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Li HX, Fei J, Xu W, Peng Y, Yan PJ, Xu Y, Qin G, Teng FY. The characterization and validation of regulated cell death-related genes in chronic rhinosinusitis with nasal polyps. Int Immunopharmacol 2025; 154:114509. [PMID: 40158428 DOI: 10.1016/j.intimp.2025.114509] [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: 12/19/2024] [Revised: 02/20/2025] [Accepted: 03/16/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Regulated cell death (RCD), a genetically controlled process mediated by specialized molecular pathways (commonly termed programmed cell death), plays pivotal roles in diverse pathophysiological processes. However, the landscape and functional implications of RCD subtypes in chronic rhinosinusitis with nasal polyps (CRSwNP) remain poorly characterized. This study aimed to systematically investigate the involvement of RCD mechanisms in the pathogenesis and progression of CRSwNP. METHODS Transcriptomic datasets (GSE136825, GSE23552, GSE198950, GSE196169, GSE156285) related to CRSwNP were retrieved from the Gene Expression Omnibus (GEO) database. A comprehensive panel of 18 RCD-associated gene sets was compiled through a systematic literature review. Gene set variation analysis (GSVA) was employed to profile RCD activation patterns in CRSwNP. Integrative bioinformatics approaches including weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression were implemented to identify hub RCD-related genes and construct a cell death index (CDI). Single-cell RNA sequencing (scRNA-seq) data were analyzed to map RCD dynamics across cellular subpopulations. Clinical validation was performed using qRT-PCR quantification of key genes in nasal polyp/inferior turbinate tissues, with the concurrent assessment of symptom severity via visual analogue scale (VAS) scores. RESULTS GSVA revealed significant upregulation of 8 RCD subtypes in CRSwNP: apoptosis, ferroptosis, necroptosis, entotic cell death, lysosome-dependent cell death, NETosis, immunogenic cell death, and anoikis. Pathway enrichment analysis demonstrated that RCD-related differentially expressed genes were predominantly involved in epithelial-mesenchymal transition (EMT) and immune-inflammatory regulation. Furthermore, the WGCNA algorithm and LASSO analysis identified 8 key cell death genes (PTHLH, GRINA, S100A9, SCG2, HMOX1, RNF183, TYROBP, SEMA7A), which were utilized to construct the cell death-related index (CDI). In training and validation cohorts, the CDI was significantly elevated in CRSwNP compared to control and exhibited high diagnostic performance, with elevated scores correlating with enhanced immune cell infiltration. Single-cell resolution analysis uncovered cell type-specific RCD activation patterns. Clinical validation confirmed significantly higher expression of S100A9, PTHLH, and HMOX1 in eosinophilic versus non-eosinophilic polyps. Notably, expression levels of PTHLH, S100A9, HMOX1, GRINA, and TYROBP showed strong positive correlations with VAS scores. CONCLUSIONS Our investigation delineates an RCD activation signature in CRSwNP pathogenesis, characterized by 8 key cell death modalities and their regulatory genes. The novel CDI exhibits promising diagnostic potential, while mechanistic insights suggest RCD pathways may drive disease progression through EMT potentiation and inflammatory cascade amplification. These findings provide a framework for developing RCD-targeted therapeutic strategies in CRSwNP.
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Affiliation(s)
- Hong-Xia Li
- Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Metabolic Vascular Diseases Key Laboratory of Sichuan Province, and Metabolic Vascular Diseases Key Laboratory of Sichuan-Chongqing Cooperation, Luzhou, Sichuan 646000, China
| | - Jing Fei
- Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Wei Xu
- Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yi Peng
- Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Pi-Jun Yan
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, and Metabolic Vascular Diseases Key Laboratory of Sichuan-Chongqing Cooperation, Luzhou, Sichuan 646000, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Sichuan Clinical Research Center for Nephropathy, and Sichuan Clinical Research Center for Diabetes and Metabolic Disease, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yong Xu
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, and Metabolic Vascular Diseases Key Laboratory of Sichuan-Chongqing Cooperation, Luzhou, Sichuan 646000, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Sichuan Clinical Research Center for Nephropathy, and Sichuan Clinical Research Center for Diabetes and Metabolic Disease, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Gang Qin
- Department of Otolaryngology-Head and Neck Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
| | - Fang-Yuan Teng
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, and Metabolic Vascular Diseases Key Laboratory of Sichuan-Chongqing Cooperation, Luzhou, Sichuan 646000, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Sichuan Clinical Research Center for Nephropathy, and Sichuan Clinical Research Center for Diabetes and Metabolic Disease, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
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Cao C, Gong W, Shuai Y, Rasouli S, Ge Q, Khan A, Dakic A, Putluri N, Shvets G, Zheng YL, Daneshdoust D, Mahyoob R, Li J, Liu X. Canonical and non-canonical functions of the non-coding RNA component (TERC) of telomerase complex. Cell Biosci 2025; 15:30. [PMID: 40025596 PMCID: PMC11871756 DOI: 10.1186/s13578-025-01367-0] [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: 12/23/2024] [Accepted: 02/11/2025] [Indexed: 03/04/2025] Open
Abstract
The telomerase complex consists of a protein component (TERT), which has reverse transcriptase activity, and an RNA component (TERC), which serves as a template for telomere synthesis. Evidence is rapidly accumulating regarding the non-canonical functions of these components in both normal or diseased cells. An oligonucleotide-based drug, the first telomerase inhibitor, secured FDA approval in June 2024. We recently summarized the non-canonical functions of TERT in viral infections and cancer. In this review, we expand on these non-canonical functions of TERC beyond telomere maintenance. Specifically, we explore TERC's roles in cellular aging and senescence, immune regulation, genetic diseases, human cancer, as well as involvement in viral infections and host interactions. Finally, we discuss a transcription product of telomere repeats, TERRA, and explore strategies for targeting TERC as a therapeutic approach.
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Affiliation(s)
- Chongwen Cao
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Weiyi Gong
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
- Biomedical Science Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Yuanlong Shuai
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
- Biomedical Science Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Sara Rasouli
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
- Biomedical Science Graduate Program, The Ohio State University, Columbus, OH, USA
| | - Qianyun Ge
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Anam Khan
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Aleksandra Dakic
- Division of Neuroscience, National Institute of Aging, Bethesda, MD, USA
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Gennady Shvets
- School of Applied and Engineering Physics, Cornell University, Ithaca, NY, USA
| | - Yun-Ling Zheng
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Danyal Daneshdoust
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Rani Mahyoob
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Jenny Li
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
- Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Xuefeng Liu
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
- Departments of Pathology, Urology and Radiation Oncology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
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Sater MS, AlDehaini DMB, Malalla ZHA, Ali ME, Giha HA. A Perceived Dissociation Between Systemic Chronic Inflammation, Age, and the Telomere/Telomerase System in Type 2 Diabetes. Biomedicines 2025; 13:531. [PMID: 40149509 PMCID: PMC11940364 DOI: 10.3390/biomedicines13030531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 03/29/2025] Open
Abstract
Background: Chronic inflammation is associated with leukocyte telomere length (LTL) shortening and type 2 diabetes (T2D). The latter is also associated with LTL shortening, while the three variables are associated with aging. Objective: It is tempting to test whether inflammation, age, or both are behind the telomere system aberrations in diabetic patients. Methods: In this cross-sectional observational study, blood samples collected from 118 T2D patients were analyzed via ELISA to estimate the plasma levels of four inflammatory markers, IL6, IL8, TREM1, and uPAR, and the telomerase enzyme (TE). Moreover, the extracted DNA was used for the LTL estimation via qPCR and for single nucleotide polymorphisms (SNP) genotyping of TE genes (TERT, TERC, and ACYP2) via rtPCR. Results: The results showed no correlation between the levels of all tested inflammatory markers and the LTL, TE level, and age. There were no significant differences between the marker levels in diabetic patients in the four quartiles of the LTL and TE levels. Moreover, there were no significant differences in the levels of the markers between carriers of the different TE genotypes. Conclusions: There were no associations between the tested inflammatory markers' levels and the LTL, TE plasma levels, or age in T2D. Explanations for the dissociation between the above-known associations in T2D were proposed; however, the subject is worth further investigation.
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Affiliation(s)
- Mai S. Sater
- Department of Biochemistry, College of Medicine and Health Sciences (CMHS), Arabian Gulf University (AGU), Manama P.O. Box 26671, Bahrain; (D.M.B.A.); (Z.H.A.M.); (M.E.A.)
| | - Dhuha M. B. AlDehaini
- Department of Biochemistry, College of Medicine and Health Sciences (CMHS), Arabian Gulf University (AGU), Manama P.O. Box 26671, Bahrain; (D.M.B.A.); (Z.H.A.M.); (M.E.A.)
- Kuwait Medical Genetic Center, Al-Assima (Kuwait) P.O. Box 22488, Alsafat, Kuwait City 13085, Kuwait
| | - Zainab H. A. Malalla
- Department of Biochemistry, College of Medicine and Health Sciences (CMHS), Arabian Gulf University (AGU), Manama P.O. Box 26671, Bahrain; (D.M.B.A.); (Z.H.A.M.); (M.E.A.)
| | - Muhalab E. Ali
- Department of Biochemistry, College of Medicine and Health Sciences (CMHS), Arabian Gulf University (AGU), Manama P.O. Box 26671, Bahrain; (D.M.B.A.); (Z.H.A.M.); (M.E.A.)
| | - Hayder A. Giha
- Medical Biochemistry and Molecular Biology, Khartoum, Sudan;
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Wu S, Cai Y, Zhang L, Li X, Liu X, Zhou G, Luo H, Li R, Huo Y, Zhang Z, Chen S, Huang J, Shi J, Ding S, Sun Z, Zhou Z, Wang P, Wang G. Noncoding RNA Terc-53 and hyaluronan receptor Hmmr regulate aging in mice. Protein Cell 2025; 16:28-48. [PMID: 38721690 DOI: 10.1093/procel/pwae023] [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: 01/14/2024] [Accepted: 04/11/2024] [Indexed: 01/07/2025] Open
Abstract
One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.
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Affiliation(s)
- Sipeng Wu
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Yiqi Cai
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Lixiao Zhang
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Xiang Li
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Xu Liu
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Guangkeng Zhou
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Hongdi Luo
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Renjian Li
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Yujia Huo
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Zhirong Zhang
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Siyi Chen
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Jinliang Huang
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Jiahao Shi
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Shanwei Ding
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Zhe Sun
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Zizhuo Zhou
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Pengcheng Wang
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Geng Wang
- State Key Laboratory for Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361102, China
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Reisser Y, Hornung F, Häder A, Lauf T, Nietzsche S, Löffler B, Deinhardt-Emmer S. Telomerase RNA component knockout exacerbates Staphylococcus aureus pneumonia by extensive inflammation and dysfunction of T cells. eLife 2024; 13:RP100433. [PMID: 39607755 PMCID: PMC11604217 DOI: 10.7554/elife.100433] [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: 11/29/2024] Open
Abstract
The telomerase RNA component (Terc) constitutes a non-coding RNA critical for telomerase function, commonly associated with aging and pivotal in immunomodulation during inflammation. Our study unveils heightened susceptibility to pneumonia caused by Staphylococcus aureus (S. aureus) in Terc knockout (Tercko/ko) mice compared to both young and old infected counterparts. The exacerbated infection in Tercko/ko mice correlates with heightened inflammation, manifested by elevated interleukin-1β (IL-1β) levels and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome within the lung. Employing mRNA sequencing methods alongside in vitro analysis of alveolar macrophages (AMs) and T cells, our study elucidates a compelling correlation between Tercko/ko, inflammation, and impaired T cell functionality. Terc deletion results in compromised T cell function, characterized by dysregulation of the T cell receptor and absence of CD247, potentially compromising the host's capacity to mount an effective immune response against S. aureus. This investigation provides insights into the intricate mechanisms governing increased vulnerability to severe pneumonia in the context of Terc deficiency, which might also contribute to aging-related pathologies, while also highlighting the influence of Terc on T cell function.
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Affiliation(s)
- Yasmina Reisser
- Institute of Medical Microbiology, Jena University HospitalJenaGermany
| | - Franziska Hornung
- Institute of Medical Microbiology, Jena University HospitalJenaGermany
| | - Antje Häder
- Institute of Medical Microbiology, Jena University HospitalJenaGermany
| | - Thurid Lauf
- Institute of Medical Microbiology, Jena University HospitalJenaGermany
- Else Kröner Graduate School for Medical Students 'JSAM', Jena University HospitalJenaGermany
| | - Sandor Nietzsche
- Center for Electron Microscopy, Jena University HospitalJenaGermany
| | - Bettina Löffler
- Institute of Medical Microbiology, Jena University HospitalJenaGermany
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Burkatovskii D, Bogorodskiy A, Maslov I, Moiseeva O, Chuprov-Netochin R, Smirnova E, Ilyinsky N, Mishin A, Leonov S, Bueldt G, Gordeliy V, Gensch T, Borshchevskiy V. Examining transfer of TERT to mitochondria under oxidative stress. Sci Rep 2024; 14:24185. [PMID: 39406807 PMCID: PMC11480324 DOI: 10.1038/s41598-024-75127-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 10/01/2024] [Indexed: 10/19/2024] Open
Abstract
The primary role of telomerase is the lengthening of telomeres. Nonetheless, emerging evidence highlights additional functions of telomerase outside of the nucleus. Specifically, its catalytic subunit, TERT (Telomerase Reverse Transcriptase), is detected in the cytosol and mitochondria. Several studies have suggested an elevation in TERT concentration within mitochondria in response to oxidative stress. However, the origin of this mitochondrial TERT, whether transported from the nucleus or synthesized de novo, remains uncertain. In this study, we investigate the redistribution of TERT, labeled with a SNAP-tag, in response to oxidative stress using laser scanning fluorescence microscopy. Our findings reveal that, under our experimental conditions, there is no discernible transport of TERT from the nucleus to the mitochondria due to oxidative stress.
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Affiliation(s)
- Dmitrii Burkatovskii
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
| | - Andrey Bogorodskiy
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
| | - Ivan Maslov
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
| | - Olga Moiseeva
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
- G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", 5 Prospekt Nauki, Pushchino, 142290, Russian Federation
| | - Roman Chuprov-Netochin
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
| | - Ekaterina Smirnova
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
| | - Nikolay Ilyinsky
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
| | - Alexey Mishin
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
| | - Sergey Leonov
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
- Institute of Cell Biophysics, Russian Academy of Sciences, Institutskaya st., Pushchino, 142290, Russian Federation
| | - Georg Bueldt
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
| | - Valentin Gordeliy
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation
| | - Thomas Gensch
- Laboratory for Photochemistry and Spectroscopy, Division for Molecular Imaging and Photonics, Department of Chemistry, KU Leuven, 3001, Leuven, Belgium
| | - Valentin Borshchevskiy
- Moscow Institute of Physics and Technology (MIPT), 9 Institutsky lane, Dolgoprudny, 141700, Russian Federation.
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Rubtsova MP, Nikishin DA, Vyssokikh MY, Koriagina MS, Vasiliev AV, Dontsova OA. Telomere Reprogramming and Cellular Metabolism: Is There a Link? Int J Mol Sci 2024; 25:10500. [PMID: 39408829 PMCID: PMC11476947 DOI: 10.3390/ijms251910500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Telomeres-special DNA-protein structures at the ends of linear eukaryotic chromosomes-define the proliferation potential of cells. Extremely short telomeres promote a DNA damage response and cell death to eliminate cells that may have accumulated mutations after multiple divisions. However, telomere elongation is associated with the increased proliferative potential of specific cell types, such as stem and germ cells. This elongation can be permanent in these cells and is activated temporally during immune response activation and regeneration processes. The activation of telomere lengthening mechanisms is coupled with increased proliferation and the cells' need for energy and building resources. To obtain the necessary nutrients, cells are capable of finely regulating energy production and consumption, switching between catabolic and anabolic processes. In this review, we focused on the interconnection between metabolism programs and telomere lengthening mechanisms during programmed activation of proliferation, such as in germ cell maturation, early embryonic development, neoplastic lesion growth, and immune response activation. It is generally accepted that telomere disturbance influences biological processes and promotes dysfunctionality. Here, we propose that metabolic conditions within proliferating cells should be involved in regulating telomere lengthening mechanisms, and telomere length may serve as a marker of defects in cellular functionality. We propose that it is possible to reprogram metabolism in order to regulate the telomere length and proliferative activity of cells, which may be important for the development of approaches to regeneration, immune response modulation, and cancer therapy. However, further investigations in this area are necessary to improve the understanding and manipulation of the molecular mechanisms involved in the regulation of proliferation, metabolism, and aging.
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Affiliation(s)
- Maria P. Rubtsova
- Chemistry Department, Lomonosov Moscow State University, Moscow 119234, Russia; (M.S.K.); (O.A.D.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117437, Russia
| | - Denis A. Nikishin
- Department of Embryology, Faculty of Biology, Lomonosov Moscow State University, Moscow 119234, Russia; (D.A.N.); (A.V.V.)
| | - Mikhail Y. Vyssokikh
- A.N.Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia;
| | - Maria S. Koriagina
- Chemistry Department, Lomonosov Moscow State University, Moscow 119234, Russia; (M.S.K.); (O.A.D.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117437, Russia
| | - Andrey V. Vasiliev
- Department of Embryology, Faculty of Biology, Lomonosov Moscow State University, Moscow 119234, Russia; (D.A.N.); (A.V.V.)
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, Moscow 119334, Russia
| | - Olga A. Dontsova
- Chemistry Department, Lomonosov Moscow State University, Moscow 119234, Russia; (M.S.K.); (O.A.D.)
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117437, Russia
- A.N.Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia;
- Skolkovo Institute of Science and Technology, Center for Molecular and Cellular Biology, Moscow 121205, Russia
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Sun H, Li X, Long Q, Wang X, Zhu W, Chen E, Zhou W, Yang H, Huang C, Deng W, Chen M. TERC promotes non-small cell lung cancer progression by facilitating the nuclear localization of TERT. iScience 2024; 27:109869. [PMID: 38799568 PMCID: PMC11126826 DOI: 10.1016/j.isci.2024.109869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/26/2024] [Accepted: 04/29/2024] [Indexed: 05/29/2024] Open
Abstract
The core of telomerase consists of the protein subunit telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC). So far, the role of TERC in cancer development has remained elusive. Here, we found TERC expression elevated in non-small cell lung cancer (NSCLC) tissues, which was associated with disease progression and poor prognosis in patients. Using NSCLC cell lines and xenograft models, we showed that knockdown of TERC caused cell cycle arrest, and inhibition of cell proliferation and migration. Mechanistically, TERC was exported to the cytoplasm by nuclear RNA export factor 1 (NXF1), where it mediated the interaction of TERT with other telomerase subunits. Depletion of TERC hindered the assembly and subsequent nuclear localization of the telomerase complex, preventing TERT from functioning in telomere maintenance and transcription regulation. Our findings suggest that TERC is a potential biomarker for NSCLC diagnosis and prognosis and can be a target for NSCLC treatment.
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Affiliation(s)
- Haohui Sun
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Xiaodi Li
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Qian Long
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xiaonan Wang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Wancui Zhu
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Enni Chen
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Wenhao Zhou
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Han Yang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Chuyang Huang
- Department of Urology, Shaoyang Central Hospital, University of South China, Shaoyang, Hunan 422000, China
| | - Wuguo Deng
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Miao Chen
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
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Ni J, Huang K, Xu J, Lu Q, Chen C. Novel biomarkers identified by weighted gene co-expression network analysis for atherosclerosis. Herz 2024; 49:198-209. [PMID: 37721628 DOI: 10.1007/s00059-023-05204-3] [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: 04/21/2023] [Revised: 04/21/2023] [Accepted: 07/25/2023] [Indexed: 09/19/2023]
Abstract
BACKGROUND This study aimed to screen out the potential diagnostic biomarkers for atherosclerosis (AS). METHODS We downloaded the gene expression profiles GSE66360, GSE28829, GSE41571, GSE71226, and GSE100927 from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the "limma" package in R. Weighted gene co-expression network analysis (WGCNA) was applied to reveal the correlation between genes in different samples. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The interaction pairs of proteins were retained by the STRING database, and the protein-protein interaction (PPI) network was visualized with the hub genes. Finally, the R packages "ggpubr" and "preprocessCore" were used to analyze immune cell infiltration. RESULTS In total, 40 overlapping genes both in GSE66360 and GSE28829 were found to be related to the occurrence of AS. Further, the top 10 network hub genes including TYROBP, CSF1R, TLR2, CD14, CCL4, FCER1G, CD163, TREM1, PLEK, and C5AR1 were identified as significant key genes. Moreover, four genes (TYROBP, CSF1R, FCGR1B, and CD14) were verified that could efficiently diagnose AS. Finally, the gene TYROBP was found to have a strong correlation with immune-infiltrating cells. CONCLUSION Our study identified four genes (TYROBP, CSF1R, FCGR1B, and CD14) that may be effective biomarkers for AS, with the potential to guide the clinical diagnosis of AS.
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Affiliation(s)
- Jiajun Ni
- Clinical Medicine-Internal Medicine, School of Medicine of Nantong University, Nantong University, No. 19 Qixiu Road, 22600, Nantong City, Jiangsu Province, China
- Department of Cardiology, Qidong Hospital Affiliated to Nantong University (Qidong People's Hospital), No. 568 Minle Middle Road, 226200, Qidong City, Nantong City, Jiangsu Province, China
| | - Kaijian Huang
- Department of Cardiology, Qidong Hospital Affiliated to Nantong University (Qidong People's Hospital), No. 568 Minle Middle Road, 226200, Qidong City, Nantong City, Jiangsu Province, China
| | - Jialin Xu
- Endocrinology department, Qidong Hospital Affiliated to Nantong University (Qidong People's Hospital), No. 568 Minle Middle Road, 226200, Qidong City, Nantong City, Jiangsu Province, China
| | - Qi Lu
- Department of Cardiology, Affiliated Hospital of Nantong University, No. 568 Minle Middle Road, 226200, Qidong City, Nantong City, Jiangsu Province, China.
| | - Chu Chen
- Department of Cardiology, Affiliated Hospital of Nantong University, No. 568 Minle Middle Road, 226200, Qidong City, Nantong City, Jiangsu Province, China
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Moustakli E, Zikopoulos A, Skentou C, Dafopoulos S, Stavros S, Dafopoulos K, Drakakis P, Georgiou I, Zachariou A. Association of Obesity with Telomere Length in Human Sperm. J Clin Med 2024; 13:2150. [PMID: 38610915 PMCID: PMC11012429 DOI: 10.3390/jcm13072150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/01/2024] [Accepted: 04/04/2024] [Indexed: 04/14/2024] Open
Abstract
Background: Telomere attrition and mitochondrial dysfunction are two fundamental aspects of aging. Calorie restriction (CR) is the best strategy to postpone aging since it can enhance telomere attrition, boost antioxidant capacity, and lower the generation of reactive oxygen species (ROS). Since ROS is produced by mitochondria and can readily travel to cell nuclei, it is thought to be a crucial molecule for information transfer between mitochondria and cell nuclei. Important variables that affect the quality and functionality of sperm and may affect male reproductive health and fertility include telomere length, mitochondrial content, and the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA). Telomere damage results from mitochondrial failure, whereas nuclear DNA remains unaffected. This research aims to investigate potential associations between these three variables and how they might relate to body mass index. Methods: Data were collected from 82 men who underwent IVF/ICSI at the University Hospital of Ioannina's IVF Unit in the Obstetrics and Gynecology Department. Evaluations included sperm morphology, sperm count, sperm motility, and participant history. To address this, male participants who were categorized into three body mass index (ΒΜΙ) groups-normal, overweight, and obese-had their sperm samples tested. Results: For both the normal and overweight groups, our results show a negative connection between relative telomere length and ΒΜI. As an illustration of a potential connection between mitochondrial health and telomere maintenance, a positive correlation was found for the obese group. Only the obese group's results were statistically significant (p < 0.05). More evidence that longer telomeres are associated with lower mitochondrial content can be found in the negative connection between telomere length and mitochondrial content in both the normal and overweight groups. However, the obese group showed a positive association. The data did not reach statistical significance for any of the three groups. These associations may affect sperm quality since telomere length and mitochondrial concentration are indicators of cellular integrity and health. Moreover, the ratio of mtDNA to nDNA was positively correlated with the relative telomere lengths of the obese group, but negatively correlated with the normal and overweight groups. In every group that was studied, the results were not statistically significant. According to this, male fertility may be negatively impacted by an imbalance in the copy number of the mitochondrial genome compared to the nuclear DNA in sperm. Conclusions: Essentially, the goal of our work is to determine whether mitochondria and telomere length in human sperm interact. Understanding these connections may aid in the explanation of some male infertility causes and possibly contribute to the creation of new treatment modalities for problems pertaining to reproductive health. The functional implications of these connections and their applications in therapeutic settings require further investigation.
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Affiliation(s)
- Efthalia Moustakli
- Laboratory of Medical Genetics, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | - Athanasios Zikopoulos
- Obstetrics and Gynecology, Royal Devon and Exeter Hospital, Barrack Rd., Exeter EX 25 DW, UK;
| | - Charikleia Skentou
- Department of Obstetrics and Gynecology, Medical School of Ioannina, University General Hospital, 45110 Ioannina, Greece;
| | - Stefanos Dafopoulos
- Department of Health Sciences, European University Cyprus, Nicosia 2404, Cyprus;
| | - Sofoklis Stavros
- Third Department of Obstetrics and Gynecology, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.S.); (P.D.)
| | - Konstantinos Dafopoulos
- IVF Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41500 Larissa, Greece;
| | - Peter Drakakis
- Third Department of Obstetrics and Gynecology, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.S.); (P.D.)
| | - Ioannis Georgiou
- Laboratory of Medical Genetics, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | - Athanasios Zachariou
- Department of Urology, School of Medicine, Ioannina University, 45110 Ioannina, Greece;
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11
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Alsufyani D. Evidence of zoonotic pathogens through biophysically induced genomic variance. Q Rev Biophys 2024; 57:e2. [PMID: 38477116 DOI: 10.1017/s0033583524000039] [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] [Indexed: 03/14/2024]
Abstract
Zoonoses are infectious agents that are transmissible between animals and humans. Up to 60% of known infectious diseases and 75% of emergent diseases are zoonotic. Genomic variation between homeostatic populations provides a novel window into the effect of environmental pathogens on allelic distributions within the populations. Genodynamics is a biophysical approach utilizing developed metrics on biallelic single-nucleotide polymorphisms (SNPs) that can be used to quantify the adaptive influences due to pathogens. A genomic free energy that is minimized when overall population health is optimized describes the influence of environmental agents upon genomic variation. A double-blind exploration of over 100 thousand SNPs searching for smooth functional dependencies upon four zoonotic pathogens carried by four possible hosts amidst populations that live in their ancestral environments has been conducted. Exemplars that infectious agents can have significant adaptive influence on human populations are presented. One discussed SNP is likely associated with both adaptive and innate immune regulation. The adaptive response of another SNP suggests an intriguing connection between zoonoses and human cancers. The adaptive forces of the presented pathogens upon the human genome have been quantified.
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Affiliation(s)
- Daniah Alsufyani
- College of Sciences and Health Professions, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- Ministry of the National Guard - Health Affairs, Jeddah, Saudi Arabia
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12
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farrukh S, Baig S, Hussain R, Imad R, kulsoom O, Yousaf Rana M. Identification of polymorphic alleles in TERC and TERT gene reprogramming the telomeres of newborn and legacy with parental health. Saudi J Biol Sci 2024; 31:103897. [PMID: 38192544 PMCID: PMC10772381 DOI: 10.1016/j.sjbs.2023.103897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 12/02/2023] [Accepted: 12/08/2023] [Indexed: 01/10/2024] Open
Abstract
Telomere and telomerase genes (TERC and TERT) highlighted many novel genetic polymorphisms related to common diseases. This study explored the polymorphic alleles of TERC and TERT gene in parents-newborn (triad) and its association with telomere length (TL) and parental diseases (mother: Gestational Diabetes Mellitus (GDM), Preeclampsia, fathers: Diabetes, Hypertension). In this cross-sectional study, the blood samples (n = 612) were collected from parents-newborn triad (204 each) for TL (T/S ratio) quantification by using qPCR, and gene (TERC and TERT) polymorphism was detected by Sanger sequencing. The correlation analysis was used to find an association between paternal TL (T/S ratio) and newborn TL. The multivariate linear regression was applied to determine the effect of parents genes and diseases on newborn TL. A positive association (r = 0.42,0.39) (p < 0.0001) among parents and newborn TL was observed. In the diseased group, both TERC (rs10936599) and TERT (rs2736100) genes had a high frequency of allele C in newborns (OR = 0.94, P = 0.90, OR = 4.24, P = 0.012). However, among parents, TERT gene [Mother CC (B = 0.575; P = 0.196), Father CC (B = -0.739; P = 0.071)] was found significant contributing factor for Newborn TL. Diseased parents with T/T and A/C genotypes had longer newborn TL (2.82 ± 2.43, p < 0.022; 1.80 ± 1.20, p < 0.00) than the C/C genotype. Therefore, the study, confirmed that major allele C of TERC and TERT genes is associated with smaller TL in diseased parents-newborns of the targeted population.
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Affiliation(s)
- Sadia farrukh
- Department of Biochemistry, Ziauddin University, Karachi, Pakistan
- Department of Community Health Sciences, The Agha Khan University, Karachi, Pakistan
| | - Saeeda Baig
- Department of Biochemistry, Ziauddin University, Karachi, Pakistan
| | - Rubina Hussain
- Department Gynecology and obstetrician, Ziauddin university and hospitals, Karachi, Pakistan
| | - Rehan Imad
- Department of Molecular medicine, Ziauddin University Karachi, Pakistan
| | - Ome kulsoom
- Department Gynecology and obstetrician, Ziauddin hospital, Karachi, Pakistan
| | - Mehreen Yousaf Rana
- Department Gynecology and obstetrician, Ziauddin hospital, Karachi, Pakistan
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13
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Karajovic J, Kovacevic B, Uzelac B, Stefik D, Jovanovic B, Ristic P, Cerovic S, Supic G. Association of HOTAIR, MIR155HG, TERC, miR-155, -196a2, and -146a Genes Polymorphisms with Papillary Thyroid Cancer Susceptibility and Prognosis. Cancers (Basel) 2024; 16:485. [PMID: 38339237 PMCID: PMC10854783 DOI: 10.3390/cancers16030485] [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: 10/06/2023] [Revised: 11/01/2023] [Accepted: 11/05/2023] [Indexed: 02/12/2024] Open
Abstract
Polymorphisms in long non-coding RNA and microRNA genes may play a significant role in the susceptibility and progression of papillary thyroid carcinoma (PTC). The current study investigates the polymorphisms HOTAIR rs920778, MIR155HG rs1893650, TERC rs10936599, miR-155 rs767649, miR-196a2 rs11614913 and miR-146a rs2910164 in 102 PTC patients and 106 age- and sex-matched controls of the Caucasian Serbian population, using real-time PCR. We observed differences in genotype distributions of the HOTAIR rs920778 (p = 0.016) and MIR155HG rs1893650 (p = 0.0002) polymorphisms between PTC patients and controls. HOTAIR rs920778 was associated with increased PTC susceptibility (adjusted OR = 1.497, p = 0.021), with the TT variant genotype increasing the risk compared to the CC genotype (OR = 2.466, p = 0.012) and C allele carriers (CC + CT) (OR = 1.585, p = 0.006). The HOTAIR rs920778 TT genotype was associated with lymph node metastasis (p = 0.022), tumor recurrence (p = 0.016), and progression-free survival (p = 0.010) compared to C allele carriers. Multivariate Cox regression revealed that ATA risk (HR = 14.210, p = 0.000004) and HOTAIR rs920778 (HR = 2.811, p = 0.010) emerged as independent prognostic factors in PTC. A novel polymorphism, MIR155HG rs1893650, was negatively correlated with susceptibility to PTC, with TC heterozygotes exerting a protective effect (OR = 0.268, p = 0.0001). These results suggest that the polymorphisms HOTAIR rs920778 and MIR155HG rs1893650 could be potential prognostic and risk biomarkers in papillary thyroid carcinomas.
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Affiliation(s)
- Jelena Karajovic
- Clinic for Endocrinology, Military Medical Academy, 11000 Belgrade, Serbia; (J.K.); (P.R.)
| | - Bozidar Kovacevic
- Institute for Pathology and Forensic Medicine, Military Medical Academy, 11000 Belgrade, Serbia; (B.K.); (B.J.); (S.C.)
- Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia
| | - Bojana Uzelac
- Institute for Medical Research, Military Medical Academy, 11000 Belgrade, Serbia; (B.U.); (D.S.)
| | - Debora Stefik
- Institute for Medical Research, Military Medical Academy, 11000 Belgrade, Serbia; (B.U.); (D.S.)
| | - Bojana Jovanovic
- Institute for Pathology and Forensic Medicine, Military Medical Academy, 11000 Belgrade, Serbia; (B.K.); (B.J.); (S.C.)
| | - Petar Ristic
- Clinic for Endocrinology, Military Medical Academy, 11000 Belgrade, Serbia; (J.K.); (P.R.)
- Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia
| | - Snezana Cerovic
- Institute for Pathology and Forensic Medicine, Military Medical Academy, 11000 Belgrade, Serbia; (B.K.); (B.J.); (S.C.)
- Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia
| | - Gordana Supic
- Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia
- Institute for Medical Research, Military Medical Academy, 11000 Belgrade, Serbia; (B.U.); (D.S.)
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14
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Kumar N, Sethi G. Telomerase and hallmarks of cancer: An intricate interplay governing cancer cell evolution. Cancer Lett 2023; 578:216459. [PMID: 37863351 DOI: 10.1016/j.canlet.2023.216459] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/02/2023] [Accepted: 10/17/2023] [Indexed: 10/22/2023]
Abstract
Transformed cells must acquire specific characteristics to be malignant. Weinberg and Hanahan characterize these characteristics as cancer hallmarks. Though these features are independently driven, substantial signaling crosstalk in transformed cells efficiently promotes these feature acquisitions. Telomerase is an enzyme complex that maintains telomere length. However, its main component, Telomere reverse transcriptase (TERT), has been found to interact with various signaling molecules like cMYC, NF-kB, BRG1 and cooperate in transcription and metabolic reprogramming, acting as a strong proponent of malignant features such as cell death resistance, sustained proliferation, angiogenesis activation, and metastasis, among others. It allows cells to avoid replicative senescence and achieve endless replicative potential. This review summarizes both the canonical and noncanonical functions of TERT and discusses how they promote cancer hallmarks. Understanding the role of Telomerase in promoting cancer hallmarks provides vital insight into the underlying mechanism of cancer genesis and progression and telomerase intervention as a possible therapeutic target for cancer treatment. More investigation into the precise molecular mechanisms of telomerase-mediated impacts on cancer hallmarks will contribute to developing more focused and customized cancer treatment methods.
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Affiliation(s)
- Naveen Kumar
- Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, 138673, Singapore
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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15
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Rumšaitė G, Gedvilaitė G, Balnytė R, Kriaučiūnienė L, Liutkevičienė R. The Influence of TEP1 and TERC Genetic Variants on the Susceptibility to Multiple Sclerosis. J Clin Med 2023; 12:5863. [PMID: 37762804 PMCID: PMC10531829 DOI: 10.3390/jcm12185863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/04/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. According to recent studies, cellular senescence caused by telomere shortening may contribute to the development of MS. AIM OF THE STUDY Our aim was to determine the associations of TEP1 rs1760904, rs1713418, TERC rs12696304, rs35073794 gene polymorphisms with the occurrence of MS. METHODS The study included 200 patients with MS and 230 healthy controls. Genotyping of TEP1 rs1760904, rs1713418 and TERC rs12696304, rs35073794 was performed using RT-PCR. The obtained data were analysed using the program "IBM SPSS Statistics 29.0". Haplotype analysis was performed using the online program "SNPStats". RESULTS The TERC rs12696304 G allele of this SNP is associated with 1.4-fold lower odds of developing MS (p = 0.035). TERC rs35073794 is associated with approximately 2.4-fold reduced odds of MS occurrence in the codominant, dominant, overdominant, and additive models (p < 0.001; p < 0.001; p < 0.001; p < 0.001, respectively). Haplotype analysis shows that the rs1760904-G-rs1713418-A haplotype is statistically significantly associated with 1.75-fold increased odds of developing MS (p = 0.006). The rs12696304-C-rs35073794-A haplotype is statistically significantly associated with twofold decreased odds of developing MS (p = 0.008). In addition, the rs12696304-G-rs35073794-A haplotype was found to be statistically significantly associated with 5.3-fold decreased odds of developing MS (p < 0.001). CONCLUSION The current evidence may suggest a protective role of TERC SNP in the occurrence of MS, while TEP1 has the opposite effect.
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Affiliation(s)
- Gintarė Rumšaitė
- Medical Faculty, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania;
| | - Greta Gedvilaitė
- Medical Faculty, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania;
- Neurosciences Institute, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (L.K.); (R.L.)
| | - Renata Balnytė
- Department of Neurology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania;
| | - Loresa Kriaučiūnienė
- Neurosciences Institute, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (L.K.); (R.L.)
| | - Rasa Liutkevičienė
- Neurosciences Institute, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (L.K.); (R.L.)
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16
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Sanpedro-Luna JA, Vega-Alvarado L, Vázquez-Cruz C, Sánchez-Alonso P. Global Gene Expression of Post-Senescent Telomerase-Negative ter1Δ Strain of Ustilago maydis. J Fungi (Basel) 2023; 9:896. [PMID: 37755003 PMCID: PMC10532341 DOI: 10.3390/jof9090896] [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: 05/14/2023] [Revised: 08/15/2023] [Accepted: 08/16/2023] [Indexed: 09/28/2023] Open
Abstract
We analyzed the global expression patterns of telomerase-negative mutants from haploid cells of Ustilago maydis to identify the gene network required for cell survival in the absence of telomerase. Mutations in either of the telomerase core subunits (trt1 and ter1) of the dimorphic fungus U. maydis cause deficiencies in teliospore formation. We report the global transcriptome analysis of two ter1Δ survivor strains of U. maydis, revealing the deregulation of telomerase-deleted responses (TDR) genes, such as DNA-damage response, stress response, cell cycle, subtelomeric, and proximal telomere genes. Other differentially expressed genes (DEGs) found in the ter1Δ survivor strains were related to pathogenic lifestyle factors, plant-pathogen crosstalk, iron uptake, meiosis, and melanin synthesis. The two ter1Δ survivors were phenotypically comparable, yet DEGs were identified when comparing these strains. Our findings suggest that teliospore formation in U. maydis is controlled by key pathogenic lifestyle and meiosis genes.
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Affiliation(s)
- Juan Antonio Sanpedro-Luna
- Posgrado en Microbiología, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla 72570, Mexico;
| | - Leticia Vega-Alvarado
- Instituto de Ciencias Aplicadas y Tecnología, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico;
| | - Candelario Vázquez-Cruz
- Centro de Investigaciones en Ciencias Microbiológicas, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla 72570, Mexico;
| | - Patricia Sánchez-Alonso
- Centro de Investigaciones en Ciencias Microbiológicas, Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla 72570, Mexico;
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17
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Yuan H, Qin X, Yang Q, Liu L, Fang Z, Fan Y, Xu D. Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma. Biol Sex Differ 2023; 14:46. [PMID: 37434223 DOI: 10.1186/s13293-023-00526-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 06/16/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) displays sex-biased incidence, outcomes, molecular alterations and treatment efficacy; however, clinical managements are largely identical in male and female patients. Moreover, many biomarkers have been identified as predictors for ccRCC outcomes and response to therapeutic drugs, such as multitargeted tyrosine-kinase receptor (TKR) inhibitors, but little is known about their sex-specificity. Dyskerin (DKC1), encoded by the DKC1 gene within Xq28, is a telomerase co-factor stabilizing telomerase RNA component (TERC) and overexpressed in various cancers. Here, we determined whether DKC1 and/or TERC affect ccRCC sex-differentially. METHODS DKC1 and TERC expression in primary ccRCC tumors was assessed using RNA sequencing and qPCR. DKC1 association with molecular alterations and overall or progression-free survival (OS or PFS) was analyzed in the TCGA cohort of ccRCC. The IMmotion 151 and 150 ccRCC cohorts were analyzed to evaluate impacts of DKC1 and TERC on Sunitinib response and PFS. RESULTS DKC1 and TERC expression was significantly upregulated in ccRCC tumors. High DKC1 expression predicts shorter PFS independently in female but not male patients. Tumors in the female DKC1-high group exhibited more frequent alterations in PIK3CA, MYC and TP53 genes. Analyses of the IMmotion 151 ccRCC cohort treated with the TKR inhibitor Sunitinib showed that female patients in the DKC1-high group was significantly associated with lower response rates (P = 0.021) accompanied by markedly shortened PFS (6.1 vs 14.2 months, P = 0.004). DKC1 and TERC expression correlated positively with each other, and higher TERC expression predicted poor Sunitinib response (P = 0.031) and shorter PFS (P = 0.004), too. However, DKC1 rather than TERC acted as an independent predictor (P < 0.001, HR = 2.0, 95% CI 1.480-2.704). In male patients, DKC1 expression was associated with neither Sunitinib response (P = 0.131) nor PFS (P = 0.184), while higher TERC levels did not predict response rates. Similar results were obtained from the analysis of the Sunitinib-treated IMmotion 150 ccRCC patients. CONCLUSIONS DKC1 serves as an independent female-specific predictor for survival and Sunitinib efficacy in ccRCC, which contribute to better understanding of the sex-biased ccRCC pathogenesis and improve personalized interventions of ccRCC.
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Affiliation(s)
- Huiyang Yuan
- Department of Urology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xin Qin
- Department of Urology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Qingya Yang
- Department of Urology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Li Liu
- School of Nursing, Beijing University of Chinese Medicine, Beijing, 100191, China
| | - Zhiqing Fang
- Department of Urology, Qilu Hospital of Shandong University, Jinan, 250012, China.
| | - Yidong Fan
- Department of Urology, Qilu Hospital of Shandong University, Jinan, 250012, China.
| | - Dawei Xu
- Department of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine, Karolinska Institute and Karolinska University Hospital Solna, 171 76, Stockholm, Sweden.
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Banerjee P, Rosales JE, Chau K, Nguyen MTH, Kotla S, Lin SH, Deswal A, Dantzer R, Olmsted-Davis EA, Nguyen H, Wang G, Cooke JP, Abe JI, Le NT. Possible molecular mechanisms underlying the development of atherosclerosis in cancer survivors. Front Cardiovasc Med 2023; 10:1186679. [PMID: 37332576 PMCID: PMC10272458 DOI: 10.3389/fcvm.2023.1186679] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023] Open
Abstract
Cancer survivors undergone treatment face an increased risk of developing atherosclerotic cardiovascular disease (CVD), yet the underlying mechanisms remain elusive. Recent studies have revealed that chemotherapy can drive senescent cancer cells to acquire a proliferative phenotype known as senescence-associated stemness (SAS). These SAS cells exhibit enhanced growth and resistance to cancer treatment, thereby contributing to disease progression. Endothelial cell (EC) senescence has been implicated in atherosclerosis and cancer, including among cancer survivors. Treatment modalities for cancer can induce EC senescence, leading to the development of SAS phenotype and subsequent atherosclerosis in cancer survivors. Consequently, targeting senescent ECs displaying the SAS phenotype hold promise as a therapeutic approach for managing atherosclerotic CVD in this population. This review aims to provide a mechanistic understanding of SAS induction in ECs and its contribution to atherosclerosis among cancer survivors. We delve into the mechanisms underlying EC senescence in response to disturbed flow and ionizing radiation, which play pivotal role in atherosclerosis and cancer. Key pathways, including p90RSK/TERF2IP, TGFβR1/SMAD, and BH4 signaling are explored as potential targets for cancer treatment. By comprehending the similarities and distinctions between different types of senescence and the associated pathways, we can pave the way for targeted interventions aim at enhancing the cardiovascular health of this vulnerable population. The insights gained from this review may facilitate the development of novel therapeutic strategies for managing atherosclerotic CVD in cancer survivors.
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Affiliation(s)
- Priyanka Banerjee
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Julia Enterría Rosales
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- School of Medicine, Instituto Tecnológico de Monterrey, Guadalajara, Mexico
| | - Khanh Chau
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Minh T. H. Nguyen
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
- Department of Life Science, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | - Sivareddy Kotla
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Steven H. Lin
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anita Deswal
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Robert Dantzer
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizabeth A. Olmsted-Davis
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Hung Nguyen
- Cancer Division, Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Guangyu Wang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - John P. Cooke
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Jun-ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nhat-Tu Le
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
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19
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Liu S, Nong W, Ji L, Zhuge X, Wei H, Luo M, Zhou L, Chen S, Zhang S, Lei X, Huang H. The regulatory feedback of inflammatory signaling and telomere/telomerase complex dysfunction in chronic inflammatory diseases. Exp Gerontol 2023; 174:112132. [PMID: 36849001 DOI: 10.1016/j.exger.2023.112132] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 03/01/2023]
Abstract
Inflammation is believed to play a role in the progression of numerous human diseases. Research has shown that inflammation and telomeres are involved in a feedback regulatory loop: inflammation increases the rate of telomere attrition, leading to telomere dysfunction, while telomere components also participate in regulating the inflammatory response. However, the specific mechanism behind this feedback loop between inflammatory signaling and telomere/telomerase complex dysfunction has yet to be fully understood. This review presents the latest findings on this topic, with a particular focus on the detailed regulation and molecular mechanisms involved in the progression of aging, various chronic inflammatory diseases, cancers, and different stressors. Several feedback loops between inflammatory signaling and telomere/telomerase complex dysfunction, including NF-κB-TERT feedback, NF-κB-RAP1 feedback, NF-κB-TERC feedback, STAT3-TERT feedback, and p38 MAPK-shelterin complex-related gene feedback, are summarized. Understanding the latest discoveries of this feedback regulatory loop can help identify novel potential drug targets for the suppression of various inflammation-associated diseases.
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Affiliation(s)
- Shun Liu
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Weihua Nong
- Department of Obstetrics and Gynecology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533300, China
| | - Lin Ji
- Reproductive Hospital of Guangxi Zhuang Autonomous Region, 530021 Nanning, China
| | - Xiuhong Zhuge
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Huimei Wei
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Min Luo
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Leguang Zhou
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Shenghua Chen
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Shun Zhang
- Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China.
| | - Xiaocan Lei
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Hua Huang
- Reproductive Hospital of Guangxi Zhuang Autonomous Region, 530021 Nanning, China.
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20
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Hill C, Duffy S, Coulter T, Maxwell AP, McKnight AJ. Harnessing Genomic Analysis to Explore the Role of Telomeres in the Pathogenesis and Progression of Diabetic Kidney Disease. Genes (Basel) 2023; 14:609. [PMID: 36980881 PMCID: PMC10048490 DOI: 10.3390/genes14030609] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
The prevalence of diabetes is increasing globally, and this trend is predicted to continue for future decades. Research is needed to uncover new ways to manage diabetes and its co-morbidities. A significant secondary complication of diabetes is kidney disease, which can ultimately result in the need for renal replacement therapy, via dialysis or transplantation. Diabetic kidney disease presents a substantial burden to patients, their families and global healthcare services. This review highlights studies that have harnessed genomic, epigenomic and functional prediction tools to uncover novel genes and pathways associated with DKD that are useful for the identification of therapeutic targets or novel biomarkers for risk stratification. Telomere length regulation is a specific pathway gaining attention recently because of its association with DKD. Researchers are employing both observational and genetics-based studies to identify telomere-related genes associated with kidney function decline in diabetes. Studies have also uncovered novel functions for telomere-related genes beyond the immediate regulation of telomere length, such as transcriptional regulation and inflammation. This review summarises studies that have revealed the potential to harness therapeutics that modulate telomere length, or the associated epigenetic modifications, for the treatment of DKD, to potentially slow renal function decline and reduce the global burden of this disease.
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Affiliation(s)
- Claire Hill
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK
| | - Seamus Duffy
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK
| | - Tiernan Coulter
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK
| | - Alexander Peter Maxwell
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, UK
| | - Amy Jayne McKnight
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK
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21
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Hu H, Guo X, Mu T, Song H. Long non-coding RNA telomerase RNA elements improve glucocorticoid-induced osteoporosis by EZH2 to regulate DKK1. Int J Rheum Dis 2023; 26:638-647. [PMID: 36789537 DOI: 10.1111/1756-185x.14567] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/15/2022] [Accepted: 01/03/2023] [Indexed: 02/16/2023]
Abstract
BACKGROUND Glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis, which increases the risk of fracture. Long non-coding RNA telomerase RNA elements (TERC) has been proven to be closely related to osteoporosis. However, the role of TERC in glucocorticoid-induced osteoporosis and its underlying molecular mechanism remains unclear. METHODS The in vitro model of osteoporosis was established after bone marrow mesenchymal stem cells (BMSCs) were exposed to dexamethasone (DEX). The cell viability, alkaline phosphatase (ALP) activity and mineralized nodules of BMSCs were evaluated. The messenger RNA and protein levels were detected by quantitative real-time polymerase chain reaction and Western blot. The interaction between TERC, enhancer of zeste homolog 2 (EZH2) and dickkopf-1 (DKK1) was confirmed by chromatin immunoprecipitation and RNA immunoprecipitation assays. RESULTS Bone marrow mesenchymal stem cells were isolated, identified and induced osteogenic differentiation. The findings showed that the levels of osteogenic marker genes, including ALP, Runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) in BMSCs were increased dependent on the osteogenic induction time. Similarly, TERC was significantly increased, but DKK1 was significantly decreased during BMSC osteogenic differentiation. Functional research showed that TERC overexpression promoted cell viability, ALP activity and mineralized nodules of BMSCs and increased the levels of osteogenic differentiation-related genes (ALP, RUNX2 and OCN), and TERC overexpression increased EZH2 protein level. Moreover, the decrease of cell viability, ALP activity and mineralized nodules induced by DEX was reversed by TERC overexpression. Furthermore, TERC inhibited DKK1 expression by promoting the histone modification of DKK1, and TERC overexpression alleviated DEX suppressed osteogenic differentiation of BMSCs by interaction with EZH2 to regulate DKK1. CONCLUSION Our findings illustrated that TERC overexpression alleviated DEX-induced osteoporosis by recruiting EZH2 to regulate DKK1. Our research provided a novel direction for the treatment of glucocorticoid-induced osteoporosis.
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Affiliation(s)
- He Hu
- Department of Orthopedics, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
| | - Xiaodong Guo
- Department of Orthopedics, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
| | - Tingting Mu
- Department of Orthopedics, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
| | - Huifang Song
- Department of Pulmonary and Critical Care Medicine, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China
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22
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Ding W, Xu W, Lu D, Sheng H, Xu X, Xu B, Zheng A. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis. Open Med (Wars) 2023; 18:20220619. [PMID: 36742154 PMCID: PMC9883688 DOI: 10.1515/med-2022-0619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 01/25/2023] Open
Abstract
This study investigated the function of telomerase RNA component (TERC) in spinal cord injury (SCI). SCI models were established in rats via laminectomy and PC-12 cells were treated with lipopolysaccharide (LPS). TERC and miR-34a-5p expressions in cells and rat spinal cords were detected by quantitative reverse transcription polymerase chain reaction, followed by overexpression/knockdown of TERC/miR-34a-5p. Spinal cord histopathological changes were examined via hematoxylin-eosin staining. miR-34a-5p' relation with TERC and XBP-1 was predicted by TargetScan and checked by dual-luciferase reporter/RNA immunoprecipitation assays. Cell biological behaviors were assessed by Cell counting kit-8, wound healing, Transwell, and flow cytometry assays. XBP-1 and inflammation/apoptosis-related protein expressions were analyzed by western blot. TERC was upregulated and miR-34a-5p was low-expressed in SCI tissues and LPS-induced PC-12 cells. TERC-knockdown alleviated histopathological abnormalities yet upregulated miR-34a-5p in SCI tissues. In LPS-induced PC-12 cells, TERC knockdown promoted cell viability, migration, invasion, and inhibited apoptosis, while TERC overexpression ran oppositely. TERC knockdown downregulated the XBP-1, IL-6, TNF-α, Bax, p-p38/t-p38, and cleaved caspase-9/-3, but upregulated Bcl-2 and p-Akt/t-Akt. TERC targeted miR-34a-5p, which further targeted XBP-1. miR-34a-5p downregulation exerted effects opposite to and offset TERC knockdown-induced effects. TERC knockdown facilitated the regeneration of neuron tissues yet inhibited inflammation in SCI through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis.
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Affiliation(s)
- Weiguo Ding
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Weixing Xu
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Di Lu
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Hongfeng Sheng
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Xinwei Xu
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Bin Xu
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
| | - Aote Zheng
- Department of Orthopedics, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, 310012, China
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23
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Udroiu I, Marinaccio J, Sgura A. Many Functions of Telomerase Components: Certainties, Doubts, and Inconsistencies. Int J Mol Sci 2022; 23:ijms232315189. [PMID: 36499514 PMCID: PMC9736166 DOI: 10.3390/ijms232315189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/23/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
A growing number of studies have evidenced non-telomeric functions of "telomerase". Almost all of them, however, investigated the non-canonical effects of the catalytic subunit TERT, and not the telomerase ribonucleoprotein holoenzyme. These functions mainly comprise signal transduction, gene regulation and the increase of anti-oxidative systems. Although less studied, TERC (the RNA component of telomerase) has also been shown to be involved in gene regulation, as well as other functions. All this has led to the publication of many reviews on the subject, which, however, are often disseminating personal interpretations of experimental studies of other researchers as original proofs. Indeed, while some functions such as gene regulation seem ascertained, especially because mechanistic findings have been provided, other ones remain dubious and/or are contradicted by other direct or indirect evidence (e.g., telomerase activity at double-strand break site, RNA polymerase activity of TERT, translation of TERC, mitochondrion-processed TERC). In a critical study of the primary evidence so far obtained, we show those functions for which there is consensus, those showing contradictory results and those needing confirmation. The resulting picture, together with some usually neglected aspects, seems to indicate a link between TERT and TERC functions and cellular stemness and gives possible directions for future research.
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24
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Jin H, Chen Y, Ren J, Huang J, Zhao Y, Liu H. TERC suppresses PD-L1 expression by downregulating RNA binding protein HuR. SCIENCE CHINA. LIFE SCIENCES 2022; 65:2505-2516. [PMID: 35661964 DOI: 10.1007/s11427-021-2085-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/02/2022] [Indexed: 06/15/2023]
Abstract
TERC is the RNA component of telomerase, and provides a template for TERT to synthesize telomere repeats at chromosome ends. Increasing evidence has revealed that TERC is involved in other biological processes beyond telomerase. Here, we found that the expression level of TERC is negatively correlated with PD-L1 and that ectopic expression of TERC but not TERT in ALT cells significantly inhibits PD-L1, suggesting that TERC suppresses PD-L1 expression in a telomerase-independent manner. Mechanistically, instead of regulating PD-L1 mRNA directly, TERC accelerates PD-L1 mRNA degradation by inhibiting the expression of HuR, which binds to the 3'UTR of PD-L1 mRNA and maintains its stability. We also found that the small molecule AS1842856, a FoxO1 inhibitor, promotes TERC expression and reverses the PD-L1 upregulation caused by chemotherapy, providing a potential combination cancer therapy that avoids cancer immune escape during chemotherapy.
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Affiliation(s)
- Heping Jin
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Yanlian Chen
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Jian Ren
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Junjiu Huang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Yong Zhao
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Haiying Liu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
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25
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Möller S, Saul N, Projahn E, Barrantes I, Gézsi A, Walter M, Antal P, Fuellen G. Gene co-expression analyses of health(span) across multiple species. NAR Genom Bioinform 2022; 4:lqac083. [PMID: 36458022 PMCID: PMC9706456 DOI: 10.1093/nargab/lqac083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 08/20/2022] [Accepted: 10/31/2022] [Indexed: 12/03/2022] Open
Abstract
Health(span)-related gene clusters/modules were recently identified based on knowledge about the cross-species genetic basis of health, to interpret transcriptomic datasets describing health-related interventions. However, the cross-species comparison of health-related observations reveals a lot of heterogeneity, not least due to widely varying health(span) definitions and study designs, posing a challenge for the exploration of conserved healthspan modules and, specifically, their transfer across species. To improve the identification and exploration of conserved/transferable healthspan modules, here we apply an established workflow based on gene co-expression network analyses employing GEO/ArrayExpress data for human and animal models, and perform a comprehensive meta-study of the resulting modules related to health(span), yielding a small set of literature backed health(span) candidate genes. For each experiment, WGCNA (weighted gene correlation network analysis) was used to infer modules of genes which correlate in their expression with a 'health phenotype score' and to determine the most-connected (hub) genes (and their interactions) for each such module. After mapping these hub genes to their human orthologs, 12 health(span) genes were identified in at least two species (ACTN3, ANK1, MRPL18, MYL1, PAXIP1, PPP1CA, SCN3B, SDCBP, SKIV2L, TUBG1, TYROBP, WIPF1), for which enrichment analysis by g:profiler found an association with actin filament-based movement and associated organelles, as well as muscular structures. We conclude that a meta-study of hub genes from co-expression network analyses for the complex phenotype health(span), across multiple species, can yield molecular-mechanistic insights and can direct experimentalists to further investigate the contribution of individual genes and their interactions to health(span).
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Affiliation(s)
- Steffen Möller
- To whom correspondence should be addressed. Tel: +49 381 494 7361; Fax: +49 381 494 7203;
| | - Nadine Saul
- Humboldt-University of Berlin, Institute of Biology, Berlin, Germany
| | - Elias Projahn
- Rostock University Medical Center, Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock, Germany
| | - Israel Barrantes
- Rostock University Medical Center, Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock, Germany
| | - András Gézsi
- Budapest University of Technology and Economics, Department of Measurement and Information Systems, Budapest, Hungary
| | - Michael Walter
- Rostock University Medical Center, Institute for Clinical Chemistry and Laboratory Medicine, Rostock, Germany
| | - Péter Antal
- Budapest University of Technology and Economics, Department of Measurement and Information Systems, Budapest, Hungary
| | - Georg Fuellen
- Rostock University Medical Center, Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock, Germany
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Zou L, Yang Y, Zhou B, Li W, Liu K, Li G, Miao H, Song X, Yang J, Geng Y, Li M, Bao R, Liu Y. tRF-3013b inhibits gallbladder cancer proliferation by targeting TPRG1L. Cell Mol Biol Lett 2022; 27:99. [PMID: 36401185 PMCID: PMC9673407 DOI: 10.1186/s11658-022-00398-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 10/25/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND tRNA-derived fragments (tRFs) are newly discovered noncoding RNAs and regulate tumor progression via diverse molecular mechanisms. However, the expression and biofunction of tRFs in gallbladder cancer (GBC) have not been reported yet. METHODS The expression of tRFs in GBC was detected by tRF and tiRNA sequencing in GBC tissues and adjacent tissues. The biological function of tRFs was investigated by cell proliferation assay, clonal formation assay, cell cycle assay, and xenotransplantation model in GBC cell lines. The molecular mechanism was discovered and verified by transcriptome sequencing, fluorescence in situ hybridization (FISH), target gene site prediction, and RNA binding protein immunoprecipitation (RIP). RESULTS tRF-3013b was significantly downregulated in GBC compared with para-cancer tissues. Decreased expression of tRF-3013b in GBC patients was correlated with poor overall survival. Dicer regulated the production of tRF-3013b, and its expression was positively correlated with tRF-3013b in GBC tissues. Functional experiments demonstrated that tRF-3013b inhibited GBC cell proliferation and induced cell-cycle arrest. Mechanically, tRF-3013b exerted RNA silencing effect on TPRG1L by binding to AGO3, and then inhibited NF-κB. TPRG1L overexpression could rescue the effects of tRF-3013b on GBC cell proliferation. CONCLUSIONS This study indicated that Dicer-induced tRF-3013b inhibited GBC proliferation by targeting TPRG1L and repressed NF-κB, pointing to tRF-3013b as a novel potential therapeutic target of GBC.
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Affiliation(s)
- Lu Zou
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Yang Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Biyu Zhou
- Department of Plastic and Reconstructive Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, China
| | - Weijian Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Ke Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Guoqiang Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Huijie Miao
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Xiaoling Song
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665, Kongjiang Road, Shanghai, 200092, China
| | - Jiahua Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Yajun Geng
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Maolan Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China.
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.
| | - Runfa Bao
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China.
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665, Kongjiang Road, Shanghai, 200092, China.
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China.
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.
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Wang J, Dai M, Xing X, Wang X, Qin X, Huang T, Fang Z, Fan Y, Xu D. Genomic, epigenomic, and transcriptomic signatures for telomerase complex components: a pan-cancer analysis. Mol Oncol 2022; 17:150-172. [PMID: 36239411 PMCID: PMC9812836 DOI: 10.1002/1878-0261.13324] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 09/18/2022] [Accepted: 10/13/2022] [Indexed: 02/03/2023] Open
Abstract
Telomerase activation is required for malignant transformation. Recent advances in high-throughput technologies have enabled the generation of complex datasets, thus providing alternative approaches to exploring telomerase biology more comprehensively, which has proven to be challenging due to the need for laborious assays required to test for telomerase activity. To solve these issues, several groups have analyzed TCGA pan-cancer tumor datasets by investigating telomerase reverse transcriptase (TERT), the catalytic subunit for telomerase activity, or its surrogates. However, telomerase is a multiunit complex containing not only TERT, but also numerus cofactors required for telomerase function. Here we determined genomic and molecular alterations of 10 well-characterized telomerase components in the TCGA and CCLE datasets. We calculated a telomerase score (TS) based on their expression profiles and clustered tumors into low, high, and intermediate subtypes. To validate the in silico analysis result, we used immunoblotting and telomerase assays. High TS subtypes were significantly associated with stemness, proliferation, epithelial to mesenchymal transition, hyperactivation of oncogenic signaling pathways, shorter patient survival, and infiltration of dysfunctional T-cells or poor response to immunotherapy. Copy number alterations in 10 telomerase components were widespread and associated with the level of their expression. Surprisingly, primary tumors and cancer cell lines frequently displayed a homozygous deletion of the TCAB1 gene, encoding a telomerase protein essential for telomerase trafficking, assembling, and function, as previously reported. However, tumors or cells carrying a TCAB1 deletion still exhibited telomerase activity comparable to or even higher than their wildtype counterparts. Collectively, applying telomerase component-based TS in complex datasets provided a robust tool for telomerase analyses. Our findings also reveal a tight connection between telomerase and other oncogenic signaling pathways; TCAB1 may acts as a dispensable telomerase component. Moreover, TS may serve as a useful biomarker to predict patient outcomes and response to immunotherapy.
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Affiliation(s)
- Jing Wang
- Department of Urologic Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
| | - Mingkai Dai
- Division of Hematology, Department of Medicine, Bioclinicum and Center for Molecular MedicineKarolinska Institutet and Karolinska University Hospital SolnaStockholmSweden
| | - Xiangling Xing
- Division of Hematology, Department of Medicine, Bioclinicum and Center for Molecular MedicineKarolinska Institutet and Karolinska University Hospital SolnaStockholmSweden
| | - Xing Wang
- Department of Urology SurgeryThe First Affiliated Hospital of USTC, Wannan Medical collegeWuhuChina
| | - Xin Qin
- Department of UrologyQilu Hospital of Shandong UniversityJinanChina
| | - Tao Huang
- Department of Urologic Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina,Department of Urology SurgeryThe First Affiliated Hospital of USTC, Wannan Medical collegeWuhuChina
| | - Zhiqing Fang
- Department of UrologyQilu Hospital of Shandong UniversityJinanChina
| | - Yidong Fan
- Department of UrologyQilu Hospital of Shandong UniversityJinanChina
| | - Dawei Xu
- Division of Hematology, Department of Medicine, Bioclinicum and Center for Molecular MedicineKarolinska Institutet and Karolinska University Hospital SolnaStockholmSweden
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Judasz E, Lisiak N, Kopczyński P, Taube M, Rubiś B. The Role of Telomerase in Breast Cancer's Response to Therapy. Int J Mol Sci 2022; 23:12844. [PMID: 36361634 PMCID: PMC9654063 DOI: 10.3390/ijms232112844] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/13/2022] [Accepted: 10/24/2022] [Indexed: 11/26/2023] Open
Abstract
Currently, breast cancer appears to be the most widespread cancer in the world and the most common cause of cancer deaths. This specific type of cancer affects women in both developed and developing countries. Prevention and early diagnosis are very important factors for good prognosis. A characteristic feature of cancer cells is the ability of unlimited cell division, which makes them immortal. Telomeres, which are shortened with each cell division in normal cells, are rebuilt in cancer cells by the enzyme telomerase, which is expressed in more than 85% of cancers (up to 100% of adenocarcinomas, including breast cancer). Telomerase may have different functions that are related to telomeres or unrelated. It has been shown that high activity of the enzyme in cancer cells is associated with poor cell sensitivity to therapies. Therefore, telomerase has become a potential target for cancer therapies. The low efficacy of therapies has resulted in the search for new combined and more effective therapeutic methods, including the involvement of telomerase inhibitors and telomerase-targeted immunotherapy.
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Affiliation(s)
- Eliza Judasz
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Natalia Lisiak
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Przemysław Kopczyński
- Centre for Orthodontic Mini-Implants at the Department and Clinic of Maxillofacial Orthopedics and Orthodontics, Poznan University of Medical Sciences, 60-812 Poznan, Poland
| | - Magdalena Taube
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | - Błażej Rubiś
- Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, 60-806 Poznan, Poland
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Han X, Han J, Wang N, Ji G, Guo R, Li J, Wu H, Ma S, Fang P, Song X. Identification of Auxiliary Biomarkers and Description of the Immune Microenvironmental Characteristics in Duchenne Muscular Dystrophy by Bioinformatical Analysis and Experiment. Front Neurosci 2022; 16:891670. [PMID: 35720684 PMCID: PMC9204148 DOI: 10.3389/fnins.2022.891670] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 05/04/2022] [Indexed: 11/13/2022] Open
Abstract
Background Duchenne muscular dystrophy (DMD) is a genetic muscle disorder characterized by progressive muscle wasting associated with persistent inflammation. In this study, we aimed to identify auxiliary biomarkers and further characterize the immune microenvironment in DMD. Methods Differentially expressed genes (DEGs) were identified between DMD and normal muscle tissues based on Gene Expression Omnibus (GEO) datasets. Bioinformatical analysis was used to screen and identify potential diagnostic signatures of DMD which were further validated by real-time quantitative reverse transcription PCR (RT-qPCR). We also performed single-sample gene-set enrichment analysis (ssGSEA) to characterize the proportion of tissue-infiltrating immune cells to determine the inflammatory state of DMD. Results In total, 182 downregulated genes and 263 upregulated genes were identified in DMD. C3, SPP1, TMSB10, TYROBP were regarded as adjunct biomarkers and successfully validated by RT-qPCR. The infiltration of macrophages, CD4+, and CD8+ T cells was significantly higher (p < 0.05) in DMD compared with normal muscle tissues, while the infiltration of activated B cells, CD56dim natural killer cells, and type 17 T helper (Th17) cells was lower. In addition, the four biomarkers (C3, SPP1, TMSB10, TYROBP) were strongly associated with immune cells and immune-related pathways in DMD muscle tissues. Conclusion Analyses demonstrated C3, SPP1, TMSB10, and TYROBP may serve as biomarkers and enhance our understanding of immune responses in DMD. The infiltration of immune cells into the muscle microenvironment might exert a critical impact on the development and occurrence of DMD.
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Affiliation(s)
- Xu Han
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, China
| | - Jingzhe Han
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, China
| | - Ning Wang
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, China
| | - Guang Ji
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, China
| | - Ruoyi Guo
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, China
| | - Jing Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, China
| | - Hongran Wu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, China
| | - Shaojuan Ma
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, China
| | - Pingping Fang
- Department of Neurology, Handan Central Hospital, Handan, China
| | - Xueqin Song
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Neurological Laboratory of Hebei Province, Shijiazhuang, China
- *Correspondence: Xueqin Song,
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Shrivastava R, Gandhi P, Gothalwal R. The road-map for establishment of a prognostic molecular marker panel in glioma using liquid biopsy: current status and future directions. Clin Transl Oncol 2022; 24:1702-1714. [PMID: 35653004 DOI: 10.1007/s12094-022-02833-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/02/2022] [Indexed: 11/24/2022]
Abstract
Gliomas are primary intracranial tumors with defined molecular markers available for precise diagnosis. The prognosis of glioma is bleak as there is an overlook of the dynamic crosstalk between tumor cells and components of the microenvironment. Herein, different phases of gliomagenesis are presented with reference to the role and involvement of secreted proteomic markers at various stages of tumor initiation and development. The secreted markers of inflammatory response, namely interleukin-6, tumor necrosis factor-α, interferon-ϒ, and kynurenine, proliferation markers human telomerase reverse transcriptase and microtubule-associated-protein-Tau, and stemness marker human-mobility-group-AThook-1 are involved in glial tumor initiation and growth. Further, hypoxia and angiogenic factors, heat-shock-protein-70, endothelial-growth-factor-receptor-1 and vascular endothelial growth factor play a major role in promoting vascularization and tumor volume expansion. Eventually, molecules such as matrix-metalloprotease-7 and intercellular adhesion molecule-1 contribute to the degradation and remodeling of the extracellular matrix, ultimately leading to glioma progression. Our study delineates the roadmap to develop and evaluate a non-invasive panel of secreted biomarkers using liquid biopsy for precisely evaluating disease progression, to accomplish a clinical translation.
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Affiliation(s)
- Richa Shrivastava
- Department of Research, Bhopal Memorial Hospital and Research Centre, Raisen Bypass Road, Bhopal, M.P., 462038, India
| | - Puneet Gandhi
- Department of Research, Bhopal Memorial Hospital and Research Centre, Raisen Bypass Road, Bhopal, M.P., 462038, India.
| | - Ragini Gothalwal
- Department of Biotechnology, Barkatullah University, Bhopal, M.P., 462026, India
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González-Vasconcellos I, Cobos-Fernández MA, Atkinson MJ, Fernandez-Piqueras J, Santos J. Quantifying telomeric lncRNAs using PNA-labelled RNA-Flow FISH (RNA-Flow). Commun Biol 2022; 5:513. [PMID: 35614335 PMCID: PMC9132901 DOI: 10.1038/s42003-022-03452-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 05/05/2022] [Indexed: 11/30/2022] Open
Abstract
Here we present a method to detect and quantify long non-coding RNAs, in particular those related to telomeres. By coupling the specificity of a peptide nucleic acid (PNA) probe with flow cytometry we have quantified cellular levels of TERRA and TERC lncRNAs in culture cell lines and PBMCs. This easy-to-use method appointed RNA-Flow allows reliable lncRNA quantification with broad applications in basic research and clinical diagnostics. In addition, the staining protocol presented here was proven useful for the detection and quantification of such lncRNAs on unfixed cells using confocal microscopy. Telomeric-associated long non-coding RNAs TERRA and TERC can be quantified in culture cell lines and human PBMCs using peptide nucleic acid probes with flow cytometry (RNA-Flow).
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Affiliation(s)
- Iria González-Vasconcellos
- Genome Dynamics and Function Programme, Genome Decoding Research Unit, Centro de Biología Molecular Severo Ochoa (CBMSO), Madrid, Spain. .,Institute for Molecular Biology-IUBM (Autonomous University of Madrid), Madrid, Spain. .,Biology Department, faculty of science. Autonomous University of Madrid (UAM). Canto Blanco Campus, Madrid, Spain.
| | - María A Cobos-Fernández
- Genome Dynamics and Function Programme, Genome Decoding Research Unit, Centro de Biología Molecular Severo Ochoa (CBMSO), Madrid, Spain.,Institute for Molecular Biology-IUBM (Autonomous University of Madrid), Madrid, Spain.,Biology Department, faculty of science. Autonomous University of Madrid (UAM). Canto Blanco Campus, Madrid, Spain
| | - Michael J Atkinson
- Chair of Radiation Biology, Technical University of Munich, 81675, Munich, Germany
| | - José Fernandez-Piqueras
- Genome Dynamics and Function Programme, Genome Decoding Research Unit, Centro de Biología Molecular Severo Ochoa (CBMSO), Madrid, Spain.,Institute for Molecular Biology-IUBM (Autonomous University of Madrid), Madrid, Spain.,Biology Department, faculty of science. Autonomous University of Madrid (UAM). Canto Blanco Campus, Madrid, Spain.,Institute of Health Research Jiménez Díaz Foundation, Madrid, 28040, Spain
| | - Javier Santos
- Genome Dynamics and Function Programme, Genome Decoding Research Unit, Centro de Biología Molecular Severo Ochoa (CBMSO), Madrid, Spain.,Institute for Molecular Biology-IUBM (Autonomous University of Madrid), Madrid, Spain.,Biology Department, faculty of science. Autonomous University of Madrid (UAM). Canto Blanco Campus, Madrid, Spain.,Institute of Health Research Jiménez Díaz Foundation, Madrid, 28040, Spain
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Wu S, Ge Y, Lin K, Liu Q, Zhou H, Hu Q, Zhao Y, He W, Ju Z. Telomerase RNA TERC and the PI3K-AKT pathway form a positive feedback loop to regulate cell proliferation independent of telomerase activity. Nucleic Acids Res 2022; 50:3764-3776. [PMID: 35323972 PMCID: PMC9023280 DOI: 10.1093/nar/gkac179] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/11/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
The core catalytic unit of telomerase comprises telomerase reverse transcriptase (TERT) and telomerase RNA (TERC). Unlike TERT, which is predominantly expressed in cancer and stem cells, TERC is ubiquitously expressed in normal somatic cells without telomerase activity. However, the functions of TERC in these telomerase-negative cells remain elusive. Here, we reported positive feedback regulation between TERC and the PI3K-AKT pathway that controlled cell proliferation independent of telomerase activity in human fibroblasts. Mechanistically, we revealed that TERC activated the transcription of target genes from the PI3K-AKT pathway, such as PDPK1, by targeting their promoters. Overexpression of PDPK1 partially rescued the deficiency of AKT activation caused by TERC depletion. Furthermore, we found that FOXO1, a transcription factor negatively regulated by the PI3K-AKT pathway, bound to TERC promoter and suppressed its expression. Intriguingly, TERC-induced activation of the PI3K-AKT pathway also played a critical role in the proliferation of activated CD4+ T cells. Collectively, our findings identify a novel function of TERC that regulates the PI3K-AKT pathway via positive feedback to elevate cell proliferation independent of telomerase activity and provide a potential strategy to promote CD4+ T cells expansion that is responsible for enhancing adaptive immune reactions to defend against pathogens and tumor cells.
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Affiliation(s)
- Shu Wu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
| | - Yuanlong Ge
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China.,GCH Regenerative Medicine Group-Jinan University Joint Research and Development Center, Jinan University, Guangzhou 510632, China
| | - Kaixuan Lin
- Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Qianqian Liu
- First Affiliated Hospital, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Haoxian Zhou
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Qian Hu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
| | - Yong Zhao
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Weifeng He
- Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Army Military Medical University, Chongqing 400038, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
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Telomerase in Cancer: Function, Regulation, and Clinical Translation. Cancers (Basel) 2022; 14:cancers14030808. [PMID: 35159075 PMCID: PMC8834434 DOI: 10.3390/cancers14030808] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/29/2022] [Accepted: 02/02/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Cells undergoing malignant transformation must circumvent replicative senescence and eventual cell death associated with progressive telomere shortening that occurs through successive cell division. To do so, malignant cells reactivate telomerase to extend their telomeres and achieve cellular immortality, which is a “Hallmark of Cancer”. Here we review the telomere-dependent and -independent functions of telomerase in cancer, as well as its potential as a biomarker and therapeutic target to diagnose and treat cancer patients. Abstract During the process of malignant transformation, cells undergo a series of genetic, epigenetic, and phenotypic alterations, including the acquisition and propagation of genomic aberrations that impart survival and proliferative advantages. These changes are mediated in part by the induction of replicative immortality that is accompanied by active telomere elongation. Indeed, telomeres undergo dynamic changes to their lengths and higher-order structures throughout tumor formation and progression, processes overseen in most cancers by telomerase. Telomerase is a multimeric enzyme whose function is exquisitely regulated through diverse transcriptional, post-transcriptional, and post-translational mechanisms to facilitate telomere extension. In turn, telomerase function depends not only on its core components, but also on a suite of binding partners, transcription factors, and intra- and extracellular signaling effectors. Additionally, telomerase exhibits telomere-independent regulation of cancer cell growth by participating directly in cellular metabolism, signal transduction, and the regulation of gene expression in ways that are critical for tumorigenesis. In this review, we summarize the complex mechanisms underlying telomere maintenance, with a particular focus on both the telomeric and extratelomeric functions of telomerase. We also explore the clinical utility of telomeres and telomerase in the diagnosis, prognosis, and development of targeted therapies for primary, metastatic, and recurrent cancers.
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Urinary Exosomal Long Noncoding RNA TERC as a Noninvasive Diagnostic and Prognostic Biomarker for Bladder Urothelial Carcinoma. J Immunol Res 2022; 2022:9038808. [PMID: 35127956 PMCID: PMC8811540 DOI: 10.1155/2022/9038808] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 12/23/2021] [Indexed: 12/30/2022] Open
Abstract
Purpose Bladder cancer is one of the most common urological malignancies worldwide, and approximately 90% of bladder cancer cases are histologically typed as bladder urothelial carcinoma (BLCA). Exosomes are 30 to 200 nm extracellular vesicles that transport microRNAs, long noncoding RNAs (lncRNAs), mRNAs, circular RNAs, and proteins across tissues and through circulation. Urinary exosomes may contain genetic information from tumor cells. Herein, we explored the clinical significance of urinary exosomal lncRNA telomerase RNA component (TERC) levels to provide an urgently needed diagnostic and prognostic biomarker for BLCA. Materials and Methods In this study, we used RNA-sequencing of samples from four BLCA patients and three healthy controls to identify that TERC was differentially expressed in urinary exosomes. We then used quantitative PCR in different types of clinical samples to validate the biomarker and analyzed results using receiver operating characteristic curves. Results We found that TERC was significantly upregulated in urinary exosomes from BLCA patients compared with those from healthy controls (P < 0.0001). Urinary exosomal TERC showed higher sensitivity (78.65%) and accuracy (77.78%) than existing indicators including nuclear matrix protein-22 and urine cytometry. Using the cut-off value 4.302, the area under the curve for urinary exosomal TERC was 0.836 (95% confidence interval: 0.768–0.891, P < 0.0001). Furthermore, this noninvasive assay could distinguish low-grade and high-grade tumors (P = 0.0153). Conclusions TERC is enriched in urinary exosomes from BLCA patients. Urinary exosomal TERC could become a diagnostic and prognostic biomarker for BLCA that allows clinicians to realize noninvasive detection of BLCA.
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Abstract
Most of the transcribed human genome codes for noncoding RNAs (ncRNAs), and long noncoding RNAs (lncRNAs) make for the lion's share of the human ncRNA space. Despite growing interest in lncRNAs, because there are so many of them, and because of their tissue specialization and, often, lower abundance, their catalog remains incomplete and there are multiple ongoing efforts to improve it. Consequently, the number of human lncRNA genes may be lower than 10,000 or higher than 200,000. A key open challenge for lncRNA research, now that so many lncRNA species have been identified, is the characterization of lncRNA function and the interpretation of the roles of genetic and epigenetic alterations at their loci. After all, the most important human genes to catalog and study are those that contribute to important cellular functions-that affect development or cell differentiation and whose dysregulation may play a role in the genesis and progression of human diseases. Multiple efforts have used screens based on RNA-mediated interference (RNAi), antisense oligonucleotide (ASO), and CRISPR screens to identify the consequences of lncRNA dysregulation and predict lncRNA function in select contexts, but these approaches have unresolved scalability and accuracy challenges. Instead-as was the case for better-studied ncRNAs in the past-researchers often focus on characterizing lncRNA interactions and investigating their effects on genes and pathways with known functions. Here, we focus most of our review on computational methods to identify lncRNA interactions and to predict the effects of their alterations and dysregulation on human disease pathways.
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Liang Q, Wu J, Zhao X, Shen S, Zhu C, Liu T, Cui X, Chen L, Wei C, Cheng P, Cheng W, Wu A. Establishment of tumor inflammasome clusters with distinct immunogenomic landscape aids immunotherapy. Am J Cancer Res 2021; 11:9884-9903. [PMID: 34815793 PMCID: PMC8581407 DOI: 10.7150/thno.63202] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 10/06/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammasome signaling is a reaction cascade that influences immune response and cell death. Although the inflammasomes participate in tumorigenesis, their role as an oncogenic booster or a tumor suppresser is still controversial. Therefore, it is important to comprehensively investigate the inflammasome signaling status across various cancers to clarify its clinical and therapeutic significance. Methods: A total of 9881 patients across 33 tumor types from The Cancer Genome Atlas database were included in this study. Five gene sets were identified to step-wisely profile inflammasome signaling. Unsupervised clustering was used for sample classification based on gene set enrichment. Machine learning and in vitro and in vivo experiments were used to confirm the implications of inflammasome classification. Results: A hundred and forty-one inflammasome-signaling-related genes were identified to construct five gene sets representing the sensing, activation, and termination steps of the inflammasome signaling. Six inflammasome clusters were robustly established with distinct molecular, biological, clinical, and therapeutic features. Importantly, clusters with inflammasome signaling activation were found to be immunosuppressive and resistant to ICB treatment. Inflammasome inhibition reverted the therapeutic failure of ICB in inflammasome-activated tumors. Moreover, based on the proposed classification and therapeutic implications, an open website was established to provide tumor patients with comprehensive information on inflammasome signaling. Conclusions: Our study conducted a systematical investigation on inflammasome signaling in various tumor types. These findings highlight the importance of inflammasome evaluation in tumor classification and provide a foundation for improving relevant therapeutic regimens.
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Gandhi P, Shrivastava R, Garg N, Sorte SK. Novel molecular panel for evaluating systemic inflammation and survival in therapy naïve glioma patients. World J Clin Oncol 2021; 12:947-959. [PMID: 34733616 PMCID: PMC8546655 DOI: 10.5306/wjco.v12.i10.947] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/21/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammation is crucial to tumor progression. A traumatic event at a specific site in the brain activates the signaling molecules, which triggers inflammation as the initial response within the tumor and its surroundings. The educated immune cells and secreted proteins then initiate the inflammatory cascade leading to persistent chronic inflammation. Therefore, estimation of the circulating inflammatory indicators kynurenine (KYN), interleukin-6 (IL-6), tissue-inhibitor of matrix-metalloproteinase-1 and human telomerase reverse transcriptase (hTERT) along with neutrophil-lymphocyte ratio (NLR) has prognostic value. AIM To assess the utility of chosen inflammatory marker panel in estimating systemic inflammation. METHODS The chosen markers were quantitatively evaluated in 90 naive, molecularly sub-typed plasma samples of glioma. A correlation between the markers and confounders was assessed to establish their prognostication power. Follow-up on the levels of the indicators was done 3-mo post-surgery. To establish the validity of circulating KYN, it was also screened qualitatively by dot-immune-assay and by immunofluorescence-immunohistochemistry in tumor tissues. RESULTS Median values of circulating KYN, IL-6, hTERT, tissue-inhibitor of matrix-metalloproteinase-1 and NLR in isocitrate-dehydrogenase-mutant/wildtype and within the astrocytic sub-groups were estimated, which differed from controls, reaching statistical significance (P < 0.0001). All markers negatively correlated with mortality (P < 0.0001). Applying combination-statistics, the panel of KYN, IL-6, hTERT and NLR achieved higher sensitivity and specificity (> 90%) than stand-alone markers, to define survival. The inflammatory panel could discriminate between WHO grades, and isocitrate-dehydrogenase-mutant/wildtype and define differential survival between astrocytic isocitrate-dehydrogenase-mutant/wildtype. Therefore, its assessment for precise disease prognosis is indicated. Association of KYN with NLR, IL-6 and hTERT was significant. Cox-regression described KYN, IL-6, NLR, and hTERT as good prognostic markers, independent of confounders. Multivariate linear-regression analysis confirmed the association of KYN and hTERT with inflammation marker IL-6.There was a concomitant significant decrease in their levels in a 3-mo follow-up. CONCLUSION The first evidence-based study of circulating-KYN in molecularly defined gliomas, wherein the tissue expression was found to be concomitant with plasma levels. A non-invasive model for assessing indicators of chronic systemic inflammation is proposed.
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Affiliation(s)
- Puneet Gandhi
- Department of Research, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
| | - Richa Shrivastava
- Department of Research, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
| | - Nitin Garg
- Department of Neurosurgery, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
| | - Sandeep K Sorte
- Department of Neurosurgery, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
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Hecker M, Bühring J, Fitzner B, Rommer PS, Zettl UK. Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis. Biomolecules 2021; 11:1510. [PMID: 34680143 PMCID: PMC8533505 DOI: 10.3390/biom11101510] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 10/01/2021] [Accepted: 10/08/2021] [Indexed: 02/06/2023] Open
Abstract
Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS.
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Affiliation(s)
- Michael Hecker
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147 Rostock, Germany; (J.B.); (B.F.); (P.S.R.); (U.K.Z.)
| | - Jan Bühring
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147 Rostock, Germany; (J.B.); (B.F.); (P.S.R.); (U.K.Z.)
| | - Brit Fitzner
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147 Rostock, Germany; (J.B.); (B.F.); (P.S.R.); (U.K.Z.)
| | - Paulus Stefan Rommer
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147 Rostock, Germany; (J.B.); (B.F.); (P.S.R.); (U.K.Z.)
- Department of Neurology, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
| | - Uwe Klaus Zettl
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147 Rostock, Germany; (J.B.); (B.F.); (P.S.R.); (U.K.Z.)
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Wang Q, Zhou D, Wu F, Liang Q, He Q, Peng M, Yao T, Hu Y, Qian B, Tang J, Wang X, Liu W, Yu F, Chen C. Immune Microenvironment Signatures as Biomarkers to Predict Early Recurrence of Stage Ia-b Lung Cancer. Front Oncol 2021; 11:680287. [PMID: 34395248 PMCID: PMC8356052 DOI: 10.3389/fonc.2021.680287] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 07/14/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction Approximately 30% of patients diagnosed with stage Ia-b NSCLC die of recurrent disease after surgery. This study aimed to identify immune-related biomarkers that might predict tumor recurrence in stage Ia-b NSCLC within 40 months after curative resection. Methods Gene expression data of stage Ia-b NSCLC samples was retrieved from the TCGA database, the GEO databases, and the Second Xiangya hospital (XXEYY) database. 22 types of tumors infiltrating immune cells and the expression of immune-associated genes were investigated using CIBERSORT, immunohistochemical staining, and GSEA analyses in a total of 450 patients (80 in the training cohort and 370 in the validation cohorts). Recurrence-related immune features were selected based on the LASSO Cox regression model. Results High density of Tregs, Macrophages M0 and M1 cell could be observed in recurrence group while the memory B cell was more frequently enriched in controls, yet Tregs alone was significantly associated with tumor early recurrence in TCGA cohort, XYEYY cohort and GSE37745 dataset. A handful of immune-related genes were identified in the recurrence group. Based on Lasso regression analysis, the expressions of five immune-related genes, RLTPR, SLFN13, MIR4500HG, HYDIN and TPRG1 were closely correlated with tumor early recurrence. In the training cohort (TCGA), the combination of these five genes has sensitivity and specificity of 85% and 85%, with AUC of 0.91 (95% CI 0.84-0.98) for lung cancer early recurrence prediction, whereas in validation cohorts, the sensitivity and specificity using this panel was 61-89% and 54-82%, with AUC of 0.62-0.84. Conclusion Our study demonstrated that the immune microenvironment signatures were closely related to tumor early recurrence. Compared to tumor-infiltrating lymphocytes, the expression of five immune-related genes could be robust biomarkers to predict early recurrence of stage Ia-b NSCLC after curative resection.
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Affiliation(s)
- Qiang Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Danting Zhou
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Fang Wu
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qingchun Liang
- Department of Pathology, The Second Xiangya Hospital of Central South University, Changsha, China
| | | | - Muyun Peng
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Tianyu Yao
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yan Hu
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Banglun Qian
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jingqun Tang
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiang Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wenliang Liu
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Fenglei Yu
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chen Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, China
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Matsumoto Y, Miglietta MP. Cellular Reprogramming and Immortality: Expression Profiling Reveals Putative Genes Involved in Turritopsis dohrnii's Life Cycle Reversal. Genome Biol Evol 2021; 13:evab136. [PMID: 34132809 PMCID: PMC8480191 DOI: 10.1093/gbe/evab136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2021] [Indexed: 12/02/2022] Open
Abstract
To gather insight on the genetic network of cell reprogramming and reverse development in a nonmodel cnidarian system, we produced and annotated a transcriptome of the hydrozoan Turritopsis dohrnii, whose medusae respond to damage or senescence by metamorphosing into a juvenile stage (the polyp), briefly passing through an intermediate and uncharacterized stage (the cyst), where cellular transdifferentiation occurs. We conducted sequential and pairwise differential gene expression (DGE) analyses of the major life cycle stages involved in the ontogenetic reversal of T. dohrnii. Our DGE analyses of sequential stages of T. dohrnii's life cycle stages show that novel and characterized genes associated with aging/lifespan, regulation of transposable elements, DNA repair, and damage response, and Ubiquitin-related processes, among others, were enriched in the cyst stage. Our pairwise DGE analyses show that, when compared with the colonial polyp, the medusa is enriched with genes involved in membrane transport, the nervous system, components of the mesoglea, and muscle contraction, whereas genes involved in chitin metabolism and the formation of the primary germ layers are suppressed. The colonial polyp and reversed polyp (from cyst) show significant differences in gene expression. The reversed polyp is enriched with genes involved in processes such as chromatin remodeling and organization, matrix metalloproteinases, and embryonic development whereas suppressing genes involved in RAC G-protein signaling pathways. In summary, we identify genetic networks potentially involved in the reverse development of T. dohrnii and produce a transcriptome profile of all its life cycle stages, and paving the way for its use as a system for research on cell reprogramming.
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Affiliation(s)
- Yui Matsumoto
- Department of Marine Biology, Texas A&M University at Galveston, Texas, USA
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Hecker M, Fitzner B, Jäger K, Bühring J, Schwartz M, Hartmann A, Walter M, Zettl UK. Leukocyte Telomere Length in Patients with Multiple Sclerosis and Its Association with Clinical Phenotypes. Mol Neurobiol 2021; 58:2886-2896. [PMID: 33547621 PMCID: PMC8128833 DOI: 10.1007/s12035-021-02315-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/26/2021] [Indexed: 12/16/2022]
Abstract
Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS. We measured the average leukocyte telomere length (LTL) in biobanked DNA samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS), and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Changes in LTL over a period of >10 years were evaluated in a subset of 10 patients. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistical tests and regression models adjusted for age and sex. The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up. The LTL decrease over time was similar in RRMS patients and PPMS patients in the longitudinal analysis. Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between disease-related immune system alterations, immunosenescence, and telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained, e.g., by exploring the distribution of telomere lengths in specific blood cell populations.
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Affiliation(s)
- Michael Hecker
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany.
| | - Brit Fitzner
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany
| | - Kathrin Jäger
- Institute for Clinical Chemistry and Laboratory Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany.,Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Jan Bühring
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany
| | - Margit Schwartz
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany
| | - Alexander Hartmann
- Institute for Clinical Chemistry and Laboratory Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
| | - Michael Walter
- Institute for Clinical Chemistry and Laboratory Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany.
| | - Uwe Klaus Zettl
- Division of Neuroimmunology, Department of Neurology, Rostock University Medical Center, Gehlsheimer Str. 20, 18147, Rostock, Germany
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Amjadi-Moheb F, Paniri A, Akhavan-Niaki H. Insights into the Links between MYC and 3D Chromatin Structure and Epigenetics Regulation: Implications for Cancer Therapy. Cancer Res 2021; 81:1925-1936. [PMID: 33472888 DOI: 10.1158/0008-5472.can-20-3613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/21/2020] [Accepted: 01/06/2021] [Indexed: 11/16/2022]
Abstract
MYC is embedded in the transcriptional oasis of the 8q24 gene desert. A plethora of genomic elements has roles in MYC aberrant expression in cancer development by interacting with transcription factors and epigenetics regulators as well as altering the structure of chromatin at the MYC locus and tissue-specific long-range enhancer-promoter contacts. Furthermore, MYC is a master regulator of several human cancers by modulating the transcription of numerous cancer-related genes through epigenetic mechanisms. This review provides a comprehensive overview of the three-dimensional genomic organization around MYC and the role of epigenetic machinery in transcription and function of MYC as well as discusses various epigenetic-targeted therapeutic strategies in MYC-driven cancers.
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Affiliation(s)
- Fatemeh Amjadi-Moheb
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Alireza Paniri
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Haleh Akhavan-Niaki
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
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Gala K, Khattar E. Long non-coding RNAs at work on telomeres: Functions and implications in cancer therapy. Cancer Lett 2021; 502:120-132. [PMID: 33450357 DOI: 10.1016/j.canlet.2020.12.036] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 12/13/2020] [Accepted: 12/29/2020] [Indexed: 12/27/2022]
Abstract
Long non-coding RNAs (lncRNAs) are known to regulate various biological processes including cancer. Cancer cells possess limitless replicative potential which is attained by telomere length maintenance while normal somatic cells have a limited lifespan because their telomeres shorten with every cell division ultimately triggering replicative senescence. Two lncRNAs have been observed to play a key role in telomere length maintenance. First is the lncRNA TERC (telomerase RNA component) which functions as a template for telomeric DNA synthesis in association with telomerase reverse transcriptase (TERT) which serves as the catalytic component. Together they constitute the telomerase complex which functions as a reverse transcriptase to elongate telomeres. Second lncRNA that helps in regulating telomere length is the telomeric repeat-containing RNA (TERRA) which is transcribed from the subtelomeric region and extends to the telomeric region. TERC and TERRA exhibit important functions in cancer with implications in precision oncology. In this review, we discuss various aspects of these important lncRNAs in humans and their role in cancer along with recent advancements in their anticancer therapeutic application.
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Affiliation(s)
- Kavita Gala
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be) University, Mumbai, 400056, Maharashtra, India
| | - Ekta Khattar
- Sunandan Divatia School of Science, SVKM's NMIMS (Deemed to be) University, Mumbai, 400056, Maharashtra, India.
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44
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Yuan X, Dai M, Xu D. Telomere-related Markers for Cancer. Curr Top Med Chem 2020; 20:410-432. [PMID: 31903880 PMCID: PMC7475940 DOI: 10.2174/1568026620666200106145340] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/03/2019] [Accepted: 12/14/2019] [Indexed: 02/06/2023]
Abstract
Telomeres are structurally nucleoprotein complexes at termini of linear chromosomes and essential to chromosome stability/integrity. In normal human cells, telomere length erodes progressively with each round of cell divisions, which serves as an important barrier to uncontrolled proliferation and malignant transformation. In sharp contrast, telomere maintenance is a key feature of human malignant cells and required for their infinite proliferation and maintenance of other cancer hallmarks as well. Thus, a telomere-based anti-cancer strategy has long been suggested. However, clinically efficient and specific drugs targeting cancer telomere-maintenance have still been in their infancy thus far. To achieve this goal, it is highly necessary to elucidate how exactly cancer cells maintain functional telomeres. In the last two decades, numerous studies have provided profound mechanistic insights, and the identified mechanisms include the aberrant activation of telomerase or the alternative lengthening of telomere pathway responsible for telomere elongation, dysregulation and mutation of telomere-associated factors, and other telomere homeostasis-related signaling nodes. In the present review, these various strategies employed by malignant cells to regulate their telomere length, structure and function have been summarized, and potential implications of these findings in the rational development of telomere-based cancer therapy and other clinical applications for precision oncology have been discussed.
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Affiliation(s)
- Xiaotian Yuan
- Center for Reproductive Medicine, Shandong University, Jinan, 250012, China
| | - Mingkai Dai
- Central Research Laboratory, Shandong University Second Hospital, Jinan, 250033, China.,Karolinska Institute Collaborative Laboratory for Cancer and Stem Cell Research, Shandong University Second Hospital, Jinan, 250033, China
| | - Dawei Xu
- Karolinska Institute Collaborative Laboratory for Cancer and Stem Cell Research, Shandong University Second Hospital, Jinan, 250033, China.,Department of Medicine, Division of Hematology, Center for Molecular Medicine (CMM) and Bioclinicum, Karolinska Institute and Karolinska University Hospital Solna, Solna 171 64, Sweden
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45
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Luxton JJ, McKenna MJ, Lewis A, Taylor LE, George KA, Dixit SM, Moniz M, Benegas W, Mackay MJ, Mozsary C, Butler D, Bezdan D, Meydan C, Crucian BE, Zwart SR, Smith SM, Mason CE, Bailey SM. Telomere Length Dynamics and DNA Damage Responses Associated with Long-Duration Spaceflight. Cell Rep 2020; 33:108457. [PMID: 33242406 DOI: 10.1016/j.celrep.2020.108457] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/31/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
Telomere length dynamics and DNA damage responses were assessed before, during, and after one-year or shorter duration missions aboard the International Space Station (ISS) in a comparatively large cohort of astronauts (n = 11). Although generally healthy individuals, astronauts tended to have significantly shorter telomeres and lower telomerase activity than age- and sex-matched ground controls before and after spaceflight. Although telomeres were longer during spaceflight irrespective of mission duration, telomere length shortened rapidly upon return to Earth, and overall astronauts had shorter telomeres after spaceflight than they did before; inter-individual differences were identified. During spaceflight, all crewmembers experienced oxidative stress, which positively correlated with telomere length dynamics. Significantly increased frequencies of chromosomal inversions were observed during and after spaceflight; changes in cell populations were also detected. We propose a telomeric adaptive response to chronic oxidative damage in extreme environments, whereby the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway is transiently activated in normal somatic cells.
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Affiliation(s)
- Jared J Luxton
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
| | - Miles J McKenna
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA
| | - Aidan Lewis
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Lynn E Taylor
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | | | - Sameer M Dixit
- Center for Molecular Dynamics - Nepal (CMDN), Kathmandu, Nepal
| | | | | | - Matthew J Mackay
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Christopher Mozsary
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Daniel Butler
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Daniela Bezdan
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
| | - Cem Meydan
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA
| | - Brian E Crucian
- Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX, USA
| | - Sara R Zwart
- University of Texas Medical Branch, Galveston, TX, USA
| | - Scott M Smith
- Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX, USA
| | - Christopher E Mason
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.
| | - Susan M Bailey
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA; Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA.
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Abstract
We report a systematic unbiased analysis of small RNA molecule expression in 11 different tissues of the model organism mouse. We discovered uncharacterized noncoding RNA molecules and identified that ∼30% of total noncoding small RNA transcriptome are distributed across the body in a tissue-specific manner with some also being sexually dimorphic. Distinct distribution patterns of small RNA across the body suggest the existence of tissue-specific mechanisms involved in noncoding RNA processing. Small noncoding RNAs (ncRNAs) play a vital role in a broad range of biological processes both in health and disease. A comprehensive quantitative reference of small ncRNA expression would significantly advance our understanding of ncRNA roles in shaping tissue functions. Here, we systematically profiled the levels of five ncRNA classes (microRNA [miRNA], small nucleolar RNA [snoRNA], small nuclear RNA [snRNA], small Cajal body-specific RNA [scaRNA], and transfer RNA [tRNA] fragments) across 11 mouse tissues by deep sequencing. Using 14 biological replicates spanning both sexes, we identified that ∼30% of small ncRNAs are distributed across the body in a tissue-specific manner with some also being sexually dimorphic. We found that some miRNAs are subject to “arm switching” between healthy tissues and that tRNA fragments are retained within tissues in both a gene- and a tissue-specific manner. Out of 11 profiled tissues, we confirmed that brain contains the largest number of unique small ncRNA transcripts, some of which were previously annotated while others are identified in this study. Furthermore, by combining these findings with single-cell chromatin accessibility (scATAC-seq) data, we were able to connect identified brain-specific ncRNAs with their cell types of origin. These results yield the most comprehensive characterization of specific and ubiquitous small RNAs in individual murine tissues to date, and we expect that these data will be a resource for the further identification of ncRNAs involved in tissue function in health and dysfunction in disease.
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Lau B, Kerr K, Gu Q, Nightingale K, Antrobus R, Suárez NM, Stanton RJ, Wang ECY, Weekes MP, Davison AJ. Human Cytomegalovirus Long Non-coding RNA1.2 Suppresses Extracellular Release of the Pro-inflammatory Cytokine IL-6 by Blocking NF-κB Activation. Front Cell Infect Microbiol 2020; 10:361. [PMID: 32793512 PMCID: PMC7387431 DOI: 10.3389/fcimb.2020.00361] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/11/2020] [Indexed: 12/16/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are transcripts of >200 nucleotides that are not translated into functional proteins. Cellular lncRNAs have been shown to act as regulators by interacting with target nucleic acids or proteins and modulating their activities. We investigated the role of RNA1.2, which is one of four major lncRNAs expressed by human cytomegalovirus (HCMV), by comparing the properties of parental virus in vitro with those of deletion mutants lacking either most of the RNA1.2 gene or only the TATA element of the promoter. In comparison with parental virus, these mutants exhibited no growth defects and minimal differences in viral gene expression in human fibroblasts. In contrast, 76 cellular genes were consistently up- or down-regulated by the mutants at both the RNA and protein levels at 72 h after infection. Differential expression of the gene most highly upregulated by the mutants (Tumor protein p63-regulated gene 1-like protein; TPRG1L) was confirmed at both levels by RT-PCR and immunoblotting. Consistent with the known ability of TPRG1L to upregulate IL-6 expression via NF-κB stimulation, RNA1.2 mutant-infected fibroblasts were observed to upregulate IL-6 in addition to TPRG1L. Comparable surface expression of TNF receptors and responsiveness to TNF-α in cells infected by the parental and mutant viruses indicated that activation of signaling by TNF-α is not involved in upregulation of IL-6 by the mutants. In contrast, inhibition of NF-κB activity and knockdown of TPRG1L expression reduced the extracellular release of IL-6 by RNA1.2 mutant-infected cells, thus demonstrating that upregulation of TPRG1L activates NF-κB. The levels of MCP-1 and CXCL1 transcripts were also increased in RNA1.2 mutant-infected cells, further demonstrating the presence of active NF-κB signaling. These results suggest that RNA1.2 plays a role in manipulating intrinsic NF-κB-dependent cytokine and chemokine release during HCMV infection, thereby impacting downstream immune responses.
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Affiliation(s)
- Betty Lau
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Karen Kerr
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Quan Gu
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Katie Nightingale
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - Robin Antrobus
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - Nicolás M. Suárez
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Richard J. Stanton
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Eddie C. Y. Wang
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Michael P. Weekes
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - Andrew J. Davison
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
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Human Telomerase RNA: Telomerase Component or More? Biomolecules 2020; 10:biom10060873. [PMID: 32517215 PMCID: PMC7355840 DOI: 10.3390/biom10060873] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/04/2020] [Accepted: 06/05/2020] [Indexed: 12/16/2022] Open
Abstract
Telomerase is a ribonucleoprotein complex that maintains the lengths of telomeres. Most studies of telomerase function have focused on the involvement of telomerase activation in the immortalization of cancer cells and cellular rejuvenation. However, some studies demonstrated that the results do not meet expectations for telomerase action in telomere maintenance. Recent results give reason to think that major telomerase components-the reverse transcriptase protein subunit and telomerase RNA-may participate in many cellular processes, including the regulation of apoptosis and autophagy, cell survival, pro-proliferative effects, regulation of gene expression, and protection against oxidative stress. However, the difficulties faced by scientist when researching telomerase component functions often reduce confidence in the minor effects observed in experiments. In this review, we focus on the analysis of the functions of telomerase components (paying more attention to the telomerase RNA component), both as a complex and as independent components, providing effects that are not associated with telomerase activity and telomere length maintenance. Despite the fact that the data on alternative roles of telomerase components look illusory, it would be wrong to completely reject the possibility of their involvement in other biological processes excluded from research/discussion. Investigations to improve the understanding of every aspect of the functioning of telomerase components will provide the basis for a more precise development of approaches to regulate cellular homeostasis, which is important for carcinogenesis and aging.
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Sun Q, Liu J, Cheng G, Dai M, Liu J, Qi Z, Zhao J, Li W, Kong F, Liu G, Björkholm M, Xu D. The telomerase gene polymorphisms, but not telomere length, increase susceptibility to primary glomerulonephritis/end stage renal diseases in females. J Transl Med 2020; 18:184. [PMID: 32366311 PMCID: PMC7199377 DOI: 10.1186/s12967-020-02347-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 04/17/2020] [Indexed: 12/19/2022] Open
Abstract
Background Primary glomerulonephritis (GN) is the leading cause of chronic kidney disease (CKD) and frequently progresses into end stage renal diseases (ESRDs). Shorter leukocyte telomere length (LTL) has been implicated in the CKD susceptibility and diminished kidney function, however, it is unclear whether the variants in telomerase genes contribute to risk to GN/CKD/ESRD. Here we address this issue by determining their association with the genetic variants of rs12696304 at the telomerase RNA component (TERC) and rs2736100 at the telomerase reverse transcriptase (TERT) loci. Methods The study includes 769 patients (243 primary GN-derived CKD and 526 ESRD cases) and sex-/age-matched healthy controls. Genomic DNA was extracted from peripheral blood of both controls and patients. Genotyping of rs12696304 and rs2736100 variants was carried out using PCR-based assays. Leukocyte telomere length (LTL) was determined using quantitative PCR (qPCR). Results A significantly higher frequency of TERC rs12696304 G allele was observed in patients and associated with increased disease risk (C vs G: OR = 1.334, 95% CI 1.112–1.586, P = 0.001; CC + GC vs GG: OR = 1.334, 95% CI 1.122–1.586, P = 0.001). Further analyses showed that such significant differences were only present between female controls and patients (C vs G: OR = 1.483, 95% CI 1.140–1.929, P = 0.003; CC + GC vs CC: OR = 1.692, 95% CI 1.202–2.383, P = 0.003), but not males. There were no differences in rs2736100 variants between controls and patients, but female ESRD patients carried significantly higher C allele frequencies than did female controls (A vs C: OR = 1.306, 95% CI 1.005–1.698, P = 0.046; AA vs CC: OR = 1.781, 95% CI 1.033–3.070, P = 0.037). There was no difference in LTL between controls and patients. Conclusions Our results reveal that the TERC rs12696304 and TERT rs2736100 polymorphisms, but not LTL per se, contribute to GN/CDK/ESRD risk.
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Affiliation(s)
- Qing Sun
- Central Research Laboratory, Shandong University Second Hospital, Jinan, 250035, People's Republic of China
| | - Junli Liu
- Laboratory for Molecular Diagnostics, Shandong University Second Hospital, Jinan, 250035, People's Republic of China
| | - Guanghui Cheng
- Central Research Laboratory, Shandong University Second Hospital, Jinan, 250035, People's Republic of China
| | - Mingkai Dai
- Central Research Laboratory, Shandong University Second Hospital, Jinan, 250035, People's Republic of China
| | - Jiaxi Liu
- Central Research Laboratory, Shandong University Second Hospital, Jinan, 250035, People's Republic of China
| | - Zhenqiang Qi
- Department of Nephrology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250013, People's Republic of China
| | - Jingjie Zhao
- Laboratory for Molecular Diagnostics, Shandong University Second Hospital, Jinan, 250035, People's Republic of China
| | - Wei Li
- Department of Nephrology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250013, People's Republic of China.
| | - Feng Kong
- Central Research Laboratory, Shandong University Second Hospital, Jinan, 250035, People's Republic of China.
| | - Gang Liu
- Nephrology Research Institute of Shandong University, Shandong University Second Hospital, Jinan, 250035, People's Republic of China.
| | - Magnus Björkholm
- Department of Medicine, Center for Molecular Medicine and Bioclinicum, Karolinska Institutet, Karolinska University Hospital Solna, SE-171 76, Stockholm, Sweden
| | - Dawei Xu
- Department of Medicine, Center for Molecular Medicine and Bioclinicum, Karolinska Institutet, Karolinska University Hospital Solna, SE-171 76, Stockholm, Sweden.
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Vecoli C, Borghini A, Andreassi MG. The molecular biomarkers of vascular aging and atherosclerosis: telomere length and mitochondrial DNA 4977 common deletion. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2020; 784:108309. [PMID: 32430098 DOI: 10.1016/j.mrrev.2020.108309] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/15/2022]
Abstract
Age is the dominant risk factor for the most prevalent atherosclerotic vascular diseases, including coronary artery disease, myocardial infarction, cerebrovascular disease and stroke. In human, telomere erosion and mitochondrial DNA (mtDNA) damage play a central role in the mechanisms leading to cellular aging decline. This review summarizes the most relevant findings on the role of telomere shortening and the common mtDNA4977 deletion in the progression and evolution of atherosclerosis by combining insight from experimental models and human clinical studies. The current evidence shows a link between telomere erosion and compromised mitochondrial function and provides a new perspective regarding their potential role as clinical biomarkers and therapeutic targets.
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