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Lyu B, Niu K, Anderson D, Feng Q, Song Q. G-quadruplex structures in 16S rRNA regions correlate with thermal adaptation in prokaryotes. Nucleic Acids Res 2025; 53:gkaf042. [PMID: 39883013 PMCID: PMC11780868 DOI: 10.1093/nar/gkaf042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 01/05/2025] [Accepted: 01/16/2025] [Indexed: 01/31/2025] Open
Abstract
G-quadruplex (G4) structure is a nucleic acid secondary structure formed by guanine-rich sequences, playing essential roles in various biological processes such as gene regulation and environmental stress adaptation. Although prokaryotes growing at high temperatures have higher GC contents, the pattern of G4 structure associated with GC content variation in thermal adaptation remains elusive. This study analyzed 681 bacterial genomes to explore the role of G4 structures in thermal adaptation. Our findings revealed a strong positive correlation between G4 patterns in the region encoding 16S rRNA genes and optimal growth temperatures (Topt), whereas genomic GC content and G4 patterns did not show significant correlations with Topt. Evolutionary analysis showed distinctive differences in G4 stability between Thermotoga (Topt ≥ 80°C) and Pseudothermotoga (60°C ≤ Topt < 80°C) species, with Thermotoga species exhibiting higher G4 stability, indicating stronger selective pressure for G4 structures. In vitro spectroscopy analysis showed that base mutations at key sites resulted in the absence of G4 structural stability and integrity in Thermotoga compared to Pseudothermotoga. Collectively, this study suggests that the G4 structures in 16S rRNA regions emerged as key indicators of thermal adaptation in prokaryotes and contributes to our understanding of the molecular basis of evolutionary adaptation.
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Affiliation(s)
- Bo Lyu
- Division of Plant Science and Technology, University of Missouri, Columbia, MO 65211, United States
| | - Kangkang Niu
- Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology, School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Deborah Anderson
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211, United States
| | - Qili Feng
- Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology, School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Qisheng Song
- Division of Plant Science and Technology, University of Missouri, Columbia, MO 65211, United States
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Bisoi A, Majumdar T, Sarkar S, Singh PC. Flanking Effect on the Folding of Telomeric DNA Sequences into G-Quadruplex Induced by Antimalarial Drugs. J Phys Chem B 2025; 129:835-843. [PMID: 39807525 DOI: 10.1021/acs.jpcb.4c05133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
The folding of the guanine repetitive region in the telomere unit into G-quadruplex (G4) by drugs has been suggested as an alternative approach for cancer therapy. Hydroxychloroquine (HCQ) and chloroquine (CQ) are two important drugs in the trial stage for cancer. Both drugs can induce the folding of telomere-guanine-rich sequences into G4 even in the absence of salt. However, the guanine repetitive telomeric sequences are always flanked by other nucleobases at both the terminal (5' or 3') that can affect the drug-induced folding pathways and stability of the G4 significantly. Hence, in this study, the HCQ and CQ drug-induced folding of the guanine repetitive telomeric sequences into G4 and its stability by varying the chemical nature, number, and positions of the flanking nucleobases has been explored using several biophysical techniques and docking studies. It has been found that the drug-induced folding of telomere with single flanking nucleobases is similar to that without flanking nucleobases irrespective of the chemical nature and position of the flanking nucleobase. However, the propensity of the folding and the stability of the telomeric G4 induced by drugs decrease significantly with the increase of the flanking nucleobases more than one of any chemical nature and position. The data suggest that the number of flanking nucleobases rather than their chemical nature and location is a critical factor in the folding of the telomere into G4 induced by both drugs. Further, it has been observed that both drugs mainly interact with the G-tract and thymine of the loop region rather than the flanking nucleobases of the telomeric sequences without or with one flanking nucleobase. In contrast, the flanking nucleobases also participate in the interaction with the HCQ and CQ along with the core guanine repeat telomeric unit in the case of the telomeric sequences with more than one flanking nucleobases. The participation of the flanking nucleobases in the interaction with the HCQ and CQ affects the hydrogen bonding of the positively charged side chain of drugs with G quartet and loop nucleobases of telomere along with the with π···π and C-H···π weak interactions between the quinoline part of the drugs with the core telomeric guanine repeat unit which affects the folding pattern of the telomere sequences with more than one flanking nucleobases into G4.
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Affiliation(s)
- Asim Bisoi
- School of the Chemical Science, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
| | - Trideep Majumdar
- School of the Chemical Science, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
| | - Sunipa Sarkar
- School of the Chemical Science, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
| | - Prashant Chandra Singh
- School of the Chemical Science, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
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Mukherjee AK, Dutta S, Singh A, Sharma S, Roy SS, Sengupta A, Chatterjee M, Vinayagamurthy S, Bagri S, Khanna D, Verma M, Soni D, Budharaja A, Bhisade SK, Anand V, Perwez A, George N, Faruq M, Gupta I, Sabarinathan R, Chowdhury S. Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment. eLife 2024; 13:RP95106. [PMID: 39728924 PMCID: PMC11677240 DOI: 10.7554/elife.95106] [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] [Indexed: 12/28/2024] Open
Abstract
Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (telomeric repeat binding factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8, and TNF. Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (>90 patients), tumour-derived organoids, cancer cells, and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.
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Affiliation(s)
- Ananda Kishore Mukherjee
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | - Subhajit Dutta
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | - Ankita Singh
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
| | - Shalu Sharma
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | - Shuvra Shekhar Roy
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | - Antara Sengupta
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | - Megha Chatterjee
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
| | - Soujanya Vinayagamurthy
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | - Sulochana Bagri
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | - Divya Khanna
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
| | - Meenakshi Verma
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
| | - Dristhi Soni
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
| | | | | | - Vivek Anand
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
- Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
| | - Ahmad Perwez
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
| | - Nija George
- National Centre for Biological Sciences, Tata Institute of Fundamental ResearchBangaloreIndia
| | - Mohammed Faruq
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
- Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- GNR Knowledge Centre for Genome and Informatics, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
| | | | - Radhakrishnan Sabarinathan
- GNR Knowledge Centre for Genome and Informatics, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
| | - Shantanu Chowdhury
- Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Academy of Scientific and Innovative Research (AcSIR)GhaziabadIndia
- GNR Knowledge Centre for Genome and Informatics, CSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
- Trivedi School of Biosciences, Ashoka UniversitySonepatIndia
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Di Pietro E, Burla R, La Torre M, González-García MP, Dello Ioio R, Saggio I. Telomeres: an organized string linking plants and mammals. Biol Direct 2024; 19:119. [PMID: 39568075 PMCID: PMC11577926 DOI: 10.1186/s13062-024-00558-y] [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: 09/09/2024] [Accepted: 11/03/2024] [Indexed: 11/22/2024] Open
Abstract
Telomeres are pivotal determinants of cell stemness, organismal aging, and lifespan. Herein, we examined similarities in telomeres of Arabidopsis thaliana, mice, and humans. We report the common traits, which include their composition in multimers of TTAGGG sequences and their protection by specialized proteins. Moreover, given the link between telomeres, on the one hand, and cell proliferation and stemness on the other, we discuss the counterintuitive convergence between plants and mammals in this regard, focusing on the impact of niches on cell stemness. Finally, we suggest that tackling the study of telomere function and cell stemness by taking into consideration both plants and mammals can aid in the understanding of interconnections and contribute to research focusing on aging and organismal lifespan determinants.
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Affiliation(s)
- Edison Di Pietro
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy
| | - Romina Burla
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy
- CNR Institute of Biology and Pathology, Rome, Italy
| | - Mattia La Torre
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy
| | - Mary-Paz González-García
- Centro de Biotecnología y Genómica de Plantas (Universidad Politécnica de Madrid - Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria), UPM-INIA/CSIC. Campus de Montegancedo, Pozuelo de Alarcón, 28223, Madrid, Spain
- Departamento de Biotecnología-Biología Vegetal, Escuela Técnica Superior de Ingeniería Agronómica, Alimentaria y de Biosistemas, Universidad Politécnica de Madrid (UPM), Madrid, Spain
| | - Raffaele Dello Ioio
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy.
| | - Isabella Saggio
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza, University of Rome, Rome, Italy.
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Lv J, Zhao X, Zhao L, Gong C, Zheng W, Guo L, Wang J, Liang T. The Notable Role of Telomere Length Maintenance in Complex Diseases. Biomedicines 2024; 12:2611. [PMID: 39595175 PMCID: PMC11592153 DOI: 10.3390/biomedicines12112611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/07/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
Telomere length function serves as a critical biomarker for biological aging and overall health. Its maintenance is linked to cancer, neurodegenerative conditions, and reproductive health. This review mainly examines genetic variations and environmental influences on telomere dynamics, highlighting key regulatory genes and mechanisms. Advances in telomere measurement methodologies are also reviewed, underscoring the importance of precise telomere assessment for disease prevention and treatment. Telomerase activation offers potential for cellular lifespan extension and anti-aging effects, whereas its inhibition emerges as a promising therapeutic approach for cancer. Regulatory mechanisms of tumor suppressor genes on telomerase activity are analyzed, with a comprehensive overview of the current state and future potential of telomerase inhibitors. In addition, the association between telomeres and neurodegenerative diseases is discussed, detailing how telomere attrition heightens disease risk and outlining multiple pathways by which telomerase protects neurons from damage and apoptosis.
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Affiliation(s)
- Jiahui Lv
- State Key Laboratory of Organic Electronics and Information Displays, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (J.L.); (X.Z.); (L.Z.); (C.G.); (W.Z.); (L.G.)
| | - Xinmiao Zhao
- State Key Laboratory of Organic Electronics and Information Displays, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (J.L.); (X.Z.); (L.Z.); (C.G.); (W.Z.); (L.G.)
| | - Linjie Zhao
- State Key Laboratory of Organic Electronics and Information Displays, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (J.L.); (X.Z.); (L.Z.); (C.G.); (W.Z.); (L.G.)
| | - Chengjun Gong
- State Key Laboratory of Organic Electronics and Information Displays, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (J.L.); (X.Z.); (L.Z.); (C.G.); (W.Z.); (L.G.)
| | - Wanjie Zheng
- State Key Laboratory of Organic Electronics and Information Displays, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (J.L.); (X.Z.); (L.Z.); (C.G.); (W.Z.); (L.G.)
| | - Li Guo
- State Key Laboratory of Organic Electronics and Information Displays, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (J.L.); (X.Z.); (L.Z.); (C.G.); (W.Z.); (L.G.)
| | - Jun Wang
- State Key Laboratory of Organic Electronics and Information Displays, Institute of Advanced Materials (IAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, China; (J.L.); (X.Z.); (L.Z.); (C.G.); (W.Z.); (L.G.)
| | - Tingming Liang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Science, Nanjing Normal University, Nanjing 210023, China
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Jia Z, Qiu F, He Y, Chen H, Yang C, Liu H, Zheng T, Xu S, Wang S, Li Y. The fetal origins of metabolic health: exploring the association between newborn biological age and metabolism hormones in childhood. BMC Med 2024; 22:429. [PMID: 39379967 PMCID: PMC11462715 DOI: 10.1186/s12916-024-03629-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 09/11/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND Telomere length (TL), mitochondrial DNA copy number (mtDNAcn), and DNA methylation age (DNAmAge) are common aging biomarkers. However, research on the associations between these three markers at birth and subsequent metabolic status was limited. This study aimed to evaluate the association between TL, mtDNAcn, and DNAmAge in newborns and the variation in metabolic hormones of children at 3 years old. METHODS This research involved 895 mother-child pairs from a birth cohort in China, with TL and mtDNAcn measured using quantitative real-time PCR, DNA methylation (DNAm) assessed using Infinium MethylationEPIC Beadchip, and DNAm age (DNAmAge) determined using Horvath's epigenetic clock. Insulin and leptin levels were measured via electrochemiluminescence assay. Multivariable adjusted linear regression and restricted cubic spline (RCS) analysis were utilized to examine the association between aging markers and metabolic hormones. RESULTS The linear regression analysis indicated the percentage change of metabolism hormones for per doubling of aging biomarkers alterations and found significant associations between DNAmAge and insulin levels (adjusted percent change (95% CI), - 13.22 (- 23.21 to - 1.94)), TL and leptin levels (adjusted percent change (95% CI), 15.32 (1.32 to 31.24)), and mtDNAcn and leptin levels (adjusted percent change (95% CI), - 14.13 (- 21.59 to - 5.95)). The RCS analysis revealed significant non-linear associations between TL (Ln transformed) and insulin (Ln transformed) (P = 0.024 for nonlinearity), as well as DNAmAge (Ln transformed) and leptin (Ln transformed) (P = 0.043 for nonlinearity). Specifically, for TL and insulin, a positive association was observed when TL (Ln transformed) was less than - 0.05, which transitioned to an inverse association when TL (Ln transformed) was greater than - 0.05. Regarding DNAmAge and leptin, there was a sharp decline when DNAmAge (Ln transformed) was less than - 1.35, followed by a plateau between - 1.35 and - 0.67 and then a further decline when DNAmAge (Ln transformed) was greater than - 0.67. CONCLUSIONS In this prospective birth cohort study, variation in metabolic hormones of children at 3 years old was associated with TL, mtDNAcn, and DNAmAge at birth. These findings suggested that TL, mtDNAcn, and DNAmAge might play a role in the biological programming of metabolic health from birth.
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Affiliation(s)
- Zhenxian Jia
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Feng Qiu
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Yujie He
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Huan Chen
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Chenhui Yang
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Hongxiu Liu
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
| | - Tongzhang Zheng
- Department of Epidemiology, School of Public Health, Brown University, Providence, RI, 02912, USA
| | - Shunqing Xu
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China.
- School of Environmental Science and Engineering, Hainan University, Haikou, Hainan, 570228, China.
| | - Shiqiong Wang
- Institute of Maternal and Children Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430016, China.
| | - Yuanyuan Li
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China.
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Ege T, Tao L, North BJ. The Role of Molecular and Cellular Aging Pathways on Age-Related Hearing Loss. Int J Mol Sci 2024; 25:9705. [PMID: 39273652 PMCID: PMC11396656 DOI: 10.3390/ijms25179705] [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: 07/27/2024] [Revised: 08/27/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024] Open
Abstract
Aging, a complex process marked by molecular and cellular changes, inevitably influences tissue and organ homeostasis and leads to an increased onset or progression of many chronic diseases and conditions, one of which is age-related hearing loss (ARHL). ARHL, known as presbycusis, is characterized by the gradual and irreversible decline in auditory sensitivity, accompanied by the loss of auditory sensory cells and neurons, and the decline in auditory processing abilities associated with aging. The extended human lifespan achieved by modern medicine simultaneously exposes a rising prevalence of age-related conditions, with ARHL being one of the most significant. While our understanding of the molecular basis for aging has increased over the past three decades, a further understanding of the interrelationship between the key pathways controlling the aging process and the development of ARHL is needed to identify novel targets for the treatment of AHRL. The dysregulation of molecular pathways (AMPK, mTOR, insulin/IGF-1, and sirtuins) and cellular pathways (senescence, autophagy, and oxidative stress) have been shown to contribute to ARHL. However, the mechanistic basis for these pathways in the initiation and progression of ARHL needs to be clarified. Therefore, understanding how longevity pathways are associated with ARHL will directly influence the development of therapeutic strategies to treat or prevent ARHL. This review explores our current understanding of the molecular and cellular mechanisms of aging and hearing loss and their potential to provide new approaches for early diagnosis, prevention, and treatment of ARHL.
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Affiliation(s)
| | - Litao Tao
- Biomedical Sciences Department, School of Medicine, Creighton University, Omaha, NE 68178, USA;
| | - Brian J. North
- Biomedical Sciences Department, School of Medicine, Creighton University, Omaha, NE 68178, USA;
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8
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Rippel N, Kremyanskaya M. Recent advances in JAK2 inhibition for the treatment of myelofibrosis. Expert Opin Pharmacother 2024; 25:1175-1186. [PMID: 38919983 DOI: 10.1080/14656566.2024.2372453] [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: 05/15/2024] [Accepted: 06/21/2024] [Indexed: 06/27/2024]
Abstract
INTRODUCTION Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, cytopenias, a potential for leukemic transformation, and increased mortality. Patients who are ineligible for stem cell transplant rely on pharmacologic therapies of noncurative intent, whose cornerstone consists of JAK inhibitors (JAKi). While current JAKi are efficacious in controlling symptoms and splenic volume, none meaningfully reduce clonal burden nor halt disease progression, and patients oftentimes develop JAKi intolerant, relapsed, or refractory MF. As such, there remains an urgent necessity for second-line options and novel therapies with disease-modifying properties. AREAS COVERED In this review, we delineate the mechanistic rationale, along with the latest safety and efficacy data, of investigational JAKi-based MF treatment strategies, with a focus on JAKi monotherapies and combinations of novel agents with approved JAKi. Our literature search consisted of extensive review of PubMed and clinicaltrials.gov. EXPERT OPINION A myriad of promising MF-directed therapies are in late-phase studies. Following their approval, treatment selection should be tailored to patient-specific treatment goals and disease characteristics, with an emphasis on combination therapies of JAKi with novel agents of differing mechanistic targets that possess anti-clonal properties, in attempt to alter disease course and concurrently limit dose-dependent JAKi toxicities.
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Affiliation(s)
- Noa Rippel
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marina Kremyanskaya
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Vellingiri B, Balasubramani K, Iyer M, Raj N, Elangovan A, Song K, Yeo HC, Jayakumar N, Kinoshita M, Thangarasu R, Narayanasamy A, Dayem AA, Prajapati VK, Gopalakrishnan AV, Cho SG. Role of Telomeres and Telomerase in Parkinson's Disease-A New Theranostics? Adv Biol (Weinh) 2023; 7:e2300097. [PMID: 37590305 DOI: 10.1002/adbi.202300097] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/19/2023] [Indexed: 08/19/2023]
Abstract
Parkinson's disease (PD) is a complex condition that is significantly influenced by oxidative stress and inflammation. It is also suggested that telomere shortening (TS) is regulated by oxidative stress which leads to various diseases including age-related neurodegenerative diseases like PD. Thus, it is anticipated that PD would result in TS of peripheral blood mononuclear cells (PBMCs). Telomeres protect the ends of eukaryotic chromosomes preserving them against fusion and destruction. The TS is a normal process because DNA polymerase is unable to replicate the linear ends of the DNA due to end replication complications and telomerase activity in various cell types counteracts this process. PD is usually observed in the aged population and progresses over time therefore, disparities among telomere length in PBMCs of PD patients are recorded and it is still a question whether it has any useful role. Here, the likelihood of telomere attrition in PD and its implications concerning microglia activation, ageing, oxidative stress, and the significance of telomerase activators are addressed. Also, the possibility of telomeres and telomerase as a diagnostic and therapeutic biomarker in PD is discussed.
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Affiliation(s)
- Balachandar Vellingiri
- Stem Cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Kiruthika Balasubramani
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, 641046, India
| | - Mahalaxmi Iyer
- Department of Biotechnology, Karpagam Academy of Higher Education (Deemed to be University), Coimbatore, Tamil Nadu, 641021, India
| | - Neethu Raj
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, 641046, India
| | - Ajay Elangovan
- Stem Cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Kwonwoo Song
- Department of Stem Cell and Regenerative Biotechnology, Molecular and Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, Seoul, 05029, Republic of Korea
| | - Han-Cheol Yeo
- Department of Stem Cell and Regenerative Biotechnology, Molecular and Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, Seoul, 05029, Republic of Korea
| | - Namitha Jayakumar
- Department of Biotechnology, Sri Ramakrishna College of Arts and Science, Coimbatore, Tamil Nadu, 641006, India
| | - Masako Kinoshita
- Department of Neurology, National Hospital Organization Utano National Hospital, Ondoyama-Cho, Narutaki, Ukyo-Ku, Kyoto, 616-8255, Japan
| | - Ravimanickam Thangarasu
- Department of Zoology, School of Science, Tamil Nadu Open University, Saidapet, Chennai, 600015, India
| | - Arul Narayanasamy
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, Tamil Nadu, 641046, India
| | - Ahmed Abdal Dayem
- Department of Stem Cell and Regenerative Biotechnology, Molecular and Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, Seoul, 05029, Republic of Korea
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, 110021, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Molecular and Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, Seoul, 05029, Republic of Korea
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10
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Bryan TM. Nucleotide metabolism regulates human telomere length via telomerase activation. Nat Genet 2023; 55:532-533. [PMID: 36997693 DOI: 10.1038/s41588-023-01359-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023]
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11
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He N, Zhang X, Xie P, He J, Lv Z. Inhibition of posterior capsule opacification by adenovirus-mediated delivery of short hairpin RNAs targeting TERT in a rabbit model. Curr Eye Res 2023:1-9. [PMID: 36946600 DOI: 10.1080/02713683.2023.2194587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
PURPOSE Posterior capsule opacification (PCO) is the most common postoperative complication after cataract surgery and cannot yet be eliminated. Here, we investigated the inhibitory effects of telomerase reverse transcriptase (TERT) gene silencing on PCO in a rabbit model. METHODS After rabbit lens epithelial cells (LECs) were treated with adenovirus containing short hairpin RNAs (shRNA) targeting TERT (shTERT group), adenovirus containing scramble nonsense control shRNA (shNC group) or PBS (control group), quantitative real-time polymerase chain reaction and Western blotting were used to measure the expression levels of TERT, and a scratch assay was performed to assess the LEC migration. New Zealand white rabbits underwent sham cataract surgery followed by an injection of adenovirus carrying shTERT into their capsule bag. The intraocular pressure and anterior segment inflammation were evaluated on certain days, and EMT markers (α-SMA and E-cadherin) were evaluated by Western blotting and immunofluorescence. The telomerase activity of the capsule bag was detected by ELISA. At 28 days postoperatively, haematoxylin and eosin staining of the cornea and iris and electron microscopy of the posterior capsule were performed. RESULTS Application of shTERT to LECs downregulated the expression levels of TERT mRNA and protein. The scratch assay results showed a decrease in the migration of LECs in the shTERT group. In vivo, shTERT decreased PCO formation after cataract surgery in rabbits and downregulated the expression of EMT markers, as determined by Western blotting and immunofluorescence. In addition, telomerase activity was suppressed in the capsule bag. Despite slight inflammation in the iris, histologic results revealed no toxic effects in the cornea and iris. CONCLUSION TERT silencing effectively reduces the migration and proliferation of LECs and the formation of PCO. Our findings suggest that TERT silencing may be a potential preventive strategy for PCO.
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Affiliation(s)
- Na He
- Department of Ophthalmology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Xiangxiang Zhang
- Department of Ophthalmology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Peiling Xie
- Department of Ophthalmology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Jialing He
- Department of Ophthalmology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
| | - Zhigang Lv
- Department of Ophthalmology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, China
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12
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Wolf SE, Sanders TL, Beltran SE, Rosvall KA. The telomere regulatory gene POT1 responds to stress and predicts performance in nature: Implications for telomeres and life history evolution. Mol Ecol 2022; 31:6155-6171. [PMID: 34674335 DOI: 10.1111/mec.16237] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 09/25/2021] [Accepted: 10/12/2021] [Indexed: 02/02/2023]
Abstract
Telomeres are emerging as correlates of fitness-related traits and may be important mediators of ecologically relevant variation in life history strategies. Growing evidence suggests that telomere dynamics can be more predictive of performance than length itself, but very little work considers how telomere regulatory mechanisms respond to environmental challenges or influence performance in nature. Here, we combine observational and experimental data sets from free-living tree swallows (Tachycineta bicolor) to assess how performance is predicted by the telomere regulatory gene POT1, which encodes a shelterin protein that sterically blocks telomerase from repairing the telomere. First, we show that lower POT1 gene expression in the blood was associated with higher female quality, that is, earlier breeding and heavier body mass. We next challenged mothers with an immune stressor (lipopolysaccharide injection) that led to "sickness" in mothers and 24 h of food restriction in their offspring. While POT1 did not respond to maternal injection, females with lower constitutive POT1 gene expression were better able to maintain feeding rates following treatment. Maternal injection also generated a 1-day stressor for chicks, which responded with lower POT1 gene expression and elongated telomeres. Other putatively stress-responsive mechanisms (i.e., glucocorticoids, antioxidants) showed marginal responses in stress-exposed chicks. Model comparisons indicated that POT1 mRNA abundance was a largely better predictor of performance than telomere dynamics, indicating that telomere regulators may be powerful modulators of variation in life history strategies.
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Affiliation(s)
- Sarah E Wolf
- Department of Biology, Indiana University, Bloomington, Indiana, USA.,Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, Indiana, USA
| | - Tiana L Sanders
- Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, Indiana, USA
| | - Sol E Beltran
- Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, Indiana, USA
| | - Kimberly A Rosvall
- Department of Biology, Indiana University, Bloomington, Indiana, USA.,Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, Indiana, USA
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13
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Abstract
Germline genetic defects impairing telomere length maintenance may result in severe medical conditions in humans, from aplastic anemia and myeloid neoplasms to interstitial lung disease and liver cirrhosis, from childhood (dyskeratosis congenita) to old age (pulmonary fibrosis). The molecular mechanisms underlying these clinically distinct disorders are pathologically excessive telomere erosion, limiting cell proliferation and differentiation, tissue regeneration, and increasing genomic instability. Recent findings also indicate that telomere shortening imbalances stem cell fate and is associated with an abnormal inflammatory response and the senescent-associated secretory phenotype. Bone marrow failure is the most common phenotype in patients with telomere diseases. Pulmonary fibrosis is a typical phenotype in older patients, and disease progression appears faster than in pulmonary fibrosis not associated with telomeropathies. Liver cirrhosis may present in isolation or in combination with other phenotypes. Diagnosis is based on clinical suspicion and may be confirmed by telomere length measurement and genetic testing. Next-generation sequencing (NGS) techniques have improved genetic testing; today, at least 16 genes have been implicated in telomeropathies. NGS also allows tracking of clonal hematopoiesis and malignant transformation. Patients with telomere diseases are at high risk of developing cancers, including myeloid neoplasms and head and neck cancer. However, treatment options are still limited. Transplant modalities (bone marrow, lung, and liver) may be definitive to the respective organ involvement but limited by donor availability, comorbidities, and impact on other affected organs. In clinical trials, androgens elongate telomeres of peripheral blood leukocytes and improve hematopoiesis. Further understanding of how telomere erosion impairs organ function and how somatic mutations evolve in the hematopoietic tissue may help develop new strategies to treat and prevent telomere diseases.
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Affiliation(s)
- Vinicius S Carvalho
- Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Willian R Gomes
- Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Rodrigo T Calado
- Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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14
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Identification of protective biologic factors in patients with high cardiovascular risk, but normal coronary arteries (NormCorn). Coron Artery Dis 2022; 33:540-546. [PMID: 35866511 DOI: 10.1097/mca.0000000000001174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Endothelial progenitor cells (EPCs) have an important role in repair following vascular injury. Telomere length has been shown to be correlated with genome stability and overall cell health. We hypothesized that both EPCs and telomere size are related to protective mechanisms against coronary artery disease. Our aim was to evaluate the level and function of circulating EPCs and telomere length in patients with multiple cardiovascular risk factors and anatomically normal coronary arteries vs. matched controls. METHODS We included 24 patients, with coronary CTA demonstrating normal coronaries and a high risk of CAD of >10% by ASCVD risk estimator. Control groups included 17 patients with similar cardiovascular profiles but with established CAD and a group of 20 healthy volunteers. Circulating EPCs levels were assessed by flow cytometry for expression of vascular endothelial growth factor receptor 2, CD34 and CD133. The capacity of the cells to form colony forming units (CFUs) was quantified after 1 week of culture. Telomere length was determined by the southern blotting technique. RESULTS Patients with high risk for CVD and normal coronaries had augmented EPCs function, compared with the CAD group (1.1 vs. 0.22 CFU/f; P = 0.04) and longer telomeres compared with the CAD group (10.7 kb vs. 2.8 kb P = 0.015). These patients displayed a similar profile to the healthy group. CONCLUSION Patients with a high risk for CAD, but normal coronary arteries have EPCs function and telomere length which resemble healthy volunteers, and augmented compared with patients with established CAD, which could serve as a protective mechanism against atherosclerosis development in these high-risk patients.
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15
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Song Y, Ma Z, Zhang W. Manipulation of a Single Polymer Chain: From the Nanomechanical Properties to Dynamic Structure Evolution. Macromolecules 2022. [DOI: 10.1021/acs.macromol.2c00076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Yu Song
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Ziwen Ma
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Wenke Zhang
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
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16
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Sholes SL, Karimian K, Gershman A, Kelly TJ, Timp W, Greider CW. Chromosome-specific telomere lengths and the minimal functional telomere revealed by nanopore sequencing. Genome Res 2022; 32:616-628. [PMID: 34702734 PMCID: PMC8997346 DOI: 10.1101/gr.275868.121] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 10/20/2021] [Indexed: 11/26/2022]
Abstract
We developed a method to tag telomeres and measure telomere length by nanopore sequencing in the yeast S. cerevisiae Nanopore allows long-read sequencing through the telomere, through the subtelomere, and into unique chromosomal sequence, enabling assignment of telomere length to a specific chromosome end. We observed chromosome end-specific telomere lengths that were stable over 120 cell divisions. These stable chromosome-specific telomere lengths may be explained by slow clonal variation or may represent a new biological mechanism that maintains equilibrium unique to each chromosome end. We examined the role of RIF1 and TEL1 in telomere length regulation and found that TEL1 is epistatic to RIF1 at most telomeres, consistent with the literature. However, at telomeres that lack subtelomeric Y' sequences, tel1Δ rif1Δ double mutants had a very small, but significant, increase in telomere length compared with the tel1Δ single mutant, suggesting an influence of Y' elements on telomere length regulation. We sequenced telomeres in a telomerase-null mutant (est2Δ) and found the minimal telomere length to be ∼75 bp. In these est2Δ mutants, there were apparent telomere recombination events at individual telomeres before the generation of survivors, and these events were significantly reduced in est2Δ rad52Δ double mutants. The rate of telomere shortening in the absence of telomerase was similar across all chromosome ends at ∼5 bp per generation. This new method gives quantitative, high-resolution telomere length measurement at each individual chromosome end and suggests possible new biological mechanisms regulating telomere length.
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Affiliation(s)
- Samantha L Sholes
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
- Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Kayarash Karimian
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
- Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Ariel Gershman
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
- Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Thomas J Kelly
- Program in Molecular Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Winston Timp
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
| | - Carol W Greider
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
- Department of Molecular Cell and Developmental Biology, University of California, Santa Cruz, California 95064, USA
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17
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Zanetti M, Xian S, Dosset M, Carter H. The Unfolded Protein Response at the Tumor-Immune Interface. Front Immunol 2022; 13:823157. [PMID: 35237269 PMCID: PMC8882736 DOI: 10.3389/fimmu.2022.823157] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/26/2022] [Indexed: 12/14/2022] Open
Abstract
The tumor-immune interface has surged to primary relevance in an effort to understand the hurdles facing immune surveillance and cancer immunotherapy. Reports over the past decades have indicated a role for the unfolded protein response (UPR) in modulating not only tumor cell fitness and drug resistance, but also local immunity, with emphasis on the phenotype and altered function of immune cells such as myeloid cells and T cells. Emerging evidence also suggests that aneuploidy correlates with local immune dysregulation. Recently, we reported that the UPR serves as a link between aneuploidy and immune cell dysregulation in a cell nonautonomous way. These new findings add considerable complexity to the organization of the tumor microenvironment (TME) and the origin of its altered function. In this review, we summarize these data and also discuss the role of aneuploidy as a negative regulator of local immunity.
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Affiliation(s)
- Maurizio Zanetti
- The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA, United States
- *Correspondence: Maurizio Zanetti, ; orcid.org/0000-0001-6346-8776
| | - Su Xian
- Division of Medical Genetics, Department of Medicine, Bioinformatics and System Biology Program, University of California San Diego, La Jolla, CA, United States
| | - Magalie Dosset
- The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA, United States
| | - Hannah Carter
- Division of Medical Genetics, Department of Medicine, Bioinformatics and System Biology Program, University of California San Diego, La Jolla, CA, United States
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18
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Hirata M, Fujita K, Fujihara S, Mizuo T, Nakabayashi R, Kono T, Namima D, Fujita N, Yamana H, Kamada H, Tani J, Kobara H, Tsutsui K, Matsuda Y, Ono M, Masaki T. Telomerase Reverse Transcriptase Promoter Mutations in Human Hepatobiliary, Pancreatic and Gastrointestinal Cancer Cell Lines. In Vivo 2022; 36:94-102. [PMID: 34972704 DOI: 10.21873/invivo.12680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 09/27/2021] [Accepted: 10/29/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIM The promoter region of the telomerase reverse transcriptase (TERT) gene is a regulatory element capable of affecting TERT expression, telomerase activity, and telomerase length. Mutations within the TERT promoter region are the most common mutations in many cancers. In this study, we characterized the TERT promoter mutation status in hepatobiliary, pancreatic, and gastrointestinal cancer cell lines. MATERIALS AND METHODS TERT promoter mutation status was assessed by digital PCR in 12 liver cancer, 5 cholangiocarcinoma (CCA), 12 pancreatic cancer, 17 gastrointestinal cancer, and 3 healthy control cell lines. RESULTS The C228T promoter mutation was detected in 9 liver cancer lines, and the C250T TERT mutation was detected in 1 oesophageal squamous cell carcinoma line. CONCLUSION The C228T promoter mutation is specific to liver cancer cell lines among various gastrointestinal cancer cell lines. These data will contribute to future research on the tumorigenic mechanisms and clinical use of digital PCR to detect mutations.
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Affiliation(s)
- Masahiro Hirata
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Takaaki Mizuo
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Ryota Nakabayashi
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Toshiaki Kono
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Daisuke Namima
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Naoki Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hiroki Yamana
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hideki Kamada
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Kunihiko Tsutsui
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Yoko Matsuda
- Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan;
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19
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Wissler Gerdes EO, Misra A, Netto JME, Tchkonia T, Kirkland JL. Strategies for late phase preclinical and early clinical trials of senolytics. Mech Ageing Dev 2021; 200:111591. [PMID: 34699859 PMCID: PMC8627448 DOI: 10.1016/j.mad.2021.111591] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/11/2021] [Accepted: 10/21/2021] [Indexed: 01/17/2023]
Abstract
Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.
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Affiliation(s)
| | - Avanish Misra
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, United States
| | | | - Tamar Tchkonia
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, United States; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States
| | - James L Kirkland
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, United States; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States; Division of Geriatrics and Gerontology, Department of Medicine, Mayo Clinic, Rochester, MN, United States.
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20
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Fan G, Li X, Xu S, Dai C, Xue Q, Wang H. SERS-based copper-mediated signal amplification strategy for simple and sensitive detection of telomerase activity. Talanta 2021; 235:122814. [PMID: 34517670 DOI: 10.1016/j.talanta.2021.122814] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/14/2021] [Accepted: 08/17/2021] [Indexed: 11/28/2022]
Abstract
Simple and sensitive detection of telomerase activity is of vital importance for both early diagnosis and therapy of malignant tumors. Inspired by DNA-biobarcode amplification reported by Chad A. Mirkin, we developed a facile DNA-biobarcode-like SERS-based copper-mediated signal amplification strategy for sensitive detection of telomerase activity. In this strategy, a duplex DNA constructed by hybridization of a copper oxide nanoparticle (CuO NP)-labeled reporting sequence (RS) with the telomerase primer sequence (TS) is ingeniously designed, and anchored on the magnetic bead (MB) to build the CuO NPs-encoded magnetic bead (MB-CuO NPs) detection probe. Upon selective sensing of telomerase, telomerase elongation reaction and structure change of TS products make the CuO NP-RS displace and separate from MB. The separated CuO NPs are dissolved into a mass of Cu2+, which prompt monodisperse dopamine-functionalized AgNPs (D-AgNPs) signal probe into aggregation, resulting in color changes and significantly enhancing of SERS signal. The SERS signal increases with the increase of Cu2+, which is directly proportional to the telomerase. Benefiting from the transformation of CuO NP to Cu2+ with a high amplification effect, this strategy could realize the telomerase activity measurement down to 3 HeLa cells and a dynamic range of 10-10000 cells. It shows a significant improvement of sensitivity without need for other enzymes and elaborate design, which escapes from the complicated manipulations and design in polymerase chain reaction (PCR) and DNA amplification techniques. Moreover, with this strategy, telomerase activities of different cell lines and telomerase inhibitors screening were successfully performed. Significantly, it can also be utilized for visual detection of telomerase, which validates the potential on-site application and its application as point-of-care testing (POCT) for efficient monitoring. Given the high-performance for telomerase analysis, the strategy has a promising application in biological detection and clinical diagnosis, as well as point-of-care tests.
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Affiliation(s)
- Guanli Fan
- Department of Chemistry, Liaocheng University, Liaocheng, 252059, Shandong, China
| | - Xia Li
- Department of Chemistry, Liaocheng University, Liaocheng, 252059, Shandong, China
| | - Shuling Xu
- Department of Chemistry, Liaocheng University, Liaocheng, 252059, Shandong, China
| | - Caifeng Dai
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, 250012, Shandong, PR China.
| | - Qingwang Xue
- Department of Chemistry, Liaocheng University, Liaocheng, 252059, Shandong, China.
| | - Huaisheng Wang
- Department of Chemistry, Liaocheng University, Liaocheng, 252059, Shandong, China
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21
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Badmus KA, Idrus Z, Meng GY, Sazili AQ, Mamat-Hamidi K. Telomere Length and Regulatory Genes as Novel Stress Biomarkers and Their Diversities in Broiler Chickens ( Gallus gallus domesticus) Subjected to Corticosterone Feeding. Animals (Basel) 2021; 11:ani11102759. [PMID: 34679783 PMCID: PMC8532957 DOI: 10.3390/ani11102759] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/16/2021] [Accepted: 08/23/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Assessment of poultry welfare is very crucial for sustainable production in the tropics. There is a demand for alternatives to plasma corticosterone levels as they have received much criticism as an unsuitable predictor of animal welfare due to inconsistency. In this study, we noticed no effect of age on plasma corticosterone (CORT) although it was altered by CORT treatment. However, growth performances and organ weight were affected by CORT treatment and age. The broad sense evaluation of telomere length in this study revealed that telomere length in the blood, muscle, liver and heart was shortened by chronic stress induced by corticosterone administration. The expression profile of the telomere regulatory genes was altered by chronic stress. This study informed us of the potential of telomere length and its regulatory genes in the assessment of animal welfare in the poultry sector for sustainable production. Abstract This study was designed to characterize telomere length and its regulatory genes and to evaluate their potential as well-being biomarkers. Chickens were fed a diet containing corticosterone (CORT) for 4 weeks and performances, organ weight, plasma CORT levels, telomere lengths and regulatory genes were measured and recorded. Body weights of CORT-fed chickens were significantly suppressed (p < 0.05), and organ weights and circulating CORT plasma levels (p < 0.05) were altered. Interaction effect of CORT and duration was significant (p < 0.05) on heart and liver telomere length. CORT significantly (p < 0.05) shortened the telomere length of the whole blood, muscle, liver and heart. The TRF1, chTERT, TELO2 and HSF1 were significantly (p < 0.05) upregulated in the liver and heart at week 4 although these genes and TERRA were downregulated in the muscles at weeks 2 and 4. Therefore, telomere lengths and their regulators are associated and diverse, so they can be used as novel biomarkers of stress in broiler chickens fed with CORT.
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Affiliation(s)
- Kazeem Ajasa Badmus
- Department of Animal Science, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia; (K.A.B.); (Z.I.); (A.Q.S.)
- Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia;
| | - Zulkifli Idrus
- Department of Animal Science, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia; (K.A.B.); (Z.I.); (A.Q.S.)
- Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia;
| | - Goh Yong Meng
- Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia;
- Department of Veterinary Pre-Clinical Science, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia
| | - Awis Qurni Sazili
- Department of Animal Science, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia; (K.A.B.); (Z.I.); (A.Q.S.)
- Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia;
| | - Kamalludin Mamat-Hamidi
- Department of Animal Science, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia; (K.A.B.); (Z.I.); (A.Q.S.)
- Institute of Tropical Agriculture and Food Security, Universiti Putra Malaysia, Seri Kembangan 43400, Selangor, Malaysia;
- Correspondence:
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22
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Ramasamy TS, Yee YM, Khan IM. Chondrocyte Aging: The Molecular Determinants and Therapeutic Opportunities. Front Cell Dev Biol 2021; 9:625497. [PMID: 34336816 PMCID: PMC8318388 DOI: 10.3389/fcell.2021.625497] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/28/2021] [Indexed: 12/17/2022] Open
Abstract
Osteoarthritis (OA) is a joint degenerative disease that is an exceedingly common problem associated with aging. Aging is the principal risk factor for OA, but damage-related physiopathology of articular chondrocytes probably drives the mechanisms of joint degeneration by a progressive decline in the homeostatic and regenerative capacity of cells. Cellular aging is the manifestation of a complex interplay of cellular and molecular pathways underpinned by transcriptional, translational, and epigenetic mechanisms and niche factors, and unraveling this complexity will improve our understanding of underlying molecular changes that affect the ability of the articular cartilage to maintain or regenerate itself. This insight is imperative for developing new cell and drug therapies for OA disease that will target the specific causes of age-related functional decline. This review explores the key age-related changes within articular chondrocytes and discusses the molecular mechanisms that are commonly perturbed as cartilage ages and degenerates. Current efforts and emerging potential therapies in treating OA that are being employed to halt or decelerate the aging processes are also discussed.
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Affiliation(s)
- Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.,Cell and Molecular Biology Laboratory, The Dean's Office, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Yong Mei Yee
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Ilyas M Khan
- Centre of NanoHealth, Swansea University Medical School, Swansea, United Kingdom
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23
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Agrawal V, Gbolahan OB, Stahl M, Zeidan AM, Zaid MA, Farag SS, Konig H. Vaccine and Cell-based Therapeutic Approaches in Acute Myeloid Leukemia. Curr Cancer Drug Targets 2021; 20:473-489. [PMID: 32357813 DOI: 10.2174/1568009620666200502011059] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 03/05/2020] [Accepted: 03/29/2020] [Indexed: 12/13/2022]
Abstract
Over the past decade, our increased understanding of the interactions between the immune system and cancer cells has led to paradigm shifts in the clinical management of solid and hematologic malignancies. The incorporation of immune-targeted strategies into the treatment landscape of acute myeloid leukemia (AML), however, has been challenging. While this is in part due to the inability of the immune system to mount an effective tumor-specific immunogenic response against the heterogeneous nature of AML, the decreased immunogenicity of AML cells also represents a major obstacle in the effort to design effective immunotherapeutic strategies. In fact, AML cells have been shown to employ sophisticated escape mechanisms to evade elimination, such as direct immunosuppression of natural killer cells and decreased surface receptor expression leading to impaired recognition by the immune system. Yet, cellular and humoral immune reactions against tumor-associated antigens (TAA) of acute leukemia cells have been reported and the success of allogeneic stem cell transplantation and monoclonal antibodies in the treatment of AML clearly provides proof that an immunotherapeutic approach is feasible in the management of this disease. This review discusses the recent progress and persisting challenges in cellular immunotherapy for patients with AML.
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Affiliation(s)
- Vaibhav Agrawal
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Olumide B Gbolahan
- Division of Hematology and Oncology, University of Alabama School of Medicine, Birmingham, AL 35294, United States
| | - Maximilian Stahl
- Department of Medicine, Division of Hematology and Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
| | - Amer M Zeidan
- Department of Internal Medicine, Section of Hematology, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Mohammad Abu Zaid
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Sherif S Farag
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Heiko Konig
- Department of Medicine, Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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24
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Liu X, Meng F, Sun R, Wang K, Yu Z, Miao P. Three-dimensional bipedal DNA walker enabled logic gates responding to telomerase and miRNA. Chem Commun (Camb) 2021; 57:2629-2632. [PMID: 33587067 DOI: 10.1039/d0cc08089f] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
In this work, we have developed a simple and reliable platform for simultaneous analysis of telomerase and miRNA. A three-dimensional bipedal DNA walking strategy is designed utilizing gold nanoparticles and MnO2 nanosheets. Given the merits of fast, sensitive and selective analysis, the developed method has great potential application in early clinical diagnosis.
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Affiliation(s)
- Xin Liu
- Department of Pharmacy, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan 528300, China.
| | - Fanyu Meng
- Ji Hua Laboratory, Foshan 528200, China.
| | - Rui Sun
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Kangnan Wang
- Department of Pharmacy, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan 528300, China.
| | - Zhiqiang Yu
- Department of Pharmacy, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan 528300, China. and Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Peng Miao
- Ji Hua Laboratory, Foshan 528200, China. and Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
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25
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Noureen N, Wu S, Lv Y, Yang J, Alfred Yung WK, Gelfond J, Wang X, Koul D, Ludlow A, Zheng S. Integrated analysis of telomerase enzymatic activity unravels an association with cancer stemness and proliferation. Nat Commun 2021; 12:139. [PMID: 33420056 PMCID: PMC7794223 DOI: 10.1038/s41467-020-20474-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022] Open
Abstract
Active telomerase is essential for stem cells and most cancers to maintain telomeres. The enzymatic activity of telomerase is related but not equivalent to the expression of TERT, the catalytic subunit of the complex. Here we show that telomerase enzymatic activity can be robustly estimated from the expression of a 13-gene signature. We demonstrate the validity of the expression-based approach, named EXTEND, using cell lines, cancer samples, and non-neoplastic samples. When applied to over 9,000 tumors and single cells, we find a strong correlation between telomerase activity and cancer stemness. This correlation is largely driven by a small population of proliferating cancer cells that exhibits both high telomerase activity and cancer stemness. This study establishes a computational framework for quantifying telomerase enzymatic activity and provides new insights into the relationships among telomerase, cancer proliferation, and stemness.
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Affiliation(s)
- Nighat Noureen
- Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA
- Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA
| | - Shaofang Wu
- Department of Neuro-Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Yingli Lv
- Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA
| | - Juechen Yang
- Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA
| | - W K Alfred Yung
- Department of Neuro-Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Jonathan Gelfond
- Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA
| | - Xiaojing Wang
- Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA
- Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA
| | - Dimpy Koul
- Department of Neuro-Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew Ludlow
- Department of Movement Science, University of Michigan, Ann Arbor, MI, USA
| | - Siyuan Zheng
- Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA.
- Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA.
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26
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Sadie-Van Gijsen H. Is Adipose Tissue the Fountain of Youth? The Impact of Adipose Stem Cell Aging on Metabolic Homeostasis, Longevity, and Cell-Based Therapies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1286:225-250. [PMID: 33725357 DOI: 10.1007/978-3-030-55035-6_16] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Aging is driven by four interlinked processes: (1) low-grade sterile inflammation; (2) macromolecular and organelle dysfunction, including DNA damage, telomere erosion, and mitochondrial dysfunction; (3) stem cell dysfunction; and (4) an accumulation of senescent cells in tissues. Adipose tissue is not immune to the effects of time, and all four of these processes contribute to a decline of adipose tissue function with advanced age. This decline is associated with an increase in metabolic disorders. Conversely, optimally functioning adipose tissue generates signals that promote longevity. As tissue-resident progenitor cells that actively participate in adipose tissue homeostasis and dysregulation, adipose stem cells (ASCs) have emerged as a key feature in the relationship between age and adipose tissue function. This review will give a mechanistic overview of the myriad ways in which age affects ASC function and, conversely, how ASC function contribute to healthspan and lifespan. A central mediator in this relationship is the degree of resilience of ASCs to maintain stemness into advanced age and the consequent preservation of adipose tissue function, in particular subcutaneous fat. The last sections of this review will discuss therapeutic options that target senescent ASCs to extend healthspan and lifespan, as well as ASC-based therapies that can be used to treat age-related pathologies, and collectively, these therapeutic applications may transform the way we age.
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Affiliation(s)
- Hanél Sadie-Van Gijsen
- Centre for Cardiometabolic Research in Africa (CARMA), Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus, Parow, South Africa.
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27
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McKelvey BA, Zeiger MA, Umbricht CB. Exploring the epigenetic regulation of telomerase reverse transcriptase (TERT) in human cancer cell lines. Mol Oncol 2020; 14:2355-2357. [PMID: 32920953 PMCID: PMC7530778 DOI: 10.1002/1878-0261.12798] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 11/10/2022] Open
Abstract
Telomerase regulation, including TERT promoter methylation, has been of long-standing interest to cancer biologists. Rowland et al. have now vastly expanded their ongoing characterization of TERT promoter methylation in cancer cells, analyzing the methylation patterns of 833 cell lines from 23 human cancers. They document a highly conserved pattern of hypomethylation around the proximal promoter, as well as a more heterogeneous region of hypermethylation further upstream, both associated with active TERT expression in cancer cells. They further describe the interplay between activating TERT promoter mutations and allelic methylation and transcription patterns. This valuable dataset represents the most extensive characterization of TERT promoter methylation in cancer cells to date and will help guide the future study of transcriptional regulation of telomerase. Comment on: https://doi.org/10.1002/1878-0261.12786.
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Affiliation(s)
- Brittany A. McKelvey
- Department of SurgeryJohns Hopkins UniversityBaltimoreMDUSA
- Department of Molecular Biology and GeneticsJohns Hopkins UniversityBaltimoreMDUSA
| | - Martha A. Zeiger
- Surgical Oncology ProgramNational Cancer InstituteNational Institutes of HealthBethesdaMDUSA
| | - Christopher B. Umbricht
- Department of SurgeryJohns Hopkins UniversityBaltimoreMDUSA
- Department of OncologyJohns Hopkins UniversityBaltimoreMDUSA
- Department of PathologyJohns Hopkins UniversityBaltimoreMDUSA
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28
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Zhang X, Zhang Y, Zhang W. Dynamic topology of double-stranded telomeric DNA studied by single-molecule manipulation in vitro. Nucleic Acids Res 2020; 48:6458-6470. [PMID: 32496520 PMCID: PMC7337930 DOI: 10.1093/nar/gkaa479] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 05/17/2020] [Accepted: 05/27/2020] [Indexed: 12/18/2022] Open
Abstract
The dynamic topological structure of telomeric DNA is closely related to its biological function; however, no such structural information on full-length telomeric DNA has been reported due to difficulties synthesizing long double-stranded telomeric DNA. Herein, we developed an EM-PCR and TA cloning-based approach to synthesize long-chain double-stranded tandem repeats of telomeric DNA. Using mechanical manipulation assays based on single-molecule atomic force microscopy, we found that mechanical force can trigger the melting of double-stranded telomeric DNA and the formation of higher-order structures (G-quadruplexes or i-motifs). Our results show that only when both the G-strand and C-strand of double-stranded telomeric DNA form higher-order structures (G-quadruplexes or i-motifs) at the same time (e.g. in the presence of 100 mM KCl under pH 4.7), that the higher-order structure(s) can remain after the external force is removed. The presence of monovalent K+, single-wall carbon nanotubes (SWCNTs), acidic conditions, or short G-rich fragments (∼30 nt) can shift the transition from dsDNA to higher-order structures. Our results provide a new way to regulate the topology of telomeric DNA.
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Affiliation(s)
- Xiaonong Zhang
- State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun 130012, People's Republic of China
| | - Yingqi Zhang
- State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun 130012, People's Republic of China
| | - Wenke Zhang
- State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun 130012, People's Republic of China
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29
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Stabilization of telomere by the antioxidant property of polyphenols: Anti-aging potential. Life Sci 2020; 259:118341. [PMID: 32853653 DOI: 10.1016/j.lfs.2020.118341] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/19/2020] [Accepted: 08/22/2020] [Indexed: 12/28/2022]
Abstract
Aging is a form of a gradual loss of physiological integrity that results in impaired cellular function and ultimately increased vulnerability to disease and death. This process is a significant risk factor for critical age-related disorders such as cancer, diabetes, cardiovascular disease, and neurological conditions. Several mechanisms contribute to aging, most notably progressive telomeres shortening, which can be counteracted by telomerase enzyme activity and increasing in this enzyme activity associated with partly delaying the onset of aging. Individual behaviors and environmental factors such as nutrition affect the life-span by impact the telomerase activity rate. Healthy eating habits, including antioxidant intakes, such as polyphenols, can have a positive effect on telomere length by this mechanism. In this review, after studying the underlying mechanisms of aging and understanding the relationships between telomeres, telomerase, and aging, it has been attempted to explain the effect of polyphenols on reversing the oxidative stress and aging process.
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30
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Kim HY, Lee CY, Kim H, Park KS, Park HG. Portable glucose meter-utilized label-free and washing-free telomerase assay. Analyst 2020; 145:5578-5583. [PMID: 32627768 DOI: 10.1039/d0an00655f] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We herein describe a portable glucose meter (PGM)-utilized label-free and washing-free method for the facile determination of telomerase activity that relies on the kinase-catalyzed cascade enzymatic reaction (KCER) that transduces the telomerase activity to the glucose level. In the sensor, the telomerase that elongates telomere sequences ((TTAGGG)n) from the 3'-terminus of telomerase substrate primer (TSP) consumes deoxynucleoside triphosphate (dNTP), which serves as a phosphate source for KCER promoted by hexokinase and pyruvate kinase. Thus, the presence of telomerase protects KCER from working effectively, resulting in the maintenance of an initial, high glucose level that is readily determined using hand-held PGM. With this strategy, the telomerase activities in various types of cell lines were successfully determined with high sensitivity. Furthermore, the ability of this method to screen candidate inhibitors for telomerase activity was also verified.
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Affiliation(s)
- Hyo Yong Kim
- Department of Chemical and Biomolecular Engineering (BK21+ Program), KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
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Galangin Inhibits Cholangiocarcinoma Cell Growth and Metastasis through Downregulation of MicroRNA-21 Expression. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5846938. [PMID: 32626749 PMCID: PMC7306077 DOI: 10.1155/2020/5846938] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 04/25/2020] [Indexed: 02/06/2023]
Abstract
Galangin, a natural flavonoid product derived from the root of galangal, is emerging as a promising anticancer agent against multiple cancers. Yet, whether it also has antitumor effects on cholangiocarcinoma (CCA) and the underlying mechanism is still unknown. Herein, we demonstrate that galangin exhibits multiple antitumor effects on CCA cells including decreases cell viability; inhibits proliferation, migration, and invasion; and induces apoptosis. Moreover, those phenotypic changes are associated with downregulated microRNA-21 (miR-21) expression. To support, overexpression of miR-21 blocks galangin-mediated antisurvival and metastasis effects on CCA cells. Mechanically, galangin increases the expression of phosphatase and tensin homolog (PTEN), a direct target of miR-21, resulting in decreased phosphorylation of AKT, a protein kinase which plays a critical role in controlling survival and apoptosis. In contrast, overexpression of miR-21 abrogates galangin-regulated PTEN expression and AKT phosphorylation. Taken together, these findings indicate that galangin inhibits CCA cell proliferation and metastasis and induces cell apoptosis through a miR-21-dependent manner, and galangin may provide a novel potential therapeutic adjuvant to treat CCA.
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32
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Rodvold JJ, Xian S, Nussbacher J, Tsui B, Cameron Waller T, Searles SC, Lew A, Jiang P, Babic I, Nomura N, Lin JH, Kesari S, Carter H, Zanetti M. IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells. Sci Rep 2020; 10:8348. [PMID: 32433555 PMCID: PMC7239929 DOI: 10.1038/s41598-020-65320-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 04/22/2020] [Indexed: 12/20/2022] Open
Abstract
To date current therapies of glioblastoma multiforme (GBM) are largely ineffective. The induction of apoptosis by an unresolvable unfolded protein response (UPR) represents a potential new therapeutic strategy. Here we tested 12ADT, a sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor, on a panel of unselected patient-derived neurosphere-forming cells and found that GBM cells can be distinguished into "responder" and "non-responder". By RNASeq analysis we found that the non-responder phenotype is significantly linked with the expression of UPR genes, and in particular ERN1 (IRE1) and ATF4. We also identified two additional genes selectively overexpressed among non-responders, IGFBP3 and IGFBP5. CRISPR-mediated deletion of the ERN1, IGFBP3, IGFBP5 signature genes in the U251 human GBM cell line increased responsiveness to 12ADT. Remarkably, >65% of GBM cases in The Cancer Genome Atlas express the non-responder (ERN1, IGFBP3, IGFBP5) gene signature. Thus, elevated levels of IRE1α and IGFBPs predict a poor response to drugs inducing unresolvable UPR and possibly other forms of chemotherapy helping in a better stratification GBM patients.
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Affiliation(s)
- Jeffrey J Rodvold
- The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman Drive, La Jolla, CA, 92093-0815, USA
| | - Su Xian
- Division of Medical Genetics, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Julia Nussbacher
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA
| | - Brian Tsui
- Division of Medical Genetics, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - T Cameron Waller
- Division of Medical Genetics, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Stephen C Searles
- The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman Drive, La Jolla, CA, 92093-0815, USA
| | - Alyssa Lew
- The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman Drive, La Jolla, CA, 92093-0815, USA
| | - Pengfei Jiang
- Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USA
| | - Ivan Babic
- Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USA
| | - Natsuko Nomura
- Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USA
| | - Jonathan H Lin
- Department of Pathology, Stanford University, Palo Alto, CA, 94305, USA
| | - Santosh Kesari
- Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USA.
| | - Hannah Carter
- Division of Medical Genetics, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
| | - Maurizio Zanetti
- The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego 9500 Gilman Drive, La Jolla, CA, 92093-0815, USA.
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Comparative Cytogenetic Mapping and Telomere Analysis Provide Evolutionary Predictions for Devil Facial Tumour 2. Genes (Basel) 2020; 11:genes11050480. [PMID: 32354058 PMCID: PMC7290341 DOI: 10.3390/genes11050480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/06/2020] [Accepted: 04/26/2020] [Indexed: 01/20/2023] Open
Abstract
The emergence of a second transmissible tumour in the Tasmanian devil population, devil facial tumour 2 (DFT2), has prompted questions on the origin and evolution of these transmissible tumours. We used a combination of cytogenetic mapping and telomere length measurements to predict the evolutionary trajectory of chromosome rearrangements in DFT2. Gene mapping by fluorescence in situ hybridization (FISH) provided insight into the chromosome rearrangements in DFT2 and identified the evolution of two distinct DFT2 lineages. A comparison of devil facial tumour 1 (DFT1) and DFT2 chromosome rearrangements indicated that both started with the fusion of a chromosome, with potentially critically short telomeres, to chromosome 1 to form dicentric chromosomes. In DFT1, the dicentric chromosome resulted in breakage–fusion–bridge cycles leading to highly rearranged chromosomes. In contrast, the silencing of a centromere on the dicentric chromosome in DFT2 stabilized the chromosome, resulting in a less rearranged karyotype than DFT1. DFT2 retains a bimodal distribution of telomere length dimorphism observed on Tasmanian devil chromosomes, a feature lost in DFT1. Using long term cell culture, we observed homogenization of telomere length over time. We predict a similar homogenization of telomere lengths occurred in DFT1, and that DFT2 is unlikely to undergo further substantial rearrangements due to maintained telomere length.
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34
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Huang S, Zhang Q, Yao H, Wang W, Zhang JR, Zhu JJ. Quantitative Detection and Imaging of Multiple Biological Molecules in Living Cells for Cell Screening. ACS Sens 2020; 5:1149-1157. [PMID: 32164417 DOI: 10.1021/acssensors.0c00170] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Because of insufficient information, a single biomarker is not sufficient for early diagnosis of cancer, whereas sensitive and selective detection of multiple biomolecules can significantly reduce analysis time, sample size, and accurately perform cell screening in early cancer. Therefore, the development of a noninvasive strategy that can simultaneously quantify multiple biomarkers (i.e., nucleic acids, proteins, and small molecules) in a single cell is particularly important. Herein, a universal sensing system (functional DNA@mesoporous silica nanoparticles (MSN)-Black Hole Quencher-rhodamine 6G (RhB), FDSBR), which is based on the combination of functionalized DNA and smart responsive nanomaterial, was successfully constructed. After incubation with the cells, different types of targets trigger the strand displacement reaction to release the fluorophore-labeled nucleic acids as the output signals to reflect the intracellular level of the telomerase and adenosine triphosphate (ATP), respectively. Simultaneously, intracellular miR-21 can be clearly indicated by the restored fluorescence of RhB when the caged double-stranded DNA was substituted into single-stranded DNA to open the pore. The concentrations of intracellular telomerase, miR-21, and ATP were identified successfully in three cell lines at the single-cell level. The results show that the contents of three biomolecules have significant differences in the three model cell lines and provide a promising route for developing innovative early disease diagnosis and cell screening assay.
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Affiliation(s)
- Shan Huang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Qianying Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
| | - Huiqin Yao
- Department of Chemistry, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China
| | - Wenjing Wang
- State Key Laboratory of Agricultural Microbiology, College of Science, Huazhong Agricultural University, Wuhan 430070, China
| | - Jian-Rong Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
- School of Chemistry and Life Science, Nanjing University Jinling College, Nanjing 210089, China
| | - Jun-Jie Zhu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
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Roggisch J, Ecke T, Koch S. Molecular identification of telomerase reverse transcriptase (TERT) promotor mutations in primary and recurrent tumors of invasive and noninvasive urothelial bladder cancer. Urol Oncol 2020; 38:77.e17-77.e25. [DOI: 10.1016/j.urolonc.2019.08.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/09/2019] [Accepted: 08/14/2019] [Indexed: 11/26/2022]
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Nalobin D, Alipkina S, Gaidamaka A, Glukhov A, Khuchua Z. Telomeres and Telomerase in Heart Ontogenesis, Aging and Regeneration. Cells 2020; 9:cells9020503. [PMID: 32098394 PMCID: PMC7072777 DOI: 10.3390/cells9020503] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 12/14/2022] Open
Abstract
The main purpose of the review article is to assess the contributions of telomere length and telomerase activity to the cardiac function at different stages of development and clarify their role in cardiac disorders. It has been shown that the telomerase complex and telomeres are of great importance in many periods of ontogenesis due to the regulation of the proliferative capacity of heart cells. The review article also discusses the problems of heart regeneration and the identification of possible causes of dysfunction of telomeres and telomerase.
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Affiliation(s)
- Denis Nalobin
- Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russian
- Correspondence: ; Tel.: +7-916-939-0990
| | - Svetlana Alipkina
- Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russian
| | - Anna Gaidamaka
- Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russian
| | - Alexander Glukhov
- Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russian
- Department of Biochemistry, Sechenov First Moscow State Medical University, 119991 Moscow, Russian
| | - Zaza Khuchua
- Department of Biochemistry, Sechenov First Moscow State Medical University, 119991 Moscow, Russian
- Institute of Chemical Biology Ilia State University, 0162 Tbilisi, Georgia
- Division of Molecular and Cardiovascular Biology, Cincinnati Children’s Medical Center, Cincinnati, OH 45229, USA
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He G, Song T, Zhang Y, Chen X, Xiong W, Chen H, Sun C, Zhao C, Chen Y, Wu H. TERT rs10069690 polymorphism and cancers risk: A meta-analysis. Mol Genet Genomic Med 2019; 7:e00903. [PMID: 31454181 PMCID: PMC6785442 DOI: 10.1002/mgg3.903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 06/21/2019] [Accepted: 07/17/2019] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Studies have identified that the telomerase reverse transcriptase (TERT) gene polymorphism rs10069690 (C>T) is associated with cancer risk, but the results remain inconclusive. METHODS To provide a more precise estimation of the relationship, we performed a meta-analysis of 45 published studies including 329,035 cases and 730,940 controls. We conducted a search in PubMed, Google Scholar and Web of Science to select studies on the association between rs10069690 and cancer risk. Stratification by ethnicity, cancer type, cancers' classification, source of control, sample size, and genotype method was used to explore the source of heterogeneity. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were evaluated using random effects models. Sensitivity, publication bias, false-positive report probability (FPRP) and statistical power were also assessed. RESULTS The result demonstrated that rs10069690 was significantly associated with an increased risk of cancer overall (OR = 1.09, 95% CI: 1.06-1.12, p < .001) under the allele model. Stratification analysis revealed an increased cancer risk in subgroups of breast cancer, ovarian cancer, lung cancer, thyroid cancer, and renal cell carcinoma (RCC). However, a significantly decreased association was observed in pancreatic cancer in the European population (OR = 0.93,95% CI: 0.87-0.99, p = .031). In the subgroup analysis based on cancer type, no significant association was found in prostate cancer, leukemia, colorectal cancer and glioma. CONCLUSIONS This meta-analysis suggested that the TERT rs10069690 polymorphism may be a risk factor for cancer, especially breast cancer, ovarian cancer, lung cancer, thyroid cancer, and RCC. Further functional studies are warranted to reveal the role of the polymorphism in carcinogenesis.
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Affiliation(s)
- Guisheng He
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
| | - Tao Song
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
| | - Yazhen Zhang
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
| | - Xiuxiu Chen
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
| | - Wei Xiong
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
| | - Huamin Chen
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
| | - Chuanwei Sun
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
| | - Chaoyang Zhao
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
| | - Yunjing Chen
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
| | - Huangfu Wu
- Department of Surgical OncologySecond Affiliated Hospital of Hainan Medical CollegeHaikouHainan ProvinceChina
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Feng E, Zheng T, Tian Y. Dual-Mode Au Nanoprobe Based on Surface Enhancement Raman Scattering and Colorimetry for Sensitive Determination of Telomerase Activity Both in Cell Extracts and in the Urine of Patients. ACS Sens 2019; 4:211-217. [PMID: 30489069 DOI: 10.1021/acssensors.8b01244] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Telomerase is a valuable biomarker, which is highly correlated to cancer diseases. However, the single-mode probe for telomerase detection cannot satisfy the challenge of detection of telomerase activity rapidly, simply with high selectivity, sensitivity, and accuracy both in preliminary diagnosis and in point of care (POC) testing. Therefore, there is an urgent need to develop a robust approach with controllable assembly and high accuracy to consider both the simplification of preliminary diagnosis and POC testing and the quantification requirement for early clinical diagnosis and treatment. Herein, a novel dual-mode Au NPs probe was developed for determination of telomerase activity with controllable assembly and aggregation statement based on surface enhancement Raman scattering (SERS) and colorimetry. In this strategy, an Au dimer-based probe with high uniformity was assembled successfully, telomerase activity was reflected according to the color variations of solution and the Raman intensity of Raman reporter. Taking advantage of the uniformity of Au dimers and the combination of colorimetry and SERS techniques, our strategy determined the telomerase activity with high accuracy, sensitivity, and wide range. The established probe possessed of high selectivity, sensitivity, and accuracy, which was approved as a reliable, intuitional, and convenient approach for detecting telomerase activity.
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Affiliation(s)
- Enduo Feng
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai 200241, P. R. China
| | - Tingting Zheng
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai 200241, P. R. China
| | - Yang Tian
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai 200241, P. R. China
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Amisaki M, Tsuchiya H, Sakabe T, Fujiwara Y, Shiota G. Identification of genes involved in the regulation of TERT in hepatocellular carcinoma. Cancer Sci 2019; 110:550-560. [PMID: 30447097 PMCID: PMC6361581 DOI: 10.1111/cas.13884] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 11/08/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023] Open
Abstract
Telomerase reverse transcriptase (TERT) promotes immortalization by protecting telomeres in cancer cells. Mutation of the TERT promoter is one of the most common genetic alterations in hepatocellular carcinoma (HCC), indicating that TERT upregulation is a critical event in hepatocarcinogenesis. Regulators of TERT transcription are, therefore, predicted to be plausible targets for HCC treatment. We undertook a genome‐wide shRNA library screen and identified C15orf55 and C7orf43 as regulators of TERT expression in HepG2 cells. Promoter assays showed that C15orf55‐ and C7orf43‐responsive sites exist between base pairs −58 and +36 and −169 and −59 in the TERT promoter, respectively. C15orf55 upregulates TERT expression by binding to two GC motifs in the SP1 binding site of the TERT promoter. C7orf43 upregulates TERT expression through Yes‐associated protein 1. The expression levels of C15orf55 and C7orf43 also correlated with that of TERT, and were significantly increased in both HCC tissues and their adjacent non‐tumor tissues, compared to normal liver tissues from non‐HCC patients. Analysis of 377 HCC patients in The Cancer Genome Atlas dataset showed that overall survival of patients with low levels of C15orf55 and C7orf43 expression in tumor tissues was better compared with patients with high levels of C15orf55 and/or high C7orf43 expression. These results indicate that C15orf55 and C7orf43 are involved in the incidence and progression of HCC by upregulating TERT. In conclusion, we identified C15orf55 and C7orf43 as positive regulators of TERT expression in HCC tissues. These genes are promising targets for HCC treatment.
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Affiliation(s)
- Masataka Amisaki
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, Yonago, Japan.,Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago, Japan
| | - Hiroyuki Tsuchiya
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, Yonago, Japan
| | - Tomohiko Sakabe
- Division of Organ Pathology, Department of Pathology, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Yoshiyuki Fujiwara
- Division of Surgical Oncology, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine, Yonago, Japan
| | - Goshi Shiota
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, Yonago, Japan
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40
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Liu C, Zhang S, Li X, Xue Q, Jiang W. Multi-code magnetic beads based on DNAzyme-mediated double-cycling amplification for a point-of-care assay of telomerase activity. Analyst 2019; 144:4241-4249. [DOI: 10.1039/c9an00589g] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Development of a reliable and facile telomerase activity assay with high specificity and sensitivity is a central challenge to make telomerase testing a routine part of medical care with respect to cancer.
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Affiliation(s)
- Chunxue Liu
- Department of Chemistry
- Liaocheng University
- Liaocheng
- China
| | - Susu Zhang
- Department of Chemistry
- Liaocheng University
- Liaocheng
- China
| | - Xia Li
- Department of Chemistry
- Liaocheng University
- Liaocheng
- China
- School of Chemistry and Chemical Engineering
| | - Qingwang Xue
- Department of Chemistry
- Liaocheng University
- Liaocheng
- China
- School of Chemistry and Chemical Engineering
| | - Wei Jiang
- School of Chemistry and Chemical Engineering
- Shandong University
- Jinan 250100
- P.R. China
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41
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Leão R, Lee D, Figueiredo A, Hermanns T, Wild P, Komosa M, Lau I, Mistry M, Nunes NM, Price AJ, Zhang C, Lipman T, Poyet C, Valtcheva N, Oehl K, Coelho H, Sayyid R, Gomes AM, Prado E Castro L, Sweet J, Vinagre J, Apolónio J, Stephens D, Faleiro I, Fadaak K, Richard PO, Kulkarni G, Zlotta AR, Hamilton RJ, Castelo-Branco P, Tabori U. Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer. Int J Cancer 2018; 144:1676-1684. [PMID: 30350309 PMCID: PMC6519346 DOI: 10.1002/ijc.31935] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 09/13/2018] [Accepted: 09/26/2018] [Indexed: 01/08/2023]
Abstract
In urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self‐renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations (TERTpMut) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTpMut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTpMut were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher‐risk disease in nonmuscle invasive bladder cancers (NMIBC). TERTpMut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THORhigh/TERTpMut increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERTpwt and TERTpMut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTpMut is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer. What's new? Telomerase reverse transcriptase (TERT) activation is central to cancer cell immortalization. It acts, however, through relatively unknown mechanisms. In urothelial bladder cancer (UBC) in particular, TERT activation can occur in the presence or absence of mutation, raising questions about alternative activation mechanisms. Our study shows that hypermethylation of the TERT promoter (THOR) plays a key part in UBC, being a dynamic and progressive process, with hypermethylation levels increasing with bladder cancer severity. Moreover, both hypermethylation and TERT promoter mutation contributed to increased telomerase expression. The findings provide insight into telomere biology in UBC and may be applicable to other tumors.
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Affiliation(s)
- Ricardo Leão
- Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada.,Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.,Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Department of Urology, Coimbra University Hospital, Coimbra, Portugal
| | - Donghyun Lee
- Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Arnaldo Figueiredo
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Department of Urology, Coimbra University Hospital, Coimbra, Portugal
| | - Thomas Hermanns
- Department of Urology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Peter Wild
- Institute of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Martin Komosa
- Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Irene Lau
- Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Mathew Mistry
- Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Nuno Miguel Nunes
- Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Aryeh J Price
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA
| | - Cindy Zhang
- Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Tatiana Lipman
- Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Cédric Poyet
- Department of Urology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Nadejda Valtcheva
- Institute of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Kathrin Oehl
- Institute of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Hugo Coelho
- Department of Urology, Coimbra University Hospital, Coimbra, Portugal
| | - Rashid Sayyid
- Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Ana Melo Gomes
- Department of Pathology, Coimbra University Hospital, Coimbra, Portugal
| | | | - Joan Sweet
- Department of Pathology, University Health Network, Toronto, ON, Canada
| | - João Vinagre
- Institute for Research and Innovation in Health, (I3S), Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - Joana Apolónio
- Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.,Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.,Algarve Biomedical Center, Faro, Portugal
| | - Derek Stephens
- Biostatistics, Design and Analysis, The Hospital for Sick Children, Toronto, ON, Canada
| | - Inês Faleiro
- Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.,Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.,Algarve Biomedical Center, Faro, Portugal
| | - Kamel Fadaak
- Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada.,Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
| | - Patrick O Richard
- Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada.,Division of Urology, Faculty of Medicine, CHUS, University of Sherbrooke, Sherbrooke, QC, Canada
| | - Girish Kulkarni
- Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Alexandre R Zlotta
- Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Robert J Hamilton
- Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Pedro Castelo-Branco
- Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal.,Centre for Biomedical Research (CBMR), University of Algarve, Faro, Portugal.,Algarve Biomedical Center, Faro, Portugal
| | - Uri Tabori
- Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
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Wang Z, Zhang Z, Guo Y, Shui H, Liu G, Jin T, Wang H. Shorter Telomere Length Is Associated with Increased Breast Cancer Risk in a Chinese Han Population: A Case-Control Analysis. J Breast Cancer 2018; 21:391-398. [PMID: 30607160 PMCID: PMC6310718 DOI: 10.4048/jbc.2018.21.e52] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 09/03/2018] [Indexed: 12/31/2022] Open
Abstract
Purpose The aim of this study was to investigate the association of telomere length with breast cancer risk. We simultaneously explored the association between telomerase reverse transcriptase gene polymorphisms and telomere length. Methods We used real-time quantitative polymerase chain reaction to measure relative telomere length (RTL) in genomic DNA extracted from peripheral blood from 183 breast cancer cases and 191 healthy controls. Genotyping was performed using the Sequenom MassARRAY platform. Results Our results show that breast cancer patients had significantly shorter RTLs than control subjects (p<0.05). When the RTLs were categorized into tertiles, we found that the lowest RTL was significantly associated with increased breast cancer risk compared with the highest RTL (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.40–3.90; p=0.001). Subgroup analyses indicated that risk of breast cancer was also significantly increased in the lowest RTL compared with the highest RTL in age >40 years (OR, 2.41; 95% CI, 1.31–4.43; p=0.005), body mass index ≤24 kg/m2 (OR, 2.81; 95% CI, 1.55–5.10; p=0.001), and postmenopausal women (OR, 3.94; 95% CI, 1.63–9.51; p=0.002), respectively. In addition, individuals with the AA genotype of rs2853677 have longer telomeres than those of breast cancer patients with the AG genotype (p=0.011). Conclusion Our results suggest that shorter RTL was associated with an increased risk of breast cancer. An association was found between the AA genotype of rs2853677 and longer RTLs in the case group. Functional studies are warranted to validate this association and further investigate our findings.
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Affiliation(s)
- Zhaoxia Wang
- Oncology Department of Integrative Medicine, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China
| | - Zhenxing Zhang
- Oncology Department of Integrative Medicine, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China
| | - Yanling Guo
- Oncology Department of Integrative Medicine, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China
| | - Huifeng Shui
- Oncology Department of Integrative Medicine, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China
| | - Guoqi Liu
- Oncology Department of Integrative Medicine, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China
| | - Tianbo Jin
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, Xi'an, China
| | - Huijie Wang
- Oncology Department of Integrative Medicine, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China
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Thriveni K, Raju A, Kumar RV, Krishnamurthy S, Chaluvarayaswamy R. Patterns of Relative Telomere Length is Associated With hTERT Gene Expression in the Tissue of Patients With Breast Cancer. Clin Breast Cancer 2018; 19:27-34. [PMID: 30217473 DOI: 10.1016/j.clbc.2018.07.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 07/21/2018] [Accepted: 07/22/2018] [Indexed: 11/18/2022]
Abstract
BACKGROUND Homeostasis of telomere in breast cancer might be altered as a result of cumulative effects of various factors causing genomic instability and affecting prognosis. This study aimed to compare the relative telomere length (RTL) and hTERT mRNA expression in the tissue of patients with breast cancer along with the clinicopathologic parameters. PATIENTS AND METHODS Frozen tumor tissues and adjacent normal breast tissue from 98 patients with invasive ductal breast cancer were used for the analysis. RTL and hTERT mRNA expression were measured using quantitative real time polymerase chain reaction. RESULTS Among the 98 cases, 51% had an early-stage carcinoma, 66% were tumor size < 5 cm, 30% were node-negative, and 20% were low-grade tumors. In this study, 63% of cases showed higher hTERT gene expression with an odds ratio of 2.77 (P = .02). The median RTL for elongated telomere was 3.49, and the value was significantly elevated when compared with the shorter telomere. Shortened RTL was present in 60% of early-stage cancer cases, 55% where the tumor size was < 5 cm, 72% of the lymph node-negative cases, and 68% of low-grade carcinoma. Significantly elongated RTL, with median 4.22, 3.19, 3.17, and 3.28 was observed (P < .05) in the advanced stage, larger tumor size, node-positive, and high-grade cases respectively. CONCLUSION In this study, shortened telomere was observed in early-stage cancer, and elongated telomere was found in advanced diseases. However, 13% of patients with lower hTERT gene expression showed elongated telomeres, indicating relative telomere length measurement in tissue is different from blood leukocyte, showing the dynamic process of tumorigenesis in tissue.
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MESH Headings
- Adult
- Biomarkers, Tumor/genetics
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/surgery
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/surgery
- Carcinoma, Lobular/genetics
- Carcinoma, Lobular/pathology
- Carcinoma, Lobular/surgery
- Case-Control Studies
- Cross-Sectional Studies
- Female
- Follow-Up Studies
- Humans
- Neoplasm Grading
- Neoplasm Staging
- Receptor, ErbB-2/metabolism
- Receptors, Estrogen/metabolism
- Receptors, Progesterone/metabolism
- Telomerase/genetics
- Telomere Shortening/genetics
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Affiliation(s)
- Karuvaje Thriveni
- Department of Biochemistry, Kidwai Cancer Institute, Bangalore, India.
| | - Anisha Raju
- Department of Biochemistry, Kidwai Cancer Institute, Bangalore, India
| | - Rekha V Kumar
- Department of Pathology, Kidwai Cancer Institute, Bangalore, India
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Tran PT, Meeker AK, Platz EA. Association between statin drug use and peripheral blood leukocyte telomere length in the National Health and Nutrition Examination Survey 1999-2002: a cross-sectional study. Ann Epidemiol 2018; 28:529-534. [PMID: 29853162 PMCID: PMC6054912 DOI: 10.1016/j.annepidem.2018.04.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 04/23/2018] [Accepted: 04/26/2018] [Indexed: 11/23/2022]
Abstract
PURPOSE To evaluate the association between statin drug use and peripheral blood leukocyte telomere length in a U.S. nationally representative sample of adults. METHODS We conducted a cross-sectional analysis of data from National Health and Nutrition Examination Survey 1999-2002, representative of the noninstitutionalized U.S. POPULATION The analytic study population included 3496 men and women aged 40-84 years without a history of cancer and who had information of telomere length and statin use. RESULTS Compared with nonusers, statin users were more likely to be former smokers, older, white, male, and had more comorbidities. Statin users did not have longer telomeres than nonusers after age (coefficient -0.013, p = .30) and multivariable (0.0003, p = .98) adjustment. After multivariable adjustment, log-transformed telomere length nonstatistically significantly increased with increasing duration of use (0.003, p-trend = .11), which did not differ by number of comorbidities (p-interaction = 0.18). Compared with nonuse, more than 5 years of use had an odds ratio of telomere length above the 75th percentile of 1.62 (95% confidence interval 0.90-2.92; p-trend = .10). CONCLUSIONS Although telomere length appeared to be longer with longer duration of use of a statin, this association was not statistically significant, and we could not rule out bias as the explanation.
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Affiliation(s)
- Phuong T Tran
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Faculty of Pharmacy, Ho Chi Minh City University of Technology (HUTECH), Ho Chi Minh City, Vietnam.
| | - Alan K Meeker
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Urology and the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
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Terns MP, Terns RM. Small nucleolar RNAs: versatile trans-acting molecules of ancient evolutionary origin. Gene Expr 2018; 10:17-39. [PMID: 11868985 PMCID: PMC5977530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Abstract
The small nucleolar RNAs (snoRNAs) are an abundant class of trans-acting RNAs that function in ribosome biogenesis in the eukaryotic nucleolus. Elegant work has revealed that most known snoRNAs guide modification of pre-ribosomal RNA (pre-rRNA) by base pairing near target sites. Other snoRNAs are involved in cleavage of pre-rRNA by mechanisms that have not yet been detailed. Moreover, our appreciation of the cellular roles of the snoRNAs is expanding with new evidence that snoRNAs also target modification of small nuclear RNAs and messenger RNAs. Many snoRNAs are produced by unorthodox modes of biogenesis including salvage from introns of pre-mRNAs. The recent discovery that homologs of snoRNAs as well as associated proteins exist in the domain Archaea indicates that the RNA-guided RNA modification system is of ancient evolutionary origin. In addition, it has become clear that the RNA component of vertebrate telomerase (an enzyme implicated in cancer and cellular senescence) is related to snoRNAs. During its evolution, vertebrate telomerase RNA appears to have co-opted a snoRNA domain that is essential for the function of telomerase RNA in vivo. The unique properties of snoRNAs are now being harnessed for basic research and therapeutic applications.
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MESH Headings
- Animals
- Base Pairing
- Biological Transport
- Cell Nucleolus/metabolism
- Cell Nucleus/metabolism
- Eukaryotic Cells/metabolism
- Evolution, Molecular
- Methylation
- Prokaryotic Cells/metabolism
- Pseudouridine/metabolism
- RNA/metabolism
- RNA Precursors/metabolism
- RNA Processing, Post-Transcriptional/genetics
- RNA, Archaeal/genetics
- RNA, Archaeal/physiology
- RNA, Catalytic/metabolism
- RNA, Messenger/metabolism
- RNA, Ribosomal/biosynthesis
- RNA, Small Nucleolar/chemistry
- RNA, Small Nucleolar/classification
- RNA, Small Nucleolar/genetics
- RNA, Small Nucleolar/metabolism
- RNA, Small Nucleolar/physiology
- Ribonucleoproteins, Small Nucleolar/metabolism
- Ribosomes/metabolism
- Species Specificity
- Structure-Activity Relationship
- Telomerase/metabolism
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Affiliation(s)
- Michael P Terns
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens 30602, USA.
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Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene 2018; 37:4058-4072. [PMID: 29695835 PMCID: PMC6062502 DOI: 10.1038/s41388-018-0247-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 02/21/2018] [Accepted: 02/23/2018] [Indexed: 12/31/2022]
Abstract
Targeting RAS is one of the greatest challenges in cancer therapy. Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis. Thus far, there are no clinical agents available to effectively target NRAS or any other RAS oncogene. An alternative approach is to identify and target critical tumor vulnerabilities or non-oncogene addictions that are essential for tumor survival. We investigated the consequences of NRAS blockade in NRAS-mutant melanoma and show that decreased expression of the telomerase catalytic subunit, TERT, is a major consequence. TERT silencing or treatment of NRAS-mutant melanoma with the telomerase-dependent telomere uncapping agent, 6-thio-2'-deoxyguanosine (6-thio-dG), led to rapid cell death, along with evidence of both telomeric and non-telomeric DNA damage, increased ROS levels, and upregulation of a mitochondrial antioxidant adaptive response. Combining 6-thio-dG with the mitochondrial inhibitor Gamitrinib attenuated this adaptive response and more effectively suppressed NRAS-mutant melanoma. Our study uncovers a robust dependency of NRAS-mutant melanoma on TERT, and provides proof-of-principle for a new combination strategy to combat this class of tumors, which could be expanded to other tumor types.
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Sharafi P, Ayter S. Possible modifier genes in the variation of neurofibromatosis type 1 clinical phenotypes. J Neurogenet 2018; 32:65-77. [PMID: 29644913 DOI: 10.1080/01677063.2018.1456538] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Neurofibromatosis type 1 (NF1) is the most common neurogenetic disorder worldwide, caused by mutations in the (NF1) gene. Although NF1 is a single-gene disorder with autosomal-dominant inheritance, its clinical expression is highly variable and unpredictable. NF1 patients have the highest known mutation rate among all human disorders, with no clear genotype-phenotype correlations. Therefore, variations in NF1 mutations may not correlate with the variations in clinical phenotype. Indeed, for the same mutation, some NF1 patients may develop severe clinical symptoms whereas others will develop a mild phenotype. Variations in the mutant NF1 allele itself cannot account for all of the disease variability, indicating a contribution of modifier genes, environmental factors, or their combination. Considering the gene structure and the interaction of neurofibromin protein with cellular components, there are many possible candidate modifier genes. This review aims to provide an overview of the potential modifier genes contributing to NF1 clinical variability.
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Affiliation(s)
- Parisa Sharafi
- a Faculty of Medicine , TOBB University of Economics and Technology , Ankara , Turkey
| | - Sükriye Ayter
- a Faculty of Medicine , TOBB University of Economics and Technology , Ankara , Turkey
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Dong F, Feng E, Zheng T, Tian Y. In Situ Synthesized Silver Nanoclusters for Tracking the Role of Telomerase Activity in the Differentiation of Mesenchymal Stem Cells to Neural Stem Cells. ACS APPLIED MATERIALS & INTERFACES 2018; 10:2051-2057. [PMID: 29271193 DOI: 10.1021/acsami.7b16949] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Human mesenchymal stem cells (hMSCs) have potential use in cell replacement therapy for central nervous system disorders. However, the factors that impacted the differentiation process are unclear at the present stage because the powerful analytical method is the bottleneck. Herein, a novel strategy was developed for self-imaging and biosensing of telomerase activity in stem cells, using in situ biosynthesized silver nanoclusters (AgNCs) full of C bases. The present AgNCs possess synthetic convenience, long-time stability, and cytocompatibility. The weak fluorescence of these AgNCs is quickly turned on when approaching telomerase because of the strong interaction between C bases on AgNCs and G bases in telomerase, resulting in telomerase-dependent fluorescent signals. The developed method demonstrated high sensitivity and selectivity and broad dynamic linear range with a low detection limit. Using this powerful tool, it was first discovered that telomerase activity plays important roles in the proliferation of hMSCs and neural stem cells (NSCs) as well as during the differentiation processes from hMSCs to NSCs.
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Affiliation(s)
- Fangyuan Dong
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University , Dongchuan Road 500, Shanghai 200241, China
| | - Enduo Feng
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University , Dongchuan Road 500, Shanghai 200241, China
| | - Tingting Zheng
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University , Dongchuan Road 500, Shanghai 200241, China
| | - Yang Tian
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University , Dongchuan Road 500, Shanghai 200241, China
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Huang S, Yao H, Wang W, Zhang JR, Zhu JJ. Highly sensitive fluorescence quantification of intracellular telomerase activity by repeat G-rich DNA enhanced silver nanoclusters. J Mater Chem B 2018; 6:4583-4591. [DOI: 10.1039/c8tb00801a] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
As an important biomarker for early cancer diagnosis and a valuable therapeutic target, the detection and monitoring of telomerase activity has attracted extensive attention.
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Affiliation(s)
- Shan Huang
- State Key Laboratory of Analytical Chemistry for Life Science
- School of Chemistry and Chemical Engineering
- Nanjing University
- Nanjing
- China
| | - Huiqin Yao
- Department of Chemistry
- School of Basic Medical Sciences
- Ningxia Medical University
- Yinchuan
- China
| | - Wenjing Wang
- State Key Laboratory of Analytical Chemistry for Life Science
- School of Chemistry and Chemical Engineering
- Nanjing University
- Nanjing
- China
| | - Jian-Rong Zhang
- School of Chemistry and Life Science
- Nanjing University Jinling College
- Nanjing 210089
- China
| | - Jun-Jie Zhu
- State Key Laboratory of Analytical Chemistry for Life Science
- School of Chemistry and Chemical Engineering
- Nanjing University
- Nanjing
- China
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Wu D, Zhu G, Zeng J, Song W, Wang K, Wang X, Guo P, He D. Genetic variations in TERC and TERT genes are associated with renal cell carcinoma risk in a Chinese Han population. Oncotarget 2017; 8:76832-76842. [PMID: 29100352 PMCID: PMC5652746 DOI: 10.18632/oncotarget.20163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 06/27/2017] [Indexed: 12/19/2022] Open
Abstract
Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system, the pathogenesis of RCC is still unclear. It is reported that genetic variations in telomere length related-genes TERT and TERC are involved in the many types of cancers. However, little is known about the association between TERT and TERC polymorphisms and susceptibility to RCC risk. To solve this problem, a total of 293 patients with primary renal cell carcinoma and 459 healthy people were recruited in our study. Six SNPs of TERC and TERT were genotyped, and association analysis was performed. We found TERC-rs35073794 and TERT-rs10069690 were associated with an increased risk of RCC in an allele model. (OR =2.39, 95% CI = 0.99-5.80, p = 0.047; OR =1.39, 95% CI = 1.07-1.81, p = 0.014, respectively). The genotype "TC" of rs10069690 was associated with an increased risk of RCC in the genotype model. (OR =1.52, 95% CI = 1.11-2.08, p = 0.009).TERC-rs35073794 was associated with an increased risk of RCC in the codominant model. (OR =2.61, 95% CI = 1.01-6.76, p = 0.045). Rs10069690 was associated with an increased risk of RCC under the dominant model. (OR=1.44, 95% CI= 1.04-2.01, p = 0.03). Haplotype "CA" was found to be associated with a decreased risk of RCC while haplotype "TA" was associated with an increased risk of RCC without adjustment for gender, age and body mass index (BMI). (OR=0.07; 95% CI= 0.01-0.54; p=0.011; OR= 1.24; 95% CI= 0.92-1.65; p=0.013, respectively). Rs35073794, rs10936599 and rs10069690 were positively correlated with the age older than 55 (OR= 3.27, 95%CI= 1.08-9.93, p=0.031; OR= 1.56, 95%CI= 1.03-2.37, p= 0.034; OR= 4.94, 95%CI= 1.18-20.70, p= 0.022, respectively) with or without history of drinking(OR= 4.47, 95%CI= 0.99-20.25, p= 0.024; OR= 2.62, 95%CI= 1.13-6.08, p= 0.022; OR=2.44, 95%CI=1.03-5.78, p= 0.04, respectively) and clinical stage I/II RCC (OR=2.62, 95%CI=1.02-6.74, p= 0.045; OR= 2.23, 95%CI= 1.08-4.60, p= 0.028; OR= 1.63, 95%CI= 1.17-2.27, p= 0.014, respectively). Our study indicated a significant association between SNPs in the TERC, TERT and RCC risk in a Chinese Han population. It could be used as diagnostic and prognostic markers in clinical studies of renal cell carcinoma patients.
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Affiliation(s)
- Dapeng Wu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Guodong Zhu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Jin Zeng
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Wenbin Song
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Ke Wang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Xinyang Wang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Peng Guo
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Dalin He
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
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