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1
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Shimada S, Kawasaki H, Katoh H, Ishikawa S. Discovery of nuclear cavities in Epstein-Barr virus-infected cells. Acta Histochem 2025; 127:152253. [PMID: 40253819 DOI: 10.1016/j.acthis.2025.152253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 03/28/2025] [Accepted: 04/15/2025] [Indexed: 04/22/2025]
Abstract
Approximately 90 % of humans are infected with the Epstein-Barr virus (EBV); however, most do not develop neoplastic lesions. Despite various investigations, the underlying reasons remain largely unknown. Therefore, we aimed to address this question through morphological observations to identify the ultrastructural alterations occurring in EBV-infected cells. EBV-positive cells from legacy lymph node specimens obtained from patients with HIV and modern fresh specimens of aberrantly proliferating human EBV-positive lymphocytes in a patient-derived xenograft (PDX) of immunodeficient mouse were examined. By utilizing a special technique that allowed us to observe exactly the same specimen using both optical and electron microscopy, we were able to detect a peculiar phenomenon in EBV-infected cells. EBV-infected lymphocytes occasionally exhibited nuclear cavities, a finding that was confirmed in multiple specimens from both patients with HIV and the PDX model. It was suggested that EBV-infected cells may activate cell death pathways, based on the protein expression patterns of p53 and FAS. Taken together, these results indicated that nuclear cavity formation appeared to be a characteristic morphological alteration associated with EBV infection. Further research could clarify the potential relationship between nuclear cavities and cellular biology in EBV-infected cells, possibly shedding light on the mechanisms that prevent EBV-infected cells from progressing to tumor formation.
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Affiliation(s)
- Shinji Shimada
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hideya Kawasaki
- NanoSuit Research Laboratory, Institute of Photonics Medicine, Division of Preeminent Bioimaging Research, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Hiroto Katoh
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shumpei Ishikawa
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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2
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Zeng M, Lin A, Jiang A, Qiu Z, Zhang H, Chen S, Xu M, Liu Z, Cheng Q, Zhang J, Luo P. Decoding the mechanisms behind second primary cancers. J Transl Med 2025; 23:115. [PMID: 39856672 PMCID: PMC11762917 DOI: 10.1186/s12967-025-06151-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 01/19/2025] [Indexed: 01/27/2025] Open
Abstract
Second Primary Cancers (SPCs) are defined as cancers that develop either simultaneously or metachronously in the same individual who has been diagnosed with and survived one primary cancer. SPCs exhibit a high incidence rate and represent the primary cause of mortality among survivors of first primary cancers. There is growing concern about the dangers of SPCs. This review summarizes recent studies on the mechanisms of SPCs, including the roles of genomic changes after first primary cancer (FPC) treatments, stromal cell phenotypic and metabolic changes, hormone levels and receptor expression, immunosuppression, aberrant gene methylation, EGFR signaling, and cell-free DNA in SPC development. This comprehensive analysis contributes to elucidating current research trends in SPC mechanisms and enhances our understanding of the underlying pathophysiology. Furthermore, potential applications of intratumoral microbes, single-cell multi-omics, and metabolomics in investigating SPC mechanisms are also discussed, providing new ideas for follow-up studies.
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Affiliation(s)
- Meiyuan Zeng
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Zhengang Qiu
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Hongman Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China
| | - Shifu Chen
- HaploX Biotechnology, Shenzhen, China
- Faculty of Data Science, City University of Macau, Macau, China
| | | | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China.
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China.
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China.
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3
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The concept of intrinsic versus extrinsic apoptosis. Biochem J 2022; 479:357-384. [PMID: 35147165 DOI: 10.1042/bcj20210854] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 12/12/2022]
Abstract
Regulated cell death is a vital and dynamic process in multicellular organisms that maintains tissue homeostasis and eliminates potentially dangerous cells. Apoptosis, one of the better-known forms of regulated cell death, is activated when cell-surface death receptors like Fas are engaged by their ligands (the extrinsic pathway) or when BCL-2-family pro-apoptotic proteins cause the permeabilization of the mitochondrial outer membrane (the intrinsic pathway). Both the intrinsic and extrinsic pathways of apoptosis lead to the activation of a family of proteases, the caspases, which are responsible for the final cell demise in the so-called execution phase of apoptosis. In this review, I will first discuss the most common types of regulated cell death on a morphological basis. I will then consider in detail the molecular pathways of intrinsic and extrinsic apoptosis, discussing how they are activated in response to specific stimuli and are sometimes overlapping. In-depth knowledge of the cellular mechanisms of apoptosis is becoming more and more important not only in the field of cellular and molecular biology but also for its translational potential in several pathologies, including neurodegeneration and cancer.
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Huang H, Fang J, Fan X, Miyata T, Hu X, Zhang L, Zhang L, Cui Y, Liu Z, Wu X. Advances in Molecular Mechanisms for Traditional Chinese Medicine Actions in Regulating Tumor Immune Responses. Front Pharmacol 2020; 11:1009. [PMID: 32733246 PMCID: PMC7360845 DOI: 10.3389/fphar.2020.01009] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 06/22/2020] [Indexed: 12/19/2022] Open
Abstract
Traditional Chinese medicine (TCM) has been developed for thousands of years with its various biological activities. The interest in TCM in tumor prevention and treatment is rising with its synergistic effect on tumor cells and tumor immunosuppressive microenvironment (TIM). Characteristic of TCM fits well within the whole system and multi-target cancer treatment. Herein we discuss the underlying mechanisms of TCM actions in TIM via regulating immunosuppressive cells, including restoring the antigen presentation function of dendritic cells, enhancing NK cells-mediated killing activity, restraining the functions of myeloid cell-derived suppressor cells, and inhibiting cancer-associated fibroblasts. TCM also regulates tumor progression through enhancing immune response, preventing immune escape and inducing cell death of tumor cells, which triggers immune response in nearby cells. In addition, we discuss TCM in clinical applications and the advantages and disadvantages of TCM in cancer prevention and treatment, as well as current therapeutic challenges and strategies. It might be helpful for understanding the therapeutic potential of TCM for cancer in clinic.
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Affiliation(s)
- Han Huang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Jiansong Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiude Fan
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
| | - Tatsunori Miyata
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
| | - Xiaoyue Hu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Lihe Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Liangren Zhang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Yimin Cui
- Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Xiaoqin Wu
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States
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5
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Xie F, Zhou X, Fang M, Li H, Su P, Tu Y, Zhang L, Zhou F. Extracellular Vesicles in Cancer Immune Microenvironment and Cancer Immunotherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1901779. [PMID: 31871860 PMCID: PMC6918121 DOI: 10.1002/advs.201901779] [Citation(s) in RCA: 207] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 09/26/2019] [Indexed: 05/10/2023]
Abstract
Extracellular vesicles (EVs) are secreted by almost all cells. They contain proteins, lipids, and nucleic acids which are delivered from the parent cells to the recipient cells. Thereby, they function as mediators of intercellular communication and molecular transfer. Recent evidences suggest that exosomes, a small subset of EVs, are involved in numerous physiological and pathological processes and play essential roles in remodeling the tumor immune microenvironment even before the occurrence and metastasis of cancer. Exosomes derived from tumor cells and host cells mediate their mutual regulation locally or remotely, thereby determining the responsiveness of cancer therapies. As such, tumor-derived circulating exosomes are considered as noninvasive biomarkers for early detection and diagnosis of tumor. Exosome-based therapies are also emerging as cutting-edge and promising strategies that could be applied to suppress tumor progression or enhance anti-tumor immunity. Herein, the current understanding of exosomes and their key roles in modulating immune responses, as well as their potential therapeutic applications are outlined. The limitations of current studies are also presented and directions for future research are described.
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Affiliation(s)
- Feng Xie
- Institute of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
| | - Xiaoxue Zhou
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
- Key Laboratory of Head & Neck CancerTranslational Research of Zhejiang ProvinceZhejiang Cancer HospitalHangzhou310058P. R. China
| | - Meiyu Fang
- Key Laboratory of Head & Neck CancerTranslational Research of Zhejiang ProvinceZhejiang Cancer HospitalHangzhou310058P. R. China
| | - Heyu Li
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
| | - Peng Su
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
| | - Yifei Tu
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
| | - Long Zhang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
| | - Fangfang Zhou
- Institute of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
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6
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Zhang WL, Zhu ZL, Huang MC, Tang YJ, Tang YL, Liang XH. Susceptibility of Multiple Primary Cancers in Patients With Head and Neck Cancer: Nature or Nurture? Front Oncol 2019; 9:1275. [PMID: 31824853 PMCID: PMC6882292 DOI: 10.3389/fonc.2019.01275] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023] Open
Abstract
Multiple primary cancers (MPCs) are major obstacles to long-term survival in head and neck cancer (HNSCC), however, the molecular mechanism underlying multiple carcinogenesis remains unclear. “Field cancerization” is a classical theory to elaborate the malignant progression of MPCs. Apart from environmental and immune factors, genetic factors may have great potential as molecular markers for MPCs risk prediction. This review focuses on inherited and acquired gene mutations in MPCs, including germ-line mutation, single-nucleotide polymorphism, chromosomal instability, microsatellite instability and DNA methylation. And definition and prognosis of MPCs have also been discussed. These may pave the way for the early detection, prevention and effective treatment of MPCs in HNSCC.
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Affiliation(s)
- Wei-Long Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhuo-Li Zhu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Mei-Chang Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ya-Jie Tang
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Jiang X, Wu J, Wang J, Huang R. Tobacco and oral squamous cell carcinoma: A review of carcinogenic pathways. Tob Induc Dis 2019; 17:29. [PMID: 31582940 PMCID: PMC6752112 DOI: 10.18332/tid/105844] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/18/2019] [Accepted: 03/20/2019] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Tobacco is one of the most important risk factors for premature death globally. More than 60 toxic chemicals in tobacco can invade the body’s various systems. Oral squamous cell carcinoma (OSCC) is a pathological type of oral cancer, accounting for over 90% of oral cancers. A vast quantity of scientific, clinical and epidemiological data shows that tobacco is associated with the development of oral squamous cell carcinoma, and its carcinogenic pathways may be complicated. METHODS We conducted a thorough electronic search by Cochrane, EMBASE and PubMed to identify relevant studies. Studies published up to the end of October 2018 were included. After assessing and selecting articles based on eligibility criteria, studies were classified and elaborated according to the pathogenesis. RESULTS Tobacco as an important risk factor can cause epigenetic alteration of oral epithelial cells, inhibit multiple systemic immune functions of the host, and its toxic metabolites can cause oxidative stress on tissues and induce OSCC. In addition, some specific viruses such as EBV and HPV are thought to play a role in the development of OSCC. CONCLUSIONS Oral cancer ranks eighth among the most common causes of cancer-related deaths worldwide, and tobacco is one the most important carcinogenic factors of OSCC. This review of the literature attempts to provide directions and ideas for future related research, and emphasizes the need for efforts to reduce tobacco consumption.
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Affiliation(s)
- Xiaoge Jiang
- Department of Pediatric Dentistry, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jiaxin Wu
- Department of Pediatric Dentistry, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jiexue Wang
- Department of Pediatric Dentistry, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ruijie Huang
- Department of Pediatric Dentistry, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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da Silva GM, Saavedra V, Ianez RCF, de Sousa EA, Gomes ÁN, Kelner N, Nagai MA, Kowalski LP, Soares FA, Lourenço SV, Coutinho-Camillo CM. Apoptotic signaling in salivary mucoepidermoid carcinoma. Head Neck 2019; 41:2904-2913. [PMID: 30968512 DOI: 10.1002/hed.25763] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 02/20/2019] [Accepted: 03/25/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Mucoepidermoid carcinoma is the most common malignant tumor of salivary glands. Apoptosis plays an important role in organogenesis of glandular structures, and aberrations of apoptotic mechanisms is associated with a wide array of pathologic conditions. METHODS The immunoexpression of proteins associated with apoptosis and proliferation was evaluated in 40 mucoepidermoid carcinoma cases. RESULTS Par-4, Survivin, MUC1, PHLDA1, Fas, and Ki-67 were predominantly expressed in mucoepidermoid carcinoma. FasL was rarely expressed, and Caspase-3 expression was observed in almost 50% of the cases. SPARC expression was associated with low-grade tumors, and Ki-67 expression was associated with lymph node metastasis. Expression of Fas and decreased expression of Ki-67 and Caspase-3 were associated with better overall cancer-specific survival rates. CONCLUSIONS The association of SPARC and Ki-67 expression with pathological features and the association of Fas, Caspase-3, and Ki-67 with survival probabilities suggest that these proteins may be useful prognostic markers for mucoepidermoid carcinoma.
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Affiliation(s)
| | - Victoria Saavedra
- International Research Center, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Renata C F Ianez
- International Research Center, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Elen A de Sousa
- International Research Center, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Ágatha N Gomes
- International Research Center, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Natalie Kelner
- Department of Head and Neck Surgery and Otorhinolaryngology, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Maria A Nagai
- Discipline of Oncology, Department of Radiology and Oncology, Medical School, University of São Paulo, São Paulo, Brazil.,Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of São Paulo, São Paulo, Brazil
| | - Luiz P Kowalski
- Department of Head and Neck Surgery and Otorhinolaryngology, A.C.Camargo Cancer Center, São Paulo, Brazil
| | - Fernando A Soares
- Department of General Pathology, Dental School, University of São Paulo, São Paulo, Brazil.,Pathology Division, Rede D'Or Hospitals Network, São Paulo, Brazil
| | - Silvia V Lourenço
- Department of General Pathology, Dental School, University of São Paulo, São Paulo, Brazil
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Huang SCM, Tsao SW, Tsang CM. Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma. Cancers (Basel) 2018; 10:E106. [PMID: 29617291 PMCID: PMC5923361 DOI: 10.3390/cancers10040106] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 03/29/2018] [Accepted: 03/30/2018] [Indexed: 12/15/2022] Open
Abstract
Undifferentiated nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. In addition, heavy infiltration of leukocytes is a common characteristic of EBV-associated NPC. It has long been suggested that substantial and interactive impacts between cancer and stromal cells create a tumor microenvironment (TME) to promote tumorigenesis. The coexistence of tumor-infiltrating lymphocytes with EBV-infected NPC cells represents a distinct TME which supports immune evasion and cancer development from the early phase of EBV infection. Intracellularly, EBV-encoded viral products alter host cell signaling to facilitate tumor development and progression. Intercellularly, EBV-infected cancer cells communicate with stromal cells through secretion of cytokines and chemokines, or via release of tumor exosomes, to repress immune surveillance and enhance metastasis. Although high expression of miR-BARTs has been detected in NPC patients, contributions of these more recently discovered viral products to the establishment of TME are still vaguely defined. Further investigations are needed to delineate the mechanistic linkage of the interplay between viral and host factors, especially in relation to TME, which can be harnessed in future therapeutic strategies.
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Affiliation(s)
| | - Sai Wah Tsao
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, HK, China.
| | - Chi Man Tsang
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, HK, China.
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Ceylan C, Yahşi S, Doğan S, ÖztÜrk E, Ceylan G. Emphasis of FAS/FASL gene polymorphism in patients with non-muscle invasive bladder cancer. Ir J Med Sci 2018; 187:1115-1119. [PMID: 29453645 DOI: 10.1007/s11845-018-1764-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 02/01/2018] [Indexed: 10/18/2022]
Abstract
BACKGROUND Bladder cancer (BCa) is the seventh most common cancer among males worldwide. Some reliable markers in blood, urine, and tumor tissue, including clinicopathologic variables, molecular and inflammatory markers, gene polymorphisms, and tumor gene expression profiles are identified for predicting response to BCG immunotherapy in high-risk BCa patients. AIMS We aimed to determine if FAS and FASL polymorphisms are associated with lack of response to BCG in patients with BCa. METHODS The study included patients with primary non-muscle invasive BCa that had undergone transurethral resection (TUR). Patient demographics, BCa characteristics, use of BCG immunotherapy, lack of response to BCG (if administered), BCa recurrence, and fatty acid synthetase/fatty acid syntethase ligand (FAS/FASL) polymorphisms were investigated. RESULTS The study included 127 patients with primary BCa. Mean age of the 107 (84.3%) male and 20 (15.7%) female patients was 59.3 ± 13.2 years. Among the patients that received BCG immunotherapy, more FAS homozygous patients had BCa recurrence than FAS polymorphism-negative patients (P < 0.001) and more patients with homozygote FASL polymorphisms had BCa recurrence than those with heterozygous FASL polymorphisms and no polymorphism. CONCLUSION Evaluation of FAS/FASL polymorphisms can predict lack of response to BCG immunotherapy and prevent the loss of valuable time before such alternative treatments as early cystectomy are initiated.
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Affiliation(s)
- Cavit Ceylan
- Yuksek Ihtisas Training and Research Hospital, Clinic of Urology, Health Sciences University, 06230, Ankara, Turkey
| | - Sedat Yahşi
- Yuksek Ihtisas Training and Research Hospital, Clinic of Urology, 06230, Ankara, Turkey
| | - Serkan Doğan
- Yuksek Ihtisas Training and Research Hospital, Clinic of Urology, 06230, Ankara, Turkey
| | - Elife ÖztÜrk
- Department of Medical Genetics, Ataturk Training and Research Hospital, 06800, Ankara, Turkey
| | - Gulay Ceylan
- Department of Medical Genetics, Ankara Yildirim Beyazit University, 06800, Ankara, Turkey.
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Ozdemirkiran FG, Nalbantoglu S, Gokgoz Z, Payzin BK, Vural F, Cagirgan S, Berdeli A. FAS/FASL gene polymorphisms in Turkish patients with chronic myeloproliferative disorders. Arch Med Sci 2017; 13:426-432. [PMID: 28261298 PMCID: PMC5332439 DOI: 10.5114/aoms.2015.53963] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 03/18/2015] [Indexed: 01/17/2023] Open
Abstract
INTRODUCTION Chronic myeloproliferative disorders (CMPD) are chronic myeloid hematological disorders, characterized by increased myeloid cell proliferation and fibrosis. Impaired apoptotic mechanisms, increased cell proliferation, uncontrolled hematopoietic cell proliferation and myeloaccumulation may contribute to the pathogenesis of CMPD. The aim of our study was to show the possible role of FAS/FASL gene polymorphisms in CMPD pathogenesis and investigate the association with clinical parameters and susceptibility to disease. MATERIAL AND METHODS We included 101 (34 polycythemia vera (PV), 23 primary myelofibrosis (PMF), 44 essential thrombocythemia (ET)) CMPD patients diagnosed according to the WHO classification criteria and 95 healthy controls in this study. All the patients and the controls were investigated for FAS/FASL gene expression, allele frequencies and phenotype features, and also FAS mRNA levels were analyzed. RESULTS Chronic myeloproliferative disorders patients showed increased FAS-670AG + GG genotype distribution compared with the control group (p < 0.05). While the A allele was more frequent in both groups, AG genotype was more frequent in CMPD patients. There was no association between FAS-670A>G gene polymorphism and some clinical parameters such as splenomegaly and thrombosis (p > 0.05). No statistically significant difference in FASL+843C>T genotype or allele frequency was found between groups (p > 0.05). Moreover, no statistically significant difference was detected in FASL and JAK2V617F mutations (p > 0.05). FAS mRNA expression was 1.5-fold reduced in patients compared to healthy subjects. CONCLUSIONS According to our findings, FAS/FASL gene expression may contribute to the molecular and immunological pathogenesis of CMPD. More investigations are needed to support these data.
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Affiliation(s)
- Fusun Gediz Ozdemirkiran
- Department of Hematology, Atatürk Research and Education Hospital, Izmir Katip Çelebi University, Izmir, Turkey
| | - Sinem Nalbantoglu
- Department of Molecular Genetics, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Zafer Gokgoz
- Department of Hematology, Baskent University, Adana, Turkey
| | - Bahriye Kadriye Payzin
- Department of Hematology, Atatürk Research and Education Hospital, Izmir Katip Çelebi University, Izmir, Turkey
| | - Filiz Vural
- Department of Hematology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Seckin Cagirgan
- Department of Hematology, Izmir Medical Park Hospital, Izmir, Turkey
| | - Afig Berdeli
- Department of Molecular Genetics, Faculty of Medicine, Ege University, Izmir, Turkey
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12
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Early growth response 3 inhibits growth of hepatocellular carcinoma cells via upregulation of Fas ligand. Int J Oncol 2017; 50:805-814. [PMID: 28098878 DOI: 10.3892/ijo.2017.3855] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Accepted: 11/07/2016] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent malignancy with aggressive biological behavior and poor prognosis. Early growth response 3 (EGR3) is a zinc finger transcription factor, and has been studied primarily in the context of neurodevelopment, autoimmunity, inflammation and angiogenesis. Accumulating evidence indicates that EGR3 is a novel suppressor gene of tumor initiation and progression in certain cancer events, but little work has been carried out in exploring the relationship between EGR3 and HCC growth. The purpose of this study was to investigate the possible effects of EGR3 on cell proliferation and apoptosis in HCC, and determine the underlying mechanisms. Here, we observed that EGR3 expression was frequently downregulated in HCC tissues and cell lines. Ectopic expression of EGR3 contributed to cell proliferation inhibition and apoptosis induction in HCC cells in vitro. Furthermore, the expression of Fas ligand (FasL) was significantly enhanced following upregulation of EGR3 in HCC cells, accompanied by an obvious increase of pro-apoptotic Bak and cell cycle inhibitor p21 expression. Based on nude mouse models, we demonstrated that ectopic expression of EGR3 markedly restricted tumor growth, and the expression of FasL was significantly increased in the xenograft tumor tissues which exhibited high EGR3 expression. We further established a co-transfection in HCC cells with EGR3 overexpression plasmid and FasL siRNA. We found that silencing of FasL gene impeded the anti-proliferative and pro-apoptotic effects, as well as the increase of Bak and p21 expression, suggesting an essential role of FasL in EGR3-mediated growth suppression in HCC cells. Collectively, in conclusion, EGR3 contributes to cell growth inhibition via upregulation of FasL in HCC.
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Kouzegaran S, Shahraki K, Makateb A, Shahri F, Hatami N, Behnod V, Tanha AS. Prognostic Investigations of Expression Level of Two Genes FasL and Ki-67 as Independent Prognostic Markers of Human Retinoblastoma. Oncol Res 2016; 25:471-478. [PMID: 27625332 PMCID: PMC7841034 DOI: 10.3727/096504016x14721217330657] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
In this study, expression of FasL and Ki-67 messenger RNA (FasL and Ki-67 mRNA) in human retinoblastoma (HRB) was examined by the immunohistochemistry method and quantitative real-time PCR. Positive expression of Ki-67 in tumor cells was detected in 16 of 30 patients (53.33%), and only 9 (30%) of the tissues from patients with retinoblastoma showed positive staining for FasL. Our results revealed that FasL expression was significantly higher in tumor tissue with invasion compared with the noninvasion form (p = 0.033). Ki-67 expression was markedly increased in tumor tissues with invasion compared with the noninvasion group (p = 0.04), but no significant correlation was found between FasL expression and differentiation (p > 0.05). In addition, Ki-67 expression was strongly linked to differentiation (p < 0.002). Expression of these FasL was correlated with shorter overall survival of patients, but its expression was not significantly associated with overall survival (p = 0.15). The impact of Ki-67 expression on survival in patients was also evaluated. Ki-67 expression level was not found to be significantly associated with shorter survival (Kaplan–Meier; p = 0.09). Univariate analysis revealed that massive choroidal invasion was correlated with poor prognosis. Taken together, the data suggest that massive choroidal invasion is also an important indicator of poor prognosis for HRB.
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Affiliation(s)
- Samaneh Kouzegaran
- Department of Pediatrics, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Kourosh Shahraki
- Department of Ophthalmology, Alzahra Eye Hospital, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Ali Makateb
- Department of Ophthalmology, AJA University of Medical Sciences, Tehran, Iran
| | - Farkhondeh Shahri
- Department of Optometry, School of Rehabilitation, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Negin Hatami
- Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA
| | - Vahid Behnod
- Department of Molecular Biology, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Saber Tanha
- Department of Anesthesia, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
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Wang M, Wang Z, Wang XJ, Jin TB, Dai ZM, Kang HF, Guan HT, Ma XB, Liu XH, Dai ZJ. Distinct role of the Fas rs1800682 and FasL rs763110 polymorphisms in determining the risk of breast cancer among Han Chinese females. Drug Des Devel Ther 2016; 10:2359-2367. [PMID: 27524883 PMCID: PMC4966568 DOI: 10.2147/dddt.s111084] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND In recent years, studies have demonstrated that polymorphisms in the promoters of Fas and FasL are significantly associated with breast cancer risk. However, the results of these studies were inconsistent. This case-control study was performed to explore the associations between Fas rs1800682 and FasL rs763110 polymorphisms and breast cancer. MATERIALS AND METHODS A hospital-based case-control study of 560 Han Chinese females with breast cancer (583 controls) was conducted. The MassARRAY system was used to search for a possible association between the disease risk and the two single nucleotide polymorphisms, Fas rs1800682 and FasL rs763110. Statistical analyses were performed using SNPStats software to conduct Pearson's chi-square tests in five different genetic models. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated after adjustment to age and body mass index. PHASE v2.1 software was used to reconstruct all common haplotypes. RESULTS A statistically significant association was found between Fas rs1800682 and increased breast cancer risk (AG vs AA: OR =1.37, 95% CI =1.06-1.78; AA+AG vs GG: OR =1.32, 95% CI =1.04-1.66), and also it was found that the FasL rs763110 polymorphism may decrease the risk. Stratified analyses demonstrated that the rs763110 polymorphism was associated with lower breast cancer risk among postmenopausal females (heterozygote model: OR =0.69, 95% CI =0.49-0.97; dominant model: OR =0.70, 95% CI =0.51-0.96). The T allele of rs763110 was also associated with a decreased risk of lymph node metastasis (allele model: OR =0.75, 95% CI =0.57-0.97) and an increased risk of the breast cancer being human epidermal growth factor receptor 2 positive (allele model: OR =1.37, 95% CI =1.03-1.18). Moreover, haplotype analysis showed that Ars1800682Trs763110 was associated to a statistically significant degree with lower risk of breast cancer (OR =0.70, 95% CI =0.53-0.91). CONCLUSION These data suggest that the presence of Fas rs1800683 is an important risk factor for breast cancer, whereas FasL rs763110 may exert a protective effect against the onset of breast cancer.
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Affiliation(s)
- Meng Wang
- Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University
| | - Zheng Wang
- Department of Medical Oncology, Xi’an Central Hospital
| | - Xi-Jing Wang
- Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University
| | - Tian-Bo Jin
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University
| | - Zhi-Ming Dai
- Department of Anesthesia, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Hua-Feng Kang
- Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University
| | - Hai-Tao Guan
- Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University
| | - Xiao-Bin Ma
- Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University
| | - Xing-Han Liu
- Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University
| | - Zhi-Jun Dai
- Department of Oncology, Second Affiliated Hospital of Xi’an Jiaotong University
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Yu X, Li Y, Yu Y, Lei J, Wan G, Cao F. Associations between FAS rs2234767 and FASL rs763110 polymorphisms and the risk of lung cancer: a meta-analysis of 39,736 subjects. Onco Targets Ther 2016; 9:2049-56. [PMID: 27103831 PMCID: PMC4827906 DOI: 10.2147/ott.s102723] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background Previous studies have investigated the associations between the common polymorphisms in FAS/FASL genes and lung cancer risk; however, the results remain inconsistent and inconclusive. Hence, we performed a meta-analysis to reassess the relationships between FAS rs2234767 and FASL rs763110 polymorphisms and the risk of lung cancer. Methods Eligible studies retrieved by an electronic search were pooled to calculate the strength of the associations using the odds ratio (OR) and 95% confidence interval (95% CI). Results A total of 13 case–control studies involving 39,736 subjects (9,237 cases and 10,838 controls on FAS rs2234767 and 8,957 cases and 10,704 controls on FASL rs763110) were included in the meta-analysis. The results showed a significant association between FAS rs2234767 polymorphism and increased risk of lung cancer (A vs G: OR =1.07, 95% CI =1.01–1.13; AA vs GG: OR =1.23, 95% CI =1.06–1.43; AA vs GA + GG: OR =1.24, 95% CI =1.08–1.43). Similar association was also observed in Asian population (AA vs GA + GG: OR =1.30, 95% CI =1.01–1.67) and in the studies with large sample size (A vs G: OR =1.07, 95% CI =1.00–1.14; AA vs GG: OR =1.30, 95% CI =1.07–1.58). However, no significant association between FASL rs763110 polymorphism and lung cancer risk was found other than in the Asian population (CC vs TC + TT: OR =1.35, 95% CI =1.01–1.80). Conclusion The meta-analysis indicated that FAS rs2234767 polymorphism was significantly associated with an increased risk of lung cancer and FASL rs763110 polymorphism may not contribute to susceptibility to lung cancer other than in Asian population.
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Affiliation(s)
- Xiongjie Yu
- Department of Oncology, Hubei University of Medicine, Shiyan, Hubei, People's Republic of China
| | - Yanli Li
- Department of Endocrinology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, People's Republic of China
| | - Yuandong Yu
- Department of Oncology, Hubei University of Medicine, Shiyan, Hubei, People's Republic of China
| | - Jinhua Lei
- Department of Oncology, Hubei University of Medicine, Shiyan, Hubei, People's Republic of China
| | - Guoxing Wan
- Department of Oncology, Hubei University of Medicine, Shiyan, Hubei, People's Republic of China
| | - Fengjun Cao
- Department of Oncology, Hubei University of Medicine, Shiyan, Hubei, People's Republic of China
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Zhang M, Wu C, Li B, Du W, Zhang C, Chen Z. Quantitative assessment of the association between Fas/FasL gene polymorphism and susceptibility to esophageal carcinoma in a north Chinese population. Cancer Med 2016; 5:760-6. [PMID: 26819081 PMCID: PMC4831295 DOI: 10.1002/cam4.633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 12/06/2015] [Accepted: 12/09/2015] [Indexed: 12/22/2022] Open
Abstract
The case–control study aims to investigate the association of Fas and FasL genetic polymorphisms (Fas‐670A/G (rs1800682), Fas‐1377G/A (rs2234767) and FasL‐844T/C (rs763110)) with esophageal carcinoma susceptibility in a north Chinese population. A total of 204 patients with esophageal carcinoma and 248 healthy controls were enrolled from Henan, China and genotyped by the polymerase chain reaction and restriction fragment length polymorphism method. There were no significant differences in distributions of their genotypes frequencies between patients and controls in Fas‐670A/G, Fas‐1377G/A and FasL‐844T/C polymorphisms (P > 0.05). Stratified analysis showed that no significant association was found between esophageal carcinoma and gene polymorphisms of Fas‐670 A/G, Fas‐1377G/A, and FasL‐844T/C (P > 0.05). Genetic polymorphisms in the death pathway genes Fas and FasL were not associated with risk of developing esophageal carcinoma in a north Chinese population.
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Affiliation(s)
- Meijuan Zhang
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Cuiping Wu
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Baohuan Li
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Wenjun Du
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Chuanzhen Zhang
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Ziping Chen
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
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Synergistic Effect and Molecular Mechanisms of Traditional Chinese Medicine on Regulating Tumor Microenvironment and Cancer Cells. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1490738. [PMID: 27042656 PMCID: PMC4793102 DOI: 10.1155/2016/1490738] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Accepted: 01/26/2016] [Indexed: 12/23/2022]
Abstract
The interaction of tumor cells with the microenvironment is like a relationship between the “seeds” and “soil,” which is a hotspot in recent cancer research. Targeting at tumor microenvironment as well as tumor cells has become a new strategy for cancer treatment. Conventional cancer treatments mostly focused on single targets or single mechanism (the seeds or part of the soil); few researches intervened in the whole tumor microenvironment and achieved ideal therapeutic effect as expected. Traditional Chinese medicine displays a broad range of biological effects, and increasing evidence has shown that it may relate with synergistic effect on regulating tumor microenvironment and cancer cells. Based on literature review and our previous studies, we summarize the synergistic effect and the molecular mechanisms of traditional Chinese medicine on regulating tumor microenvironment and cancer cells.
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18
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Sun Y, Yu W, Sturgis EM, Peng W, Lei D, Wei Q, Song X, Li G. Site disparities in apoptotic variants as predictors of risk for second primary malignancy in patients with squamous cell carcinoma of the head and neck. BMC Cancer 2016; 16:70. [PMID: 26858129 PMCID: PMC4746789 DOI: 10.1186/s12885-016-2110-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 02/03/2016] [Indexed: 01/17/2023] Open
Abstract
Background FAS/FASL promoter variants are considered in altering transcriptional activity of those genes and consequently alter regulation of cell death. However, no studies have investigated whether tumor sites contribute to the association between FAS/FASL polymorphisms and risk for second primary malignancy (SPM). Method In this study, FAS670 A > G, FAS1377 G > A, FASL124 A > G, and FASL844C > T polymorphisms were genotyped in 752 OPC and 777 non-OPC patients. Both univariate and multivariable cox proportional hazard models were used to assess the associations. Results The univariate and multivariable analyses showed that patients with index OPC and FASL844 CT/TT genotype had significantly increased risk of SPM (cHR, 2.5; 95 % CI, 1.1–5.8, P = 0.043 and aHR, 2.7; 95 % CI, 1.2–6.0, P = 0.032) compared with those with FASL844 CC genotype as the reference group, while index non-OPC patients with FAS670 AG/GG and FasL844 CT/TT genotypes had significantly increased risk of SPM (cHR, 2.2 and 1.8; 95 % CI, 1.2–5.7 and 1.1–3.2; and P = 0.04 and 0.041, respectively and aHR, 2.4 and 1.7; 95 % CI, 1.1–5.1 and 1.0-3.0; and P = 0.043 and 0.049, respectively) compared with their corresponding AA and CC genotypes . Moreover, patients carrying more FAS/FASL variants significantly increased risk of SPM among index non-OPC patients. The stratified analysis showed that smoking status differently modified the associations between FAS/FASL polymorphisms and risk of SPM among index non-OPC from OPC patients. Conclusion These results suggested that FAS/FASL polymorphisms might significantly modify SPM risk among patients with SCCHN in a tumor site-specific manner.
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Affiliation(s)
- Yan Sun
- Department of Head and Neck Surgery, Unit 1445, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. .,Department of Otorhinolaryngology and Head and Neck Surgery, Yuhuangding Hospital of Qingdao University, Yantai, China.
| | - Wenbin Yu
- Department of Head and Neck Surgery, Unit 1445, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. .,Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing), Department of Head and Neck surgery, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Erich M Sturgis
- Department of Head and Neck Surgery, Unit 1445, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. .,Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Wei Peng
- Department of Biostatistics and Human Genetics Center, University of Texas School of Public Health, 1200 Herman Pressler St, Houston, TX 77030, USA.
| | - Dapeng Lei
- Department of Head and Neck Surgery, Unit 1445, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. .,Department of Otolaryngology, Qilu Hospital, Shandong University; Key Laboratory of Otolaryngology, Ministry of Health, P.R. China, Jinan, Shandong, 250012, China.
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA.
| | - Xicheng Song
- Department of Head and Neck Surgery, Unit 1445, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. .,Department of Otorhinolaryngology and Head and Neck Surgery, Yuhuangding Hospital of Qingdao University, Yantai, China.
| | - Guojun Li
- Department of Head and Neck Surgery, Unit 1445, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. .,Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Chester C, Fritsch K, Kohrt HE. Natural Killer Cell Immunomodulation: Targeting Activating, Inhibitory, and Co-stimulatory Receptor Signaling for Cancer Immunotherapy. Front Immunol 2015; 6:601. [PMID: 26697006 PMCID: PMC4667030 DOI: 10.3389/fimmu.2015.00601] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 11/09/2015] [Indexed: 01/11/2023] Open
Abstract
There is compelling clinical and experimental evidence to suggest that natural killer (NK) cells play a critical role in the recognition and eradication of tumors. Efforts at using NK cells as antitumor agents began over two decades ago, but recent advances in elucidating NK cell biology have accelerated the development of NK cell-targeting therapeutics. NK cell activation and the triggering of effector functions is governed by a complex set of activating and inhibitory receptors. In the early phases of cancer immune surveillance, NK cells directly identify and lyse cancer cells. Nascent transformed cells elicit NK cell activation and are eliminated. However, as tumors progress, cancerous cells develop immunosuppressive mechanisms that circumvent NK cell-mediated killing, allowing for tumor escape and proliferation. Therapeutic intervention aims to reverse tumor-induced NK cell suppression and sustain NK cells’ tumorlytic capacities. Here, we review tumor–NK cell interactions, discuss the mechanisms by which NK cells generate an antitumor immune response, and discuss NK cell-based therapeutic strategies targeting activating, inhibitory, and co-stimulatory receptors.
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Affiliation(s)
- Cariad Chester
- Division of Oncology, Department of Medicine, Stanford University , Stanford, CA , USA ; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine , Stanford, CA , USA
| | - Katherine Fritsch
- Division of Oncology, Department of Medicine, Stanford University , Stanford, CA , USA
| | - Holbrook E Kohrt
- Division of Oncology, Department of Medicine, Stanford University , Stanford, CA , USA
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Tan SC, Ankathil R. Genetic susceptibility to cervical cancer: role of common polymorphisms in apoptosis-related genes. Tumour Biol 2015; 36:6633-44. [PMID: 26242271 DOI: 10.1007/s13277-015-3868-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 07/29/2015] [Indexed: 12/13/2022] Open
Abstract
Cervical cancer is a common malignancy which poses a significant health burden among women, especially those living in the developing countries. Although human papillomavirus (HPV) infection has been unequivocally implicated in the etiopathogenesis of the cancer, it alone is not adequate to contribute to the malignant transformation of cervical cells. Most HPV infections regress spontaneously, and only a small proportion of women have persistent infections which eventually lead to malignancy. This suggests that interplays between HPV infection and other cofactors certainly exist during the process of cervical carcinogenesis, which synergistically contribute to the differential susceptibility of an individual to the malignancy. Undoubtedly, host genetic factors represent a major element involved in such a synergistic interaction, and accumulating evidence suggests that polymorphisms in apoptosis-related genes play an important role in the genetic susceptibility to cervical cancer. This review consolidates the recent literatures on the role of common polymorphisms in apoptosis-related genes in genetic susceptibility to cervical cancer.
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Affiliation(s)
- Shing Cheng Tan
- Human Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia.
| | - Ravindran Ankathil
- Human Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia.
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21
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Zhang F, Sturgis EM, Sun Y, Zhang Y, Wei Q, Zhang C, Zheng H, Li G. Apoptotic variants as predictors of risk of oropharyngeal cancer recurrence after definitive radiotherapy. Int J Cancer 2015; 137:2454-61. [PMID: 25976983 DOI: 10.1002/ijc.29604] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 04/07/2015] [Accepted: 04/27/2015] [Indexed: 11/11/2022]
Abstract
Single nucleotide polymorphisms (SNPs) in the promoter region of FAS and FASLG may alter their transcriptional activity. Thus, we determined the associations between four FAS and FASLG promoter variants (FAS1377G>A, rs2234767; 670A>G, rs1800682; FASLG844T>C, rs763110 and 124A>G, rs5030772) and the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated the associations between FAS and FASLG genetic variants and the risk of recurrence in a cohort of 1,008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. Compared with patients with common homozygous genotypes of FAS670 and FASLG844 polymorphisms, patients with variant genotypes had lower disease-free survival rates (log-rank p < 0.0001 and p < 0.0001, respectively) and an approximately threefold higher risk of SCCOP recurrence (HR, 3.2;95% CI, 2.2-4.6; and HR, 3.1; 95% CI, 2.2-4.4, respectively) after multivariate adjustment. Furthermore, among patients with HPV16-positive tumors, those with variant genotypes of these two polymorphisms had lower disease-free survival rates (log-rank, p < 0.0001 and p < 0.0001, respectively) and a higher recurrence risk than did patients with common homozygous genotypes (HR, 12.9; 95% CI, 3.8-43.6; and HR, 8.1; 95% CI, 3.6-18.6, respectively), whereas no significant associations were found for FAS1377 and FASLG124 polymorphisms. Our findings suggest that FAS670 and FASLG844 polymorphisms modulate the risk of recurrence of SCCOP, particularly in patients with HPV16-positive tumors. Larger studies are needed to validate these results.
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Affiliation(s)
- Fenghua Zhang
- Department of Head and Neck Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX.,Department of General Surgery, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Erich M Sturgis
- Department of Head and Neck Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX.,Department of Epidemiology, the University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yan Sun
- Department of Head and Neck Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX.,Department of Otolaryngology-Head and Neck Surgery, Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Yang Zhang
- Department of Head and Neck Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX.,Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Key Laboratory of Otolaryngology Head and Neck Surgery Capital Medical University, Ministry of Education, Beijing, China
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC
| | - Caiyun Zhang
- Department of Head and Neck Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX.,Department of Otorhinolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Hongliang Zheng
- Department of Head and Neck Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX.,Department of Otorhinolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Guojun Li
- Department of Head and Neck Surgery, the University of Texas MD Anderson Cancer Center, Houston, TX.,Department of Epidemiology, the University of Texas MD Anderson Cancer Center, Houston, TX
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Lipid rafts and raft-mediated supramolecular entities in the regulation of CD95 death receptor apoptotic signaling. Apoptosis 2015; 20:584-606. [DOI: 10.1007/s10495-015-1104-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability. Cell Death Differ 2014; 22:643-53. [PMID: 25301068 DOI: 10.1038/cdd.2014.153] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 07/24/2014] [Accepted: 08/18/2014] [Indexed: 11/09/2022] Open
Abstract
The death receptor Fas undergoes a variety of post-translational modifications including S-palmitoylation. This protein acylation has been reported essential for an optimal cell death signaling by allowing both a proper Fas localization in cholesterol and sphingolipid-enriched membrane nanodomains, as well as Fas high-molecular weight complexes. In human, S-palmitoylation is controlled by 23 members of the DHHC family through their palmitoyl acyltransferase activity. In order to better understand the role of this post-translational modification in the regulation of the Fas-mediated apoptosis pathway, we performed a screen that allowed the identification of DHHC7 as a Fas-palmitoylating enzyme. Indeed, modifying DHHC7 expression by specific silencing or overexpression, respectively, reduces or enhances Fas palmitoylation and DHHC7 co-immunoprecipitates with Fas. At a functional level, DHHC7-mediated palmitoylation of Fas allows a proper Fas expression level by preventing its degradation through the lysosomes. Indeed, the decrease of Fas expression obtained upon loss of Fas palmitoylation can be restored by inhibiting the lysosomal degradation pathway. We describe the modification of Fas by palmitoylation as a novel mechanism for the regulation of Fas expression through its ability to circumvent its degradation by lysosomal proteolysis.
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Haghshenas V, Fakhari S, Mirzaie S, Rahmani M, Farhadifar F, Pirzadeh S, Jalili A. Glycyrrhetinic Acid inhibits cell growth and induces apoptosis in ovarian cancer a2780 cells. Adv Pharm Bull 2014; 4:437-41. [PMID: 25364659 DOI: 10.5681/apb.2014.064] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 03/02/2014] [Accepted: 03/08/2014] [Indexed: 02/05/2023] Open
Abstract
PURPOSE Accumulating evidence indicates that glycyrrhizin (GZ) and its hydrolyzed metabolite 18-β glycyrrhetinic acid (GA) exhibit anti-inflammatory and anticancer activities. The objective of this study was to examine the in vitro cytotoxic activity of GA on human ovarian cancer A2780 cells. METHODS A2780 cells were cultured in RPMI1640 containing 10% fetal bovine serum. Cells were treated with different doses of GA and cell viability and proliferation were detected by dye exclusion and 3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assays. Apoptosis induction and expression of Fas and Fas ligand (FasL) were analyzed by flow cytometry. RESULTS We observed that GA decreases cell viability and suppressed cells proliferation in a dose-dependent manner as detected by dye-exclusion and XTT assayes. In addition, our flow cytometry data show that GA not only induces apoptosis in A2780 cells but also upregulates both Fas and FasL on these cells in a dose-dependent manner. CONCLUSION we demonstrate that GA causes cell death in A2780 cells by inducing apoptosis.
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Affiliation(s)
- Venus Haghshenas
- Department of Biochemistry, Research and Science, Islamic Azad University, Sanandaj, Iran
| | - Shohreh Fakhari
- Kurdistan Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Sako Mirzaie
- Department of Biochemistry, Sanandaj Branch, Islamic Azad University, Iran
| | - Mohammadreza Rahmani
- Kurdistan Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Fariba Farhadifar
- Department of Gynecology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Sara Pirzadeh
- Department of Biochemistry, Research and Science, Islamic Azad University, Sanandaj, Iran
| | - Ali Jalili
- Kurdistan Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Piwil2 inhibits keratin 8 degradation through promoting p38-induced phosphorylation to resist Fas-mediated apoptosis. Mol Cell Biol 2014; 34:3928-38. [PMID: 25113562 DOI: 10.1128/mcb.00745-14] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The piwi-like 2 (piwil2) gene is widely expressed in tumors and protects cells from apoptosis induced by a variety of stress stimuli. However, the role of Piwil2 in Fas-mediated apoptosis remains unknown. Here, we present evidence that Piwil2 inhibits Fas-mediated apoptosis. By a bacterial two-hybrid screening, we identify a new Piwil2-interacting partner, keratin 8 (K8), a major intermediate filament protein protecting the cell from Fas-mediated apoptosis. Our results show that Piwil2 binds to K8 and p38 through its PIWI domain and forms a Piwil2/K8/P38 triple protein-protein complex. Thus, Piwil2 increases the phosphorylation level of K8 Ser-73 and then inhibits ubiquitin-mediated degradation of K8. As a result, the knockdown of Piwil2 increases the Fas protein level at the membrane. In addition to our previous finding that Piwil2 inhibits the expression of p53 through the Src/STAT3 pathway, here we demonstrate that Piwil2 represses p53 phosphorylation through p38. Our present study indicates that Piwil2 plays a role in Fas-mediated apoptosis for the first time and also can affect p53 phosphorylation in tumor cells, revealing a novel mechanism of Piwil2 in apoptosis, and supports that Piwil2 plays an active role in tumorigenesis.
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Wang K, Zhu X, Zhang K, Zhu L, Zhou F. Investigation of gallic acid induced anticancer effect in human breast carcinoma MCF-7 cells. J Biochem Mol Toxicol 2014; 28:387-93. [PMID: 24864015 DOI: 10.1002/jbt.21575] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 04/08/2014] [Accepted: 04/30/2014] [Indexed: 11/11/2022]
Abstract
Gallic acid (GA), a polyhydroxylphenolic compound abundantly distributed in plants, fruits, and foods, has been reported to have various biological activities including an anticancer effect. In this study, we extensively investigated the anticancer effect of GA in human breast carcinoma MCF-7 cells. Our study indicated that treatment with GA resulted in inhibition of proliferation and induction of apoptosis in MCF-7 cells. Then, the molecular mechanism of GA's apoptotic action in MCF-7 cells was further investigated. The results revealed that GA induced apoptosis by triggering the extrinsic or Fas/FasL pathway as well as the intrinsic or mitochondrial pathway. Furthermore, the apoptotic signaling induced by GA was amplified by cross-link between the two pathways. Taken together, our findings may be useful for understanding the mechanism of action of GA on breast cancer cells and provide new insights into the possible application of such compound and its derivatives in breast cancer therapy.
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Affiliation(s)
- Ke Wang
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu Province, People's Republic of China.
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Association of the polymorphisms in the Fas/FasL promoter regions with cancer susceptibility: a systematic review and meta-analysis of 52 studies. PLoS One 2014; 9:e90090. [PMID: 24598538 PMCID: PMC3943814 DOI: 10.1371/journal.pone.0090090] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 01/28/2014] [Indexed: 01/31/2023] Open
Abstract
Fas and its ligand (FasL) play an important role in apoptosis and carcinogenesis. Therefore, the potential association of polymorphisms in the Fas (-670A>G, rs1800682; -1377G>A, rs2234767) and FasL (-844C>T, rs763110) with cancer risk has been widely investigated. However, all the currently available results are not always consistent. In this work, we performed a meta-analysis to further determine whether carriers of the polymorphisms in Fas and FasL of interest could confer an altered susceptibility to cancer. All relevant data were retrieved by PubMed and Web of Science, and 52 eligible studies were chosen for this meta-analysis. There was no association of the Fas -670A>G polymorphism with cancer risk in the pooled data. For the Fas -1377G>A and FasL -844C>T polymorphisms, results revealed that the homozygotes of -1377A and -844C were associated with elevated risk of cancer as a whole. Further stratified analysis indicated markedly increased risk for developing breast cancer, gastric cancer, and esophageal cancer, in particular in Asian population. We conclude that carriers of the Fas-1377A and the FasL -844C are more susceptible to the majority of cancers than non-carriers.
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Wang X, Xing GH, Fan CC. Association between the FAS rs2234767G/A polymorphism and cancer risk: a systematic review and meta-analysis. DNA Cell Biol 2014; 33:320-7. [PMID: 24568648 DOI: 10.1089/dna.2013.2273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Abnormal regulation of apoptosis can lead to carcinogenesis. Single nucleotide polymorphisms in apoptotic genes have been associated with cancer risk, such as the FAS rs2234767G/A polymorphism, which alters transcription of the FAS promoter. Downregulation of FAS, with resultant cellular resistance to death signals, has been found in many cancers. However, the association between the FAS rs2234767G/A polymorphism and cancer risk is still controversial. Here, we performed a meta-analysis including 41 articles (44 case-control studies, 17,814 cases and 24,307 controls) identified from PubMed and Chinese language (CNKI and WanFang) databases related to cancer susceptibility and the FAS rs2234767G/A polymorphism. We used odds ratios (ORs) and 95% confidence intervals (CIs) to assess the strength of the associations. We found that the rs2234767 G-allele was a protective factor for cancer risk (GG vs. AA: OR=0.88, 95% CI=0.79-0.98; GG+GA vs. AA: OR=0.87, 95% CI=0.79-0.96). Similar associations were detected in the "source of control", ethnicity, and cancer type subgroups. Further studies on a larger sample size and considering gene-environment interactions should be conducted to confirm the role of FAS polymorphisms, especially rs2234767G/A, in cancer risk.
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Affiliation(s)
- Xin Wang
- 1 Department of Respiration, General Hospital of Jinan Military Command , Jinan, People's Republic of China
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Zhong-Xing Z, Yuan-Yuan M, Hai Zhen M, Jian-Gang Z, Li-Feng Z. FAS-1377 G/A (rs2234767) polymorphism and cancer susceptibility: a meta-analysis of 17,858 cases and 24,311 controls. PLoS One 2013; 8:e73700. [PMID: 24014103 PMCID: PMC3754923 DOI: 10.1371/journal.pone.0073700] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Accepted: 07/19/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Disruption of apoptosis has been implicated in carcinogenesis. Specifically, various single-nucleotide polymorphisms (SNPs) in apoptotic genes, such as FAS-1377 G/A SNP, have been associated with cancer risk. FAS-1377 G/A SNP has been shown to alter FAS gene promoter transcriptional activity. Down-regulation of FAS and cell death resistance is key to many cancers, but an association between FAS-1377 G/A SNP and cancer risk is uncertain. Therefore, we conducted a meta-analysis of the current literature to clarify this relationship. METHODOLOGY/PRINCIPAL FINDINGS From PubMed and Chinese language (CNKI and WanFang) databases, we located articles published up to March 5, 2013, obtaining 44 case-control studies from 41 different articles containing 17,858 cases and 24,311 controls based on search criteria for cancer susceptibility related to the FAS gene -1377 G/A SNP. Odds ratios (ORs) and 95% confidence intervals (CI) revealed association strengths. Data show that the -1377 G allele was protective against cancer risk. Similar associations were detected in "source of control," ethnicity and cancer type subgroups. Lower cancer risk was found in both smokers with a GG+GA genotype and in non-smokers with the GG+GA genotype, when compared to smokers and nonsmokers with the AA genotype. Males carrying the -1377G allele (GG+GA) had lower cancer incidence than those with the AA genotype. Individuals who carried both FAS-1377(GG+GA)/FASL-844(TT+TC) genotypes appeared to have lower risk of cancer than those who carried both FAS-1377 AA/FASL-844 CC genotypes. CONCLUSIONS/SIGNIFICANCE The FAS-1377 G/A SNP may decrease cancer risk. Studies with larger samples to study gene-environment interactions are warranted to understand the role of FAS gene polymorphisms, especially -1377 G/A SNP, in cancer risk.
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Affiliation(s)
- Zhou Zhong-Xing
- Department of Urology, The Affiliated Changzhou No 2. Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Mi Yuan-Yuan
- Department of Urology, The Third Affiliated Hospital of Nantong University, Wuxi, Jiangsu, China
| | - Ma Hai Zhen
- Department of Operating Room, The Third Affiliated Hospital of Nantong University, Wuxi, Jiangsu, China
| | - Zou Jian-Gang
- Department of Urology, The Affiliated Changzhou No 2. Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Zhang Li-Feng
- Department of Urology, The Affiliated Changzhou No 2. Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
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Park EY, Park JB. Dose- and time-dependent effect of high glucose concentration on viability of notochordal cells and expression of matrix degrading and fibrotic enzymes. INTERNATIONAL ORTHOPAEDICS 2013; 37:1179-86. [PMID: 23503638 DOI: 10.1007/s00264-013-1836-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 02/15/2013] [Indexed: 11/28/2022]
Abstract
PURPOSE Diabetes mellitus is an important aetiological factor in intervertebral disc degeneration. The disappearance of notochordal cells in the nucleus pulposus is thought to be the starting point for intervertebral disc degeneration. A cellular effect of diabetes mellitus on apoptosis of notochordal cells and intervertebral disc degeneration has been recently reported. However, how the duration and severity of diabetes mellitus affects viability of notochordal cells and intervertebral disc degeneration is still unknown . METHODS Rat notochordal cells were isolated, cultured, and placed in either 10 % foetal bovine serum (FBS) (normal control) or 10 % FBS plus three different high glucose concentrations (0.1 M, 0.2 M, and 0.4 M) (experimental conditions) for one, three, five and seven days, respectively. We identified and quantified the degree of proliferation and apoptosis, caspase activities, and cleavages of Bid and cytochrome-c. In addition, we examined the cells for expression of matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs). RESULTS Each three high glucose concentrations significantly decreased proliferation and increased apoptosis of notochordal cells from culture days one to seven in a dose-dependent manner. Compared with those of 10 % FBS, caspase-9 and -3 activities and cleavage of Bid and cytochrome-c were significantly increased in each three high glucose concentrations, accompanied by increased expression of MMP-1, -2, -3, -7, -9, and -13 and TIMP-1 and -2. CONCLUSIONS High glucose concentration significantly decreased proliferation and increased apoptosis of notochordal cells via the intrinsic pathway with dose- and time-dependent effects. We also found that expression of MMPs and TIMPs was increased with dose- and time-dependent effects. Therefore, these results suggest that aggressive glucose control from an early stage of diabetes mellitus should be recommended to prevent or limit intervertebral disc degeneration.
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Affiliation(s)
- Eun-Young Park
- Orthopaedic Surgery, Uijongbu St. Mary's Hospital , The Catholic University of Korea School of Medicine, Seoul, South Korea
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31
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Tian J, Pan F, Li J, Ma Y, Cen H, Pan HF, Pan YY, Ye DQ. Association between the FAS/FASL polymorphisms and gastric cancer risk: a meta-analysis. Asian Pac J Cancer Prev 2012; 13:945-51. [PMID: 22631677 DOI: 10.7314/apjcp.2012.13.3.945] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE FAS/FASL gene promoter polymorphisms have been repeatedly associated with gastric cancer risk, but findings are inconclusive across studies. To address a more precise estimation of the relationship, a meta-analysis was performed. METHODS Data were collected from the Pubmed, Medline and EMBASE databases, with the last report up to 1 December, 2011. Crude ORs with 95% CIs were used to assess the strength of the association by (1) the additive, (2) the codominant, (3) the dominant, and (4) the recessive models. RESULTS A total of seven studies, including six studies on FAS -1377G>A polymorphism, five studies on FAS -670A>G polymorphism, and six studies on FASL -844T>C polymorphism, were identified in the current meta-analysis. Overall, an association of FAS -1377G>A (AA versus GG: OR = 1.313, 95% CI = 1.045-1.650, Ph = 0.347, I2 = 10.8) and FASL -844T>C (CC versus TT: OR = 1.352, 95% CI = 1.043-1.752, Ph = 0.461, I2 = 0.0) polymorphisms with gastric cancer was found in the codominant model. However, we did not detect any association between gastric cancer and the FAS -670A>G polymorphism. In the subgroup analysis by ethnicity, similar elevated risks were also observed in Asian population for FAS -1377G>A (AA versus GG: OR = 1.309, 95% CI = 1.041- 1.646, Ph = 0.240, I2 = 27.3) and FASL -844T>C (CC versus TT: OR = 1.420, 95% CI = 1.081-1.865, Ph = 0.524, I2 = 0.0) polymorphisms. CONCLUSIONS This meta-analysis indicated that FAS -1377G>A and FASL -844T>C polymorphisms might be associated with gastric cancer risk.
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Affiliation(s)
- Jing Tian
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China
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DNA-damaging drug-induced apoptosis sensitized by N-myc in neuroblastoma cells. Cell Biol Int 2012; 36:331-7. [PMID: 21929510 DOI: 10.1042/cbi20110231] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Neuroblastoma is one of the most common solid tumours in children (8-10% of all malignancies). Over 22% of cases have N-myc amplification associated with aggressively growing neuroblastomas. Oncogene-induced sensitization of cells to apoptosis is an important mechanism for suppression of tumorigenesis. Tumour suppressors often play a critical role in linking oncogenes to apoptotic machinery. For example, activated p53 then targets both intrinsic and extrinsic pathways to promote apoptosis through transcription-dependent and -independent mechanisms. Understanding of the involved mechanisms has important clinical implications. We have employed DNA-damaging drug-induced apoptosis sensitized by oncogene N-myc as a model. DNA damaging drugs trigger high levels of p53, leading to caspase-9 activation in neuroblastoma cells. Inactivation of p53 protects cells from drug-triggered apoptosis sensitized by N-myc. These findings thus define a molecular pathway for mediating DNA-damaging drug-induced apoptosis sensitized by oncogene, and suggest that inactivation of p53 or other components of this apoptotic pathway may confer drug resistance in neuroblastoma cells. The data also suggests that inactivation of apoptotic pathways through co-operating oncogenes may be necessary for the pathogenesis of neuroblastoma with N-myc amplification.
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Wang W, Zheng Z, Yu W, Lin H, Cui B, Cao F. Polymorphisms of the FAS and FASL genes and risk of breast cancer. Oncol Lett 2011; 3:625-628. [PMID: 22740964 DOI: 10.3892/ol.2011.541] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Accepted: 12/13/2011] [Indexed: 02/06/2023] Open
Abstract
FAS and its ligand FASL are crucial in apoptotic cell death. Loss of FAS and gain of aberrant FASL expression are common features of malignant transformation. This study was designed to investigate whether the functional polymorphisms of FAS -1377G/A (rs2234767) and FASL -844T/C (rs763110) affect the risk of developing breast cancer. Genotypes were analyzed by a polymerase chain reaction-restriction fragment length polymorphism assay in 436 breast cancer patients and 496 healthy controls. In this study, as compared to the wild-type homozygote and heterozygote, the distribution of the FAS -1377GG, GA and AA genotypes among breast cancer patients were significantly different from those among healthy controls (P=0.011), with the AA genotype being more prevalent among patients than the controls (P=0.003). Similarly, the frequencies of the FASL -844TT, TC and CC genotypes also significantly differed among breast cancer patients and healthy controls (P<0.001), with the CC genotype being significantly over-represented in breast cancer patients compared with the controls (P<0.001). In the unconditional logistic regression model following adjustment for age, the subjects carrying the FAS -1377AA genotype had a 1.75-fold increased risk [95% confidence interval (CI), 1.13-2.69] for development of breast cancer compared with patients carrying the GG genotype. Similarly, in the recessive model, the FASL -844CC genotype significantly increased the risk of breast cancer with an odds ratio (OR) of 1.92 (95% CI 1.46-2.54) compared with the TT or TT + TC genotypes. Our results suggest that functional polymorphisms in the death pathway genes FAS and FASL significantly contribute to the occurrence of breast cancer.
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Affiliation(s)
- Wenmin Wang
- Department of Surgical Oncology, Taizhou Hospital, Wenzhou Medical College, Linhai, Zhejiang 317000, P.R. China
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Li JF, Ai HX, Zhang J, Du MX, Zhang Z, Zhang JX, Zhang SQ. Molecular cloning, functional characterization and phylogenetic analysis of TRAIL in Japanese pufferfish Takifugu rubripes. JOURNAL OF FISH BIOLOGY 2011; 79:747-760. [PMID: 21884110 DOI: 10.1111/j.1095-8649.2011.03058.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
In this study, the complementary DNA (cDNA) of Japanese pufferfish Takifugu rubripes tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) was cloned by reverse-transcription PCR. The open reading frame of the TRAIL consisted of 870 bases. The deduced amino-acid sequence of the TRAIL showed a high homology with the sequences of other teleosts. Recombinant soluble TRAIL was fused with a small ubiquitin-related modifier gene to enhance the soluble expression level in Escherichia coli BL21 (DE3). In vitro, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT) assay indicated that the purified soluble TRAIL was able to induce apoptosis of Jurkat and HeLa cells in a dose-dependent manner.
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Affiliation(s)
- J F Li
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, Life Science College, Nanjing Normal University, Nanjing, 210046 Jiangsu, People's Republic of China
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Fathi M, Amirghofran Z, Shahriari M. Soluble Fas and Fas ligand and prognosis in children with acute lymphoblastic leukemia. Med Oncol 2011; 29:2046-52. [PMID: 21528407 DOI: 10.1007/s12032-011-9965-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Accepted: 04/18/2011] [Indexed: 01/17/2023]
Abstract
The soluble forms of Fas and its ligand (sFas and sFasL) correlate with disease progression in various malignancies. We compared serum levels of sFas and sFasL in children with acute lymphoblastic leukemia and healthy children to determine the prognostic significance of these molecules. Serum levels of sFas and sFasL were measured with an enzyme-linked immunosorbent assay in 48 patients with newly diagnosed childhood acute lymphoblastic leukemia and 38 healthy children. Cut-off values of sFas and sFasL levels were based on their levels in controls. Clinical and laboratory characteristics were recorded on admission. The mean serum concentration of sFas was 243 ± 40 pg/mL in patients and 238 ± 29 pg/mL in controls. Serum levels of sFasL were 4.33 ± 0.25 ng/mL in patients and 4.27 ± 0.11 ng/mL in controls. Neither difference was significant. Based on the cut-off value, 12.5% of the patients were positive for sFas, and 16.6% were positive for sFasL. Survival was significantly longer in sFasL-positive patients (394 ± 69.6 vs. 254 ± 24.3 days) and the duration of complete remission was also longer (380 ± 65.0 vs. 246 ± 26.0 days) than in sFasL-negative patients (P < 0.02), indicating the important role of this molecule in the response to therapy. Higher sFas levels were associated with hepatosplenomegaly (P < 0.047). In conclusion, sFasL positivity was associated with a favorable outcome in ALL patients.
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Affiliation(s)
- Mina Fathi
- Department of Immunology, Shiraz Medical School, Medicinal and Natural Products Chemistry Research Center and Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, 71345-1798 Shiraz, Iran.
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Bussuan LAM, Fagundes DJ, Marks G, Bussuan PM, Teruya R. The role of Fas ligand protein in the oxidative stress induced by azoxymethane on crypt colon of rats. Acta Cir Bras 2010; 25:501-6. [DOI: 10.1590/s0102-86502010000600008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Accepted: 06/21/2010] [Indexed: 11/21/2022] Open
Abstract
PURPOSE: To study the protein Fas ligand (FasL) on the expression of apoptosis, using a model of oxidative stress induced by azoxymethane (AOM), in the crypt of colon in rats. METHODS: Wistar rats (n=14) were assigned into two groups: control (n=7) and AOM (n=7). A single subcutaneous administration of AOM (5mg/kg) or saline solution was performed at the beginning of third week and after three hours samples of proximal colon were collected. The expression of FasL was quantified (Software ImageLab) in percentage of areas in the top, base and all crypt. Results were expressed as mean ± sd (Shapiro-Wilks test and t Student test) (p < 0.05). RESULTS: In the animals of CG there was no significant difference between the FasL expression of the top (10.75±3.33) and basal (11.14±3.53) colon crypt (p=0.34293740). In the animals of AOM there was no significant difference between the FasL expression of the top (8.86±4.19) and basal (8.99±4.08) colon crypt (p=0.78486003). In the animals of CG (10.95±3.43) and AOM (8.92±4.13) there was a significant difference of the FasL expression (p=0.026466821). A significantly decrease on the FasL expression was observed in the animals of CG (10.75±3.33) and AOM (8.86±4.19) in the top crypt (p=0.00003755*). A significant decrease was also observed in the animals of CG (11.14±3.53) and AOM (8.99±4.08) in the basal colon crypt (p=0.00000381**). CONCLUSION: Azoxymethane induce the oxidative stress and the significantly decrease of FasL expression, although there is no significant difference between basal and top of colon crypt linked to consumption-activation of Fas ligand.
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Cao Y, Miao XP, Huang MY, Deng L, Lin DX, Zeng YX, Shao JY. Polymorphisms of death pathway genes FAS and FASL and risk of nasopharyngeal carcinoma. Mol Carcinog 2010; 49:944-50. [PMID: 20842669 DOI: 10.1002/mc.20676] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The FAS receptor/ligand system is a key regulator of apoptotic cell death and corruption of this signaling pathway has been shown to participate in carcinogenesis. Functional polymorphisms in the FAS (FAS -1377G/A) and FASL (FASL -844T/C) genes alter their transcriptional activity. Therefore, we examined the association between these polymorphisms and the risk of developing nasopharyngeal carcinoma (NPC). FAS -1377G/A and FASL -844T/C genotypes were determined by PCR-based RFLP analysis in 582 patients with NPC and 613 frequency-matched controls. We observed a significantly increased risk of NPC associated with the FAS -1377AA genotype [odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.21-2.35] compared with the FAS -1377 GG genotype. In addition, elevated NPC risk was also found among subjects carrying both FAS -1377AA and FASL -844CC genotypes compared with both FAS -1377GG and FASL -844CT or -844TT, the OR was 2.39 (95% CI = 1.50-3.79). After stratification by smoking status, heavy smokers (≥15 pack-years) carrying FAS -1377AA genotype had an increased risk of NPC compared with FAS -1377GG genotype (OR = 3.48, 95% CI = 1.66-7.30). Furthermore, we observed a statistically significant interaction between the two polymorphisms and heavy smoking status (OR = 5.92, 95% CI = 1.91-18.3). Our study provides the first evidence that functional FAS -1377 G/A and FASL -844 T/C polymorphisms are associated with the risk of NPC, and this association is especially noteworthy in tobacco smokers.
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Affiliation(s)
- Yun Cao
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, PR China
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Lei D, Sturgis EM, Wang LE, Liu Z, Zafereo ME, Wei Q, Li G. FAS and FASLG genetic variants and risk for second primary malignancy in patients with squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev 2010; 19:1484-91. [PMID: 20501759 PMCID: PMC2883025 DOI: 10.1158/1055-9965.epi-10-0030] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Single-nucleotide polymorphisms in the promoter region of the FAS and FASLG may alter the transcriptional activity of these genes. We therefore investigated the association between the FAS and FASLG polymorphisms and risk for second primary malignancy (SPM) after index squamous cell carcinoma of the head and neck (SCCHN). METHODS We used log-rank test and Cox proportional hazard models to assess the association of the four single-nucleotide polymorphisms (FAS -1377 G > A, FAS -670 A > G, FASLG -844 C > T, and FASLG -124 A > G) with the SPM-free survival and SPM risk among 1,286 incident SCCHN patients. RESULTS Compared with patients having the FAS -670 AA or the FASLG -844 CC genotypes, the patients having variant genotypes of FAS -670 AG/GG or FASLG -844 CT/TT genotypes had significantly increased risk for SPM, respectively. A trend for significantly increased SPM risk with increasing number of risk genotypes of the four polymorphisms was observed in a dose-response manner. Moreover, the patients with three or four combined risk genotypes had an approximately 1.8- or 2.5-fold increased risk for developing SPM compared with patients with zero or one risk genotypes, respectively. CONCLUSIONS Our results suggest a modestly increased risk for SPM after index SCCHN with FAS -670 A > G and FASLG -844 C > T polymorphisms and an even greater risk for SPM with multiple combined FAS and FASLG risk genotypes. IMPACT The FAS and FASLG polymorphisms may serve as a susceptible marker for SCCHN patients at high SPM risk.
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Affiliation(s)
- Dapeng Lei
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
- Department of Otolaryngology, Qilu Hospital, Shandong University; Key Laboratory of Otolaryngology, Ministry of Health, P.R. China, Jinan, Shandong 250012, P. R. China
| | - Erich M Sturgis
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Li-E Wang
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhensheng Liu
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Mark E Zafereo
- Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX, 77030
| | - Qingyi Wei
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Guojun Li
- Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
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Abstract
The primate-specific gene family, POTE, is expressed in many cancers but only in a limited number of normal tissues (testis, ovary, prostate). The 13 POTE paralogs are dispersed among 8 human chromosomes. They evolved by gene duplication and remodeling from an ancestral gene, Ankrd26, recently implicated in controlling body size and obesity. In addition, several POTE paralogs are fused to an actin retrogene producing POTE-actin fusion proteins. The biological function of the POTE genes is unknown, but their high expression in primary spermatocytes, some of which are undergoing apoptosis, suggests a role in inducing programmed cell death. We have chosen Hela cells as a model to study POTE function in human cancer, and have identified POTE-2alpha-actin as the major transcript and the protein it encodes in Hela cells. Transfection experiments show that both POTE-2alpha-actin and POTE-2gammaC are localized to actin filaments close to the inner plasma membrane. Transient expression of POTE-2alpha-actin or POTE-2gammaC induces apoptosis in Hela cells. Using wild-type and mutant mouse embryo cells, we find apoptosis induced by over-expression of POTE-2gammaC is decreased in Bak ( -/- ) or Bak ( -/- ) Bax ( -/- ) cells indicating POTE is acting through a mitochondrial pathway. Endogenous POTE-actin protein levels but not RNA levels increased in a time dependent manner by stimulation of death receptors with their cognate ligands. Our data indicates that the POTE gene family encodes a new family of proapoptotic proteins.
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Affiliation(s)
- Xiu Fen Liu
- National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA
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Kleinberg L, Davidson B. Cell survival and apoptosis-related molecules in cancer cells in effusions: A comprehensive review. Diagn Cytopathol 2009; 37:613-24. [DOI: 10.1002/dc.21095] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Jung SN, Park IJ, Kim MJ, Kang I, Choe W, Kim SS, Ha J. Down-regulation of AMP-activated protein kinase sensitizes DU145 carcinoma to Fas-induced apoptosis via c-FLIP degradation. Exp Cell Res 2009; 315:2433-41. [DOI: 10.1016/j.yexcr.2009.05.018] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2008] [Revised: 05/14/2009] [Accepted: 05/19/2009] [Indexed: 11/29/2022]
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Park JY, Lee WK, Jung DK, Choi JE, Park TI, Lee EB, Cho S, Park JY, Cha SI, Kim CH, Kam S, Jung TH, Jheon S. Polymorphisms in theFASandFASLGenes and Survival of Early Stage Non–small Cell Lung Cancer. Clin Cancer Res 2009; 15:1794-800. [DOI: 10.1158/1078-0432.ccr-08-1770] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Steinmann C, Landsverk ML, Barral JM, Boehning D. Requirement of inositol 1,4,5-trisphosphate receptors for tumor-mediated lymphocyte apoptosis. J Biol Chem 2008; 283:13506-9. [PMID: 18364356 DOI: 10.1074/jbc.c800029200] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Tumor cells strategically down-regulate Fas receptor expression to evade immune attack and up-regulate expression of Fas ligand to promote apoptosis of infiltrating T lymphocytes. Many pathways leading to apoptotic cell death require calcium release from inositol 1,4,5-trisphosphate receptors (IP3Rs). Here, we show that Fas-dependent killing of Jurkat T lymphoma cells by SW620 colon cancer cells requires calcium release from IP3R. General suppression of IP3R signaling significantly reduced SW620-mediated Jurkat cell apoptosis. Significantly, a specific inhibitor of apoptotic calcium release from IP3R strongly blocked lymphocyte apoptosis. Thus, selective pharmacological targeting of apoptotic calcium release from IP3R may enhance tumor cell immunogenicity.
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Affiliation(s)
- Camia Steinmann
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-0620, USA
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Dong HP, Kleinberg L, Silins I, Flørenes VA, Tropé CG, Risberg B, Nesland JM, Davidson B. Death receptor expression is associated with poor response to chemotherapy and shorter survival in metastatic ovarian carcinoma. Cancer 2008; 112:84-93. [PMID: 17985388 DOI: 10.1002/cncr.23140] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Death receptors mediate both apoptosis and survival in cancer cells. The authors analyzed death receptor expression in metastatic ovarian carcinoma. METHODS Viable tumor cells in ovarian carcinoma effusions (n = 95) were analyzed for DR4, DR5, Fas, TNFR1, and TNFR2 expression using flow cytometry. Results were analyzed for association with clinicopathologic parameters, chemotherapy response, and survival. RESULTS DR4, DR5, and Fas were expressed by the majority of specimens, with less frequent expression of TNFR1 and TNFR2. DR4 (P = .005) and TNFR2 (P = .041) expression was higher in FIGO stage IV compared with stage III tumors. Effusions from patients who responded poorly to chemotherapy administered at disease recurrence had significantly higher DR4 (P = .006), DR5 (P = .01), and Fas (P = .001) expression. In univariate survival analysis, higher DR4 expression in viable cells correlated with poor overall (P = .0352) and progression-free (P = .0411) survival. DR4 expression was found to be an independent predictor of overall (P = .008) and progression-free (P = .003) survival. CONCLUSIONS The authors have presented the first evidence of death receptor coexpression in ovarian carcinoma effusions. The association of death receptor expression in effusions with advanced stage, poor response to chemotherapy, and shorter survival suggests that these molecules are linked to an aggressive clinical course in metastatic ovarian carcinoma.
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Affiliation(s)
- Hiep Phuc Dong
- Pathology Clinic, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
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Abstract
Interference with the innate apoptotic activity is a hallmark of neoplastic transformation and tumor formation. Modulation of the apoptotic cascade has been proposed as a new approach for the treatment of cancer. In this chapter, we discuss the role of apoptosis in ovarian cancer and the use of phenoxodiol as a model for the regulation of apoptosis and potential use as chemosensitizer for chemoresistant ovarian cancer cells.
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Affiliation(s)
- Gil Mor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
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Li H, Cai X, Fan X, Moquin B, Stoicov C, Houghton J. Fas Ag-FasL coupling leads to ERK1/2-mediated proliferation of gastric mucosal cells. Am J Physiol Gastrointest Liver Physiol 2008; 294:G263-75. [PMID: 17991709 DOI: 10.1152/ajpgi.00267.2007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
When cells within the gastric mucosa progress from metaplasia to dysplasia to cancer, they acquire a Fas Ag apoptosis-resistant phenotype. It is unusual to completely abolish the pathway, suggesting other forms of Fas Ag signaling may be important or even necessary for gastric cancer to progress. Little is known about alternate signaling of the Fas Ag pathway in gastric mucosal cells. Using a cell culture model of rat gastric mucosal cells, we show that gastric mucosal cells utilize a type II signaling pathway for apoptosis. Under conditions of low receptor stimulation or under conditions where apoptosis is blocked downstream of the death-inducing signal complex, Fas Ag signaling proceeds toward proliferative signaling. Under conditions favoring proliferative signaling, cFLIP is recruited to the Fas-associated death domain-like interleukin-1beta-converting enzyme at the death-inducing signal complex and activates ERK1/2. ERK1/2 in turn activates NF-kappaB. ERK1/2 stimulates proliferation, whereas NF-kappaB activation results in upregulation of the antiapoptotic protein survivin, further promoting proliferation over apoptosis. These results suggest that factors that inhibit apoptosis confer a growth advantage to the cells beyond the survival advantage of avoiding apoptosis and in effect convert the Fas Ag signaling pathway from a tumor suppressor to a tumor promoter.
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Affiliation(s)
- Hanchen Li
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Zhang H, Sun XF, Synnerstad I, Rosdahl I. Importance of FAS-1377, FAS-670, and FASL-844 polymorphisms in tumor onset, progression, and pigment phenotypes of Swedish patients with melanoma: a case-control analysis. Cancer J 2007; 13:233-7. [PMID: 17762757 DOI: 10.1097/ppo.0b013e318046f214] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE Human skin melanoma at later stages usually has an extremely poor prognosis. It is of importance to search for biologic markers to identify and monitor individuals at risk for melanoma for early diagnosis and to avoid tumor progression. The FAS gene and its natural ligand (FASL) gene initiate the death signal cascade, playing a central role in the apoptotic signaling pathway and tumor growth and metastasis. PATIENTS AND METHODS In this study, we analyzed polymorphisms in 229 patients with melanoma and 351 age- and gender-matched tumor-free individuals. Genomic DNAs were isolated from mononuclear cells in peripheral vein blood, and the polymorphisms were examined with polymerase chain reaction-restriction fragment length polymorphism techniques. Frequency in distribution of the polymorphisms was compared between the patients with melanoma and the healthy control subjects, and associations with patients' pigment phenotypes, age at diagnosis, and melanoma characteristics were analyzed. RESULTS AND CONCLUSIONS The FAS-1377, FAS-670, and FASL-844 polymorphisms were not found to be markers of melanoma risk (P > 0.05). In patients with melanoma, frequencies of the FAS-1377, FAS-670, and FASL-844 polymorphisms were different between the patients aged <50 and > or =50 years (P < or = 0.025, P < or = 0.025, and P < or = 0.01). Moreover, the FAS-670 polymorphism correlated with tumor Breslow thickness (P < or = 0.01) and Clark level (P < or = 0.001) and was associated with tumors developing in sun-exposed locations (P < or = 0.001). FAS and FASL were not markers for melanoma risk but might be important in the development and progression of sun-induced melanoma independently of skin type.
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Affiliation(s)
- Hong Zhang
- Division of Dermatology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
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Park JB, Lee JK, Cho ST, Park EY, Riew KD. A biochemical mechanism for resistance of intervertebral discs to metastatic cancer: Fas ligand produced by disc cells induces apoptotic cell death of cancer cells. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2007; 16:1319-24. [PMID: 17684774 PMCID: PMC2200753 DOI: 10.1007/s00586-007-0463-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2007] [Accepted: 07/23/2007] [Indexed: 11/24/2022]
Abstract
Metastatic spinal cancer is characterized by the maintenance of normal disc structure until the vertebral body is severely destroyed by cancer cells. Anatomic features of the discs have been thought to be the main factor which confer the discs their resistance to metastatic cancer. However, little is known about the biochemical mechanism to prevent or attenuate the local infiltration of cancer cells into the discs. The purpose of this study was to investigate whether Fas ligand (FasL) produced by disc cells can kill Fas-bearing breast cancer cells by Fas and FasL interaction. Two human breast cancer cells (MCF-7 and MDA-MB-231) were obtained and cultured (1 x 10(6) cells/well), and the expression of Fas was investigated by western blot analysis. Annulus fibrosus cells were isolated and cultured, and the presence of FasL was quantified in the supernatants of three different numbers of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) by ELISA assay. The MCF-7 and MDA-MB-231 cancer cells were cultured with supernatants of annulus fibrosus cells for 48 h. As controls, MCF-7 and MDA-MB-231 cancer cells were also cultured by themselves for 48 h. Finally, we determined and quantified the apoptosis rates of MCF-7 and MDA-MB-231 cancer cells by Annexin V-FITC and PI and TUNEL at 48 h, respectively. The expression of Fas was identified in MCF-7 and MDA-MB-231 cancer cells. The mean concentrations of FasL in supernatants of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) were 10.8, 29.6, and 56.4 pg/mL, respectively. After treatment with the supernatant of three different numbers of annulus fibrosus cells, the mean apoptosis rate of MCF-7 cancer cells was increased (2.8%, P < 0.01; 6.7%, P < 0.001; 31.0%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (1.1%). The mean apoptosis rate of MDA-MB-231 cancer cells was also increased (5.7%, P < 0.01; 11.1%, P < 0.001; 25.3%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (2.1%). TUNEL also demonstrated direct evidence of apoptosis of MCF-7 and MDA-MB-231 cancer cells. Our results demonstrate that Fas-bearing cancer cells undergo apoptosis by FasL produced by disc cells, which may be considered as a potential biochemical explanation for the disc's resistance to metastatic cancer.
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Affiliation(s)
- Jong-Beom Park
- Department of Orthopaedic Surgery, The Catholic University of Korea School of Medicine, Uijongbu-si, Kyunggi-do 480-717, South Korea.
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Park JB, Lee JK, Park EY, Riew KD. Fas/FasL interaction of nucleus pulposus and cancer cells with the activation of caspases. INTERNATIONAL ORTHOPAEDICS 2007; 32:835-40. [PMID: 17589843 PMCID: PMC2898961 DOI: 10.1007/s00264-007-0410-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Revised: 05/17/2007] [Accepted: 05/17/2007] [Indexed: 10/23/2022]
Abstract
Spinal metastatic disease is characterised by the preservation of the intervertebral disc structure, even after severe destruction of the vertebral body by neoplastic tissues. Anatomical features of the discs are thought to be the reason for the disc's resistance to metastatic cancer. However, little is known about the biochemical mechanism to prevent or attenuate the local invasion of cancer cells into the discs. The purpose of this study was to investigate the hypothesis that Fas ligand (FasL) produced by nucleus pulposus cells can kill Fas-expressing cancer cells infiltrating into the discs by the activation of caspases. Fas-expressing MCF-7 breast cancer cells were cultured with (experimental group) and without (control group) supernatant of nucleus pulposus cells containing FasL (50 pg/ml) for 48 h. The apoptosis of MCF-7 breast cancer cells was determined by the TUNEL technique. In addition, the activation of caspase-8, -9 and -3 was investigated by Western blot analysis. After treatment with supernatant of the nucleus pulposus cells containing FasL, the apoptosis of MCF-7 breast cancer cells was significantly increased, along with the activation of caspase-8, -9 and -3 compared with those of the control group. Our results suggest that the Fas/FasL interaction of nucleus pulposus and cancer cells might be a potential mechanism of the disc's resistance to metastatic cancer.
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Affiliation(s)
- Jong-Beom Park
- Department of Orthopaedic Surgery, Uijeongbu St. Mary's Hospital, The Catholic University of Korea School of Medicine, 65-1 Kumho-dong, Uijeongbu-si, Kyunggi-do, 480-717, South Korea.
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