nursing, School of Nursing of the Health Campus of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.
| | - Pepita Giménez-Bonafé
- Departament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.
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Kucukgoz Gulec U, Gumurdulu D, Guzel AB, Paydas S, Seydaoglu G, Acikalin A, Khatib G, Zeren H, Vardar MA, Altintas A. Prognostic importance of survivin, Ki-67, and topoisomerase IIα in ovarian carcinoma. Arch Gynecol Obstet 2013; 289:393-8. [PMID: 23974278 DOI: 10.1007/s00404-013-3000-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 08/05/2013] [Indexed: 11/25/2022]
Abstract
PURPOSE Stage, tumor grade and histological subtype determine the clinical behavior in ovarian tumors. Some additional factors are related to tumor cell biology and are the useful predictors for identifying the patients with poor prognosis. The aim of this study is to evaluate the prognostic significance of survivin, Ki-67 and Topoisomerase IIα (TOPO IIα) in epithelial ovarian cancer (EOC). MATERIALS AND METHODS Seventy-three patients with EOC were included in this study. Survivin, Ki-67 and TOPO IIα expressions were studied by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections. Nuclear staining for all antibodies was scored on a three-tiered system and more than 10 % staining was accepted as expression. The relationship between the expressions of survivin, Ki-67, TOPO IIα and clinicopathological parameters including age, stage, grade, platinum resistance and survival was evaluated. RESULTS Survivin, Ki-67 and TOPO IIα expressions were found in 20, 82 and 86 % of the tumors, respectively. Ki-67 and TOPO IIα expressions were found to be related to poor overall survival (p = 0.005, 0.004, respectively), while survivin expression was not associated with overall survival. There was no association between TOPO IIα and Ki-67 expressions and histological subtype, stage or grade. However, we found an important relationship between TOPO IIα expression and platinum resistance (p = 0.044). Platinum resistance was found to be an independent prognostic factor in EOC. CONCLUSION Ki-67 and TOPO IIα expressions were found to be related to poor overall survival, and TOPO IIα expression was found to be associated with platinum resistance.
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Affiliation(s)
- Umran Kucukgoz Gulec
- Department of Obstetrics and Gynecology, Faculty of Medicine, Cukurova University, 01330, Adana, Turkey,
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Nogueira-Ferreira R, Vitorino R, Ferreira-Pinto MJ, Ferreira R, Henriques-Coelho T. Exploring the role of post-translational modifications on protein-protein interactions with survivin. Arch Biochem Biophys 2013; 538:64-70. [PMID: 23938875 DOI: 10.1016/j.abb.2013.07.027] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 07/17/2013] [Accepted: 07/25/2013] [Indexed: 12/31/2022]
Abstract
Survivin is a member of the inhibitor of apoptosis protein (IAP) family with crucial roles in apoptosis and cell cycle regulation. Post-translational modifications (PTMs) have a ubiquitous role in the regulation of a diverse range of proteins' cellular functions and survivin is not an exception. Phosphorylation, acetylation and ubiquitination seem to regulate survivin anti-apoptotic and mitotic roles and also its nuclear localization. In the present review we explore the role of PTMs on protein-protein interactions focused on survivin to provide new insights into the functions and cell localization of this IAP in pathophysiological conditions, which might help the envisioning of novel targeted therapies for diseases characterized by impaired survivin activity. Protein-protein interaction analysis was performed with bioinformatics tools based on published data aiming to give an integrated perspective of this IAP's role in the cell.
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Affiliation(s)
- Rita Nogueira-Ferreira
- QOPNA, Department of Chemistry, University of Aveiro, Aveiro, Portugal; Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal
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Zhang W, Chen H, Liu DL, Li H, Luo J, Zhang JH, Li Y, Chen KJ, Tong HF, Lin SZ. Emodin sensitizes the gemcitabine-resistant cell line Bxpc-3/Gem to gemcitabine via downregulation of NF-κB and its regulated targets. Int J Oncol 2013; 42:1189-96. [PMID: 23440366 DOI: 10.3892/ijo.2013.1839] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Accepted: 02/04/2013] [Indexed: 11/06/2022] Open
Abstract
The aim of this study was to evaluate whether emodin can overcome the chemoresistance of the gemcitabine-resistant cancer cell line (Bxpc-3/Gem) in vitro. The cell line Bxpc-3/Gem was derived from the human pancreatic cancer cell line Bxpc-3. We found that Bxpc-3/Gem cells were characterized by a series of morphological changes with a resistance index of 43.51 comparing with the parental cell line. Emodin reduced Bxpc-3/Gem cell proliferation in a dose-dependent manner. Emodin and gemcitabine combination treatments resulted in decreased cell proliferation and increased apoptosis in Bxpc-3/Gem cells. In addition, combination treatments resulted in downregulation of gene and protein expression of MDR-1 (P-gp), NF-κB, XIAP, survivin, as well as inhibition of NF-κB activity and P-gp function. These observations suggest that emodin may sensitize the pancreatic cancer gemcitabine-resistant cell line Bxpc-3/Gem to gemcitabine therapy via inhibition of survival signaling.
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Affiliation(s)
- Wei Zhang
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, P.R. China
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Cai N, Liu NN, Zhao N, Wan C, Hu YD, Zhou Y, Chen L. Expressions of survivin and vascular endothelial growth factor in a Murine model of proliferative retinopathy. Int J Ophthalmol 2012; 5:293-6. [PMID: 22773975 DOI: 10.3980/j.issn.2222-3959.2012.03.08] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Accepted: 05/20/2012] [Indexed: 11/02/2022] Open
Abstract
AIM To examine the expression of survivin and vascular endothelial growth factor(VEGF) during the development of retinal neovascularization (NV) in a mouse model. METHODS A well-characterized murine model of retinal NV was used to study the expression of survivin and VEGF. NV of the retina was induced in mice by exposure to 75% O(2) from postnatal day P7 to P12, followed by return to room air from P12 to P17. Expression of survivin and VEGF protein was analyzed by Immunohistochemistry. In addition, mouse model of proliferative retinopathy was analyzed by retinal fluorescein angiography and quantification analysis. RESULTS The normal mice had both superfiekal and deep vascular layers that extended from the optic nerve to the periphery. In intraocular pressure(IOP) mice were characterized by represent a typical pattern of pathological retinal NV. There are less or little nuclei of new vessels vascular endothelial cell breaking through the inner retinal than in retinopathy of prematurity (ROP) mice, large clusters of blood vessels were adherent to the internal limiting membrane(ILM) (0.27±0.20 vs 23.38±1.027, t=9.454, P<0.001). During the angiogenic period from P13 to P17, survivin and VEGF protein expression increased in experimental retinas compared with control samples(2.56±0.46 vs 3.34±0.40, t=17.43, P<0.01: 2.18±0.75 vs 4.34±0.25, t=19.61, P<0.01). Protein levels of VEGF and survivn has significantly positive correlation (P<0.05, r=0.411). CONCLUSION Correlation was made at the protein levels of survivin expression compared with that of VEGF in a murine model of retinal NV, which suggests a temporal role for survivin and VEGF in new vessel formation in response to hypoxic stimulation.
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Affiliation(s)
- Na Cai
- Department of Ophthalmology, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Lin CL, Chen RF, Chen JYF, Chu YC, Wang HM, Chou HL, Chang WC, Fong Y, Chang WT, Wu CY, Chiu CC. Protective effect of caffeic acid on paclitaxel induced anti-proliferation and apoptosis of lung cancer cells involves NF-κB pathway. Int J Mol Sci 2012; 13:6236-6245. [PMID: 22754361 PMCID: PMC3382759 DOI: 10.3390/ijms13056236] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 05/07/2012] [Accepted: 05/14/2012] [Indexed: 01/19/2023] Open
Abstract
Caffeic acid (CA), a natural phenolic compound, is abundant in medicinal plants. CA possesses multiple biological effects such as anti-bacterial and anti-cancer growth. CA was also reported to induce fore stomach and kidney tumors in a mouse model. Here we used two human lung cancer cell lines, A549 and H1299, to clarify the role of CA in cancer cell proliferation. The growth assay showed that CA moderately promoted the proliferation of the lung cancer cells. Furthermore, pre-treatment of CA rescues the proliferation inhibition induced by a sub-IC50 dose of paclitaxel (PTX), an anticancer drug. Western blot showed that CA up-regulated the pro-survival proteins survivin and Bcl-2, the down-stream targets of NF-κB. This is consistent with the observation that CA induced nuclear translocation of NF-κB p65. Our study suggested that the pro-survival effect of CA on PTX-treated lung cancer cells is mediated through a NF-κB signaling pathway. This may provide mechanistic insights into the chemoresistance of cancer calls.
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Affiliation(s)
- Chien-Liang Lin
- Department of Life Science and Institute of Zoology, National Taiwan University, Taipei 106, Taiwan; E-Mails: (C.-L.L.); (R.-F.C.)
| | - Ruei-Feng Chen
- Department of Life Science and Institute of Zoology, National Taiwan University, Taipei 106, Taiwan; E-Mails: (C.-L.L.); (R.-F.C.)
| | - Jeff Yi-Fu Chen
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; E-Mails: (J.Y.-F.C.); (Y.-C.C.); (H.-L.C.)
| | - Ying-Chieh Chu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; E-Mails: (J.Y.-F.C.); (Y.-C.C.); (H.-L.C.)
| | - Hui-Min Wang
- Department of Fragrance and Cosmetics Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan; E-Mail:
| | - Han-Lin Chou
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; E-Mails: (J.Y.-F.C.); (Y.-C.C.); (H.-L.C.)
| | - Wei-Chiao Chang
- Graduate Institute of Medical Genetics, Kaohsiung Medical University, Kaohsiung 807, Taiwan; E-Mail:
| | - Yao Fong
- Chest Surgery, Chi-Mei Foundation Medical Center, Yung Kang City, Tainan 901, Taiwan; E-Mail:
| | - Wen-Tsan Chang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; E-Mail:
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chang-Yi Wu
- Department of Biological Sciences, National Sun Yat-Sen University, 70 Lien Hai Road, Kaohsiung 804, Taiwan; E-Mail:
| | - Chien-Chih Chiu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; E-Mails: (J.Y.-F.C.); (Y.-C.C.); (H.-L.C.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +886-7-312-1101 (ext. 2368); Fax: +886-7-312-5339
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Gyorffy B, Lánczky A, Szállási Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer 2012; 19:197-208. [PMID: 22277193 DOI: 10.1530/erc-11-0329] [Citation(s) in RCA: 681] [Impact Index Per Article: 52.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The validation of prognostic biomarkers in large independent patient cohorts is a major bottleneck in ovarian cancer research. We implemented an online tool to assess the prognostic value of the expression levels of all microarray-quantified genes in ovarian cancer patients. First, a database was set up using gene expression data and survival information of 1287 ovarian cancer patients downloaded from Gene Expression Omnibus and The Cancer Genome Atlas (Affymetrix HG-U133A, HG-U133A 2.0, and HG-U133 Plus 2.0 microarrays). After quality control and normalization, only probes present on all three Affymetrix platforms were retained (n=22,277). To analyze the prognostic value of the selected gene, we divided the patients into two groups according to various quantile expressions of the gene. These groups were then compared using progression-free survival (n=1090) or overall survival (n=1287). A Kaplan-Meier survival plot was generated and significance was computed. The tool can be accessed online at www.kmplot.com/ovar. We used this integrative data analysis tool to validate the prognostic power of 37 biomarkers identified in the literature. Of these, CA125 (MUC16; P=3.7×10(-5), hazard ratio (HR)=1.4), CDKN1B (P=5.4×10(-5), HR=1.4), KLK6 (P=0.002, HR=0.79), IFNG (P=0.004, HR=0.81), P16 (P=0.02, HR=0.66), and BIRC5 (P=0.00017, HR=0.75) were associated with survival. The combination of several probe sets can further increase prediction efficiency. In summary, we developed a global online biomarker validation platform that mines all available microarray data to assess the prognostic power of 22,277 genes in 1287 ovarian cancer patients. We specifically used this tool to evaluate the effect of 37 previously published biomarkers on ovarian cancer prognosis.
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Affiliation(s)
- Balázs Gyorffy
- Research Laboratory of Pediatrics and Nephrology, Hungarian Academy of Sciences, Budapest, Hungary.
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Kalachand R, Hennessy BT, Markman M. Molecular targeted therapy in ovarian cancer: what is on the horizon? Drugs 2012; 71:947-67. [PMID: 21668036 DOI: 10.2165/11591740-000000000-00000] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Over the past two decades, empirical optimization of cytotoxic chemotherapy combinations and surgical debulking procedures have improved outcomes and survival in epithelial ovarian cancer. Yet, this disease remains the fifth leading cause of cancer-related deaths in the US, as cure rates seem to have reached a plateau at approximately 20% with conventional chemotherapy. Novel high-throughput genomic and proteomic analyses have improved the molecular understanding of ovarian carcinogenesis, thereby providing a vast array of new potential drug targets with complex signalling interactions. In order to yield the most significant impact on disease outcome, it is necessary to carefully select, and subsequently target, the driving molecular pathway(s) within a tumour or tumour subtype, which are most likely to correspond to high-frequency mutations and genomic aberrations. The identification of biomarkers predictive of response to targeted therapy is essential to avoid poor responses to potentially useful drugs in unselected trial populations. With some promising, albeit early, phase III data on the angiogenesis inhibitor bevacizumab, exciting new opportunities lie ahead with the ultimate goal of personalizing therapies to individual tumour profiles.
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Affiliation(s)
- Roshni Kalachand
- Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland.
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Church DN, Talbot DC. Survivin in Solid Tumors: Rationale for Development of Inhibitors. Curr Oncol Rep 2012; 14:120-8. [DOI: 10.1007/s11912-012-0215-2] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Hasby EA. Weapons ovarian epithelial tumors may use in immune escape: an immunohistochemical correlational study. Pathol Oncol Res 2011; 18:509-18. [PMID: 22161157 DOI: 10.1007/s12253-011-9474-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 11/03/2011] [Indexed: 02/05/2023]
Abstract
Investigate FasL and survivin expression in a series of primary ovarian surface epithelial tumors, correlate their expression with each other, and characterize the presence of CD3+ T-lymphocytes in studied tumors and determine whether their presence correlates with FasL or survivin expression in malignant cases. FasL and survivin expression was assessed in 54 ovarian epithelial tumors. The results were compared between different tumor types and grades. Correlation between both markers' expression in all studied tumors was done. Either marker's expression was compared to the mean CD3+ T-lymphocytes per HPF in the studied malignant tumors. Either FasL or survivin expression was significantly higher in malignant versus benign ovarian epithelial tumors (p < 0.001 for both) and both markers were strongly correlated to each other (r = 0.877 & p < 0.001). Malignant tumors show significantly higher mean CD3+ T-lymphocytes than benign and borderline tumors. The mean CD3+ T-lymphocytes decrease significantly on increasing malignant tumor grade (p = 0.019) and expression of both FasL and survivin (r = -0.729, -0.582, respectively & p < 0.001 for both). The higher expression of FasL and survivin in malignant as compared to benign ovarian tumors suggest that they have a significant role in pathogenesis of ovarian carcinoma. Both markers are strongly correlated to each other and may contribute to immune escape of ovarian carcinoma as their higher expression is associated with decreased number of CD3 + T-lymphocytes.
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Affiliation(s)
- Eiman Adel Hasby
- Pathology Department, Tanta Faculty of Medicine, Tanta, Ghrbia, Egypt.
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Felisiak-Golabek A, Rembiszewska A, Rzepecka IK, Szafron L, Madry R, Murawska M, Napiorkowski T, Sobiczewski P, Osuch B, Kupryjanczyk J. Nuclear survivin expression is a positive prognostic factor in taxane-platinum-treated ovarian cancer patients. J Ovarian Res 2011; 4:20. [PMID: 22075440 PMCID: PMC3223127 DOI: 10.1186/1757-2215-4-20] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2011] [Accepted: 11/10/2011] [Indexed: 11/16/2022] Open
Abstract
Background Survivin is an inhibitor of apoptosis and a regulator of mitotic progression. TP53 protein is a negative transcriptional regulator of survivin. The aim of our study was to evaluate the clinical significance of survivin expression in advanced stages ovarian cancer with respect to the TP53 status. Methods Survivin and TP53 expression was evaluated immunohistochemically in 435 archival samples of ovarian carcinomas (244 patients were treated with platinum/cyclophosphamide-PC/PAC; 191-with taxane-platinum (TP) agents). Univariate and multivariate statistical analyses were performed in patients groups divided according to the administered chemotherapeutic regimen, and in subgroups with and without TP53 accumulation (TP53+ and TP53-, respectively). Results Nuclear and cytoplasmic survivin expression was observed in 92% and 74% of the carcinomas, respectively. In patients treated with TP, high nuclear survivin expression decreased the risk of disease recurrence and death, and increased the probability of high platinum sensitivity (p < 0.01), but only in the TP53(+) group, and not in the TP53(-) group. Conclusions It appears that TP53 status determines the clinical importance of nuclear survivin expression in taxane-platinum treated ovarian cancer patients.
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Affiliation(s)
- Anna Felisiak-Golabek
- Department of Molecular Pathology, The Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
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Baykara M, Akkus M, Yildiz R, Gonul II, Dursun A, Coskun U, Benekli M, Sevinc A, Dane F, Buyukberber S. Survivin expression and its potential clinical significance in gastrointestinal stromal sarcoma. Int Immunopharmacol 2011; 11:2227-31. [PMID: 22020290 DOI: 10.1016/j.intimp.2011.10.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Revised: 10/02/2011] [Accepted: 10/03/2011] [Indexed: 11/29/2022]
Abstract
This study was designed to determine the level of survivin expression and its clinical significance as a prognostic factor in gastrointestinal stromal sarcoma (GIST). Twenty patients (12 males and 8 females) ranging in age from 25 to 72, with a median age of 53 were evaluated. Failure of TKI treatment was higher in the survivin-positive group (p=0.06). The rate of metastasis was significantly higher in the survivin positive group vs. the negative group (80% vs. 30%, p=0.18). The median overall survival (OS) time was 114 (range 29-199)months, and the median disease-free survival (DFS) time was 88 (range 40-135) months. The median progression-free survival (PFS) time was 40 (range 24-55) months. Further, a comparison of patients with survivin positive versus negative tumors, revealed no significant difference for OS, DFS, and PFS (p=0.45, p=0.19, p=0.55, respectively), number of mitoses in 50 HPF (p=0.14), and tumor size (p=0.94). In conclusion, survivin was highly expressed in GISTs, although we found no correlation between survivin expression and PFS, DFS and OS, survivin may be a predictive marker in GISTs for disease progression. We believe that additional studies are warranted to determine the clinical significance of survivin expression as a prognostic or predictive marker in patients with GIST.
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Affiliation(s)
- Meltem Baykara
- Gazi University Medical Faculty, Department Of Medical Oncology, Ankara, Turkey
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