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Gonzalez LA, Zhang W, Bai H, Taniguchi R, Ramachandra AB, Jovin DG, Ohashi Y, Nguyen M, Thaxton C, Yatsula B, Vazquez-Padron RI, Humphrey JD, Martin KA, Kyriakides TR, Dardik A. Sustained tenascin-C expression drives neointimal hyperplasia and promotes aortocaval fistula failure. Am J Physiol Heart Circ Physiol 2025; 328:H1147-H1167. [PMID: 40247455 DOI: 10.1152/ajpheart.00661.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/15/2024] [Accepted: 03/08/2025] [Indexed: 04/19/2025]
Abstract
End-stage kidney disease (ESKD) impacts over 740,000 individuals in the United States, with many patients relying on arteriovenous fistulae (AVF) for hemodialysis due to superior patency and reduced infections. However, AVF patency is reduced by thrombosis and neointimal hyperplasia, yielding a 1-yr patency of only 40%-50%. We hypothesized that tenascin-C (TNC), a regulator of inflammation and immune responses after injury, also regulates venous remodeling during AVF maturation. AVF were created in wild-type (WT) and Tnc knockout (Tnc-/-) mice, and proteomic analyses were conducted to identify protein changes between sham and AVF WT tissue. Immunofluorescence and Western blot assays compared venous tissue from WT and Tnc-/- mice. In vitro studies using human umbilical vein endothelial cells and human umbilical vein smooth muscle cells examined TNC-siRNA effects on thrombomodulin (THBD) and NF-κB. Macrophages from WT and Tnc-/- mice were assessed for anti-inflammatory phenotype polarization and tissue factor expression. TNC expression was spatially and temporally regulated in WT mice with AVF, and TNC colocalized with matrix remodeling but not with THBD expression; TNC expression was downregulated in patent AVF but sustained in occluded AVF, both in WT mice and human AVF specimens. Tnc-/- mice had reduced AVF patency, less wall thickening, and increased thrombosis, with increased THBD expression. In vitro, TNC-siRNA increased THBD and reduced NF-κB activation. Macrophages from Tnc-/- mice showed increased anti-inflammatory macrophage polarization and tissue factor expression, facilitating thrombosis. Sustained TNC expression drives neointimal hyperplasia and AVF failure by promoting a prothrombotic, inflammatory microenvironment. Targeting TNC pathways may enhance AVF patency and improve dialysis outcomes.NEW & NOTEWORTHY This study identifies Tenascin-C (TNC) as a key regulator of arteriovenous fistula (AVF) patency. TNC is spatially and temporally regulated, driving neointimal hyperplasia and thrombosis by promoting a prothrombotic, inflammatory microenvironment. In Tnc-/- mice, reduced TNC expression increased thrombomodulin and anti-inflammatory macrophage polarization but impaired wall thickening and AVF patency. These findings link sustained TNC expression to AVF failure and suggest that targeting TNC pathways could enhance AVF outcomes in patients requiring hemodialysis.
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MESH Headings
- Animals
- Tenascin/genetics
- Tenascin/metabolism
- Hyperplasia
- Neointima/metabolism
- Neointima/pathology
- Humans
- Mice, Knockout
- Thrombomodulin/metabolism
- Thrombomodulin/genetics
- Macrophages/metabolism
- Macrophages/pathology
- Arteriovenous Shunt, Surgical/adverse effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Human Umbilical Vein Endothelial Cells/pathology
- Male
- Vascular Remodeling
- Mice
- Mice, Inbred C57BL
- NF-kappa B/metabolism
- Vascular Patency
- Disease Models, Animal
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Graft Occlusion, Vascular/metabolism
- Graft Occlusion, Vascular/pathology
- Graft Occlusion, Vascular/physiopathology
- Graft Occlusion, Vascular/genetics
- Graft Occlusion, Vascular/etiology
- Vena Cava, Inferior/metabolism
- Vena Cava, Inferior/surgery
- Vena Cava, Inferior/pathology
- Vena Cava, Inferior/physiopathology
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Affiliation(s)
- Luis A Gonzalez
- Yale School of Medicine, New Haven, Connecticut, United States
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut, United States
| | - Weichang Zhang
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Hualong Bai
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Ryosuke Taniguchi
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
- Division of Vascular Surgery, Department of Surgery, The University of Tokyo, Tokyo, Japan
- Department of Cardiovascular Surgery, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Abhay B Ramachandra
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut, United States
| | - Daniel G Jovin
- Yale School of Medicine, New Haven, Connecticut, United States
| | - Yuichi Ohashi
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
- Division of Vascular Surgery, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Mytien Nguyen
- Yale School of Medicine, New Haven, Connecticut, United States
| | - Carly Thaxton
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Bogdan Yatsula
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
| | - Roberto I Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, United States
| | - Jay D Humphrey
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut, United States
| | - Kathleen A Martin
- Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut, United States
| | - Themis R Kyriakides
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut, United States
- Department of Pathology, Yale University, New Haven, Connecticut, United States
| | - Alan Dardik
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut, United States
- Department of Surgery, Yale School of Medicine, New Haven, Connecticut, United States
- Department of Surgery, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, United States
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, United States
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2
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Szymańska B, Małkiewicz B, Dembowski J, Piwowar A. Usability Evaluation of Urinary HAI-1, STMN-1 and TN-C in the Diagnosis of Bladder Cancer. J Clin Med 2025; 14:3664. [PMID: 40507426 PMCID: PMC12155572 DOI: 10.3390/jcm14113664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2025] [Revised: 05/11/2025] [Accepted: 05/20/2025] [Indexed: 06/16/2025] Open
Abstract
Background: Proteins with different functions, such as Hepatocyte growth factor activator inhibitor type 1 (HAI-1), Stathmin 1 (STMN-1), and Tenascin C (TN-C), whose activity has been observed in various types of cancers, inspired our study in bladder cancer (BC) patients. The aim of the study was to evaluate selected parameters and their combinations in the diagnosis of BC. The study took into account the degree of invasiveness and malignancy of BC. Based on the analysis of the Receiver Operating Characteristic Curve (ROC), the diagnostic value of single parameters and their combinations as potential indicators of BC was assessed. Patients and Methods: The research material consisted of urine samples from patients with BC, and urine samples from a control group without urological diseases. The concentrations of the examined parameters were measured using an immunoenzymatic method. Results: Statistically significant higher concentrations of HAI-1 (p ≤ 0.001), STMN-1 (≤0.001) and TN-C (0.002) were found in the patients with BC compared to the control group. Strong relationships were shown between these parameters. ROC analyses showed that the best single parameter for detecting BC is STMN-1, and in the combination of HAI-1+STMN-1. The highest diagnostic value was obtained for the combination of HAI-1+STMN-1 in the patients with high malignancy (sensitivity 82%, specificity 91%). Conclusions: Preliminary studies of parameters have shown their utility as potential markers in BC, especially of STMN-1 and combinations HAI-1+STMN-1. However, to learn more about the contribution of these parameters to the progression of bladder cancer, it would be appropriate to continue the studies.
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Affiliation(s)
- Beata Szymańska
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 211 Borowska Street, 50-556 Wroclaw, Poland;
| | - Bartosz Małkiewicz
- Department of Minimally Invasive and Robotic Urology, Centre of Excellence in Urology, Wroclaw Medical University, 213 Borowska Street, 50-556 Wroclaw, Poland; (B.M.); (J.D.)
| | - Janusz Dembowski
- Department of Minimally Invasive and Robotic Urology, Centre of Excellence in Urology, Wroclaw Medical University, 213 Borowska Street, 50-556 Wroclaw, Poland; (B.M.); (J.D.)
| | - Agnieszka Piwowar
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 211 Borowska Street, 50-556 Wroclaw, Poland;
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3
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Korenić M, Korenić A, Stamenković V, Dučić T, Andjus P. SR-FTIR Biomolecular Characterization of the Hippocampus: The Role of Tenascin C in Adult Murine Neurogenesis in the Subgranular Zone. Cells 2025; 14:435. [PMID: 40136684 PMCID: PMC11941197 DOI: 10.3390/cells14060435] [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] [Received: 02/16/2025] [Revised: 03/06/2025] [Accepted: 03/11/2025] [Indexed: 03/27/2025] Open
Abstract
To better understand adult neurogenesis, the biomolecular specificity of the subgranular zone should be investigated in comparison to other layers of the hippocampus. Adult neurogenesis occurs at a reduced rate in adulthood compared to the period of development, but it can be increased with exposure to an enriched environment (EE). This can be used to investigate the regulatory role of molecules present in the extracellular matrix, such as tenascin C (TnC). This study, using Synchrotron radiation Fourier Transform Infrared spectroscopy (SR-FTIR), shows that the differences between the hippocampal layers in adolescence are maintained as subtle and significant in adulthood. The main difference in FTIR spectra was observed for nucleic acid and carbohydrate and for the comparison of the subgranular zone (SGZ) with hippocampal CA3. Moreover, we have detected changes in the protein and nucleic acid content of the SGZ that accompany the process of neurogenesis under the influence of an enriched environment. The latter effects are, however, lacking in mice with a gene ablation for tenascin C. Overall, these results show that observed discrete biomolecular differences in hippocampal layers follow the rate of neurogenesis that is enhanced by EE and dependent on TnC.
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Affiliation(s)
- Milena Korenić
- Institute of Physiology and Biochemistry “Jean Giaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (M.K.); (A.K.)
| | - Andrej Korenić
- Institute of Physiology and Biochemistry “Jean Giaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (M.K.); (A.K.)
| | - Vera Stamenković
- Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98105, USA;
| | - Tanja Dučić
- ALBA-CELLS Synchrotron, 08290 Cerdanyola del Vallès, Spain;
| | - Pavle Andjus
- Institute of Physiology and Biochemistry “Jean Giaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (M.K.); (A.K.)
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4
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Wang B, Pozarickij A, Mazidi M, Wright N, Yao P, Said S, Iona A, Kartsonaki C, Fry H, Lin K, Chen Y, Du H, Avery D, Schmidt-Valle D, Yu C, Sun D, Lv J, Hill M, Li L, Bennett DA, Collins R, Walters RG, Clarke R, Millwood IY, Chen Z. Comparative studies of 2168 plasma proteins measured by two affinity-based platforms in 4000 Chinese adults. Nat Commun 2025; 16:1869. [PMID: 39984443 PMCID: PMC11845630 DOI: 10.1038/s41467-025-56935-2] [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: 12/07/2023] [Accepted: 01/27/2025] [Indexed: 02/23/2025] Open
Abstract
Proteomics offers unique insights into human biology and drug development, but few studies have directly compared the utility of different proteomics platforms. We measured plasma levels of 2168 proteins in 3976 Chinese adults using both Olink Explore and SomaScan platforms. The correlation of protein levels between platforms was modest (median rho = 0.29), with protein abundance and data quality parameters being key factors influencing correlation. For 1694 proteins with one-to-one matched reagents, 765 Olink and 513 SomaScan proteins had cis-pQTLs, including 400 with colocalising cis-pQTLs. Moreover, 1096 Olink and 1429 SomaScan proteins were associated with BMI, while 279 and 154 proteins were associated with risk of ischaemic heart disease, respectively. Addition of Olink and SomaScan proteins to conventional risk factors for ischaemic heart disease improved C-statistics from 0.845 to 0.862 (NRI: 12.2%) and 0.863 (NRI: 16.4%), respectively. These results demonstrate the utility of these platforms and could inform the design and interpretation of future studies.
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Grants
- 82192901, 82192904, 82192900 National Natural Science Foundation of China (National Science Foundation of China)
- CH/1996001/9454 British Heart Foundation (BHF)
- MC-PC-13049, MC-PC-14135 RCUK | Medical Research Council (MRC)
- FS/18/23/33512 British Heart Foundation (BHF)
- C16077/A29186, C500/A16896 Cancer Research UK (CRUK)
- Wellcome Trust
- 212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z Wellcome Trust (Wellcome)
- The CKB baseline survey and the first re-survey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up and subsequent resurveys have been supported by Wellcome grants to Oxford University (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z) and grants from the National Natural Science Foundation of China (82192901, 82192904, 82192900) and from the National Key Research and Development Program of China (2016YFC0900500).The UK Medical Research Council (MC_UU_00017/1, MC_UU_12026/2, MC_U137686851), Cancer Research UK (C16077/A29186, C500/A16896) and British Heart Foundation (CH/1996001/9454), provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit, Oxford University for the project. The proteomic assays were supported by BHF (FS/18/23/33512), Novo Nordisk, Olink, SomaScan and NDPH. DNA extraction and genotyping were supported by GlaxoSmithKline and the UK Medical Research Council (MC-PC-13049, MC-PC-14135). Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
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Affiliation(s)
- Baihan Wang
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Alfred Pozarickij
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Mohsen Mazidi
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Neil Wright
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Pang Yao
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Saredo Said
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Andri Iona
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Christiana Kartsonaki
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Hannah Fry
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Kuang Lin
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Yiping Chen
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Huaidong Du
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Daniel Avery
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Dan Schmidt-Valle
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Canqing Yu
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Dianjianyi Sun
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Jun Lv
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Michael Hill
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Liming Li
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China
- Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China
| | - Derrick A Bennett
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Rory Collins
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Robin G Walters
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Robert Clarke
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Iona Y Millwood
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
| | - Zhengming Chen
- Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
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5
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Sato T, Yamaguchi T, Minato T, Hoshizaki M, Yamamoto A, Morita M, Suzuki T, Fujio Y, Imai Y, Suzuki Y, Yamamoto T, Watanabe H, Kuba K. CNOT6L deadenylase suppresses cardiac remodeling in heart failure through downregulation of tenascin-C mRNA. J Pharmacol Exp Ther 2025; 392:100052. [PMID: 40023604 DOI: 10.1016/j.jpet.2024.100052] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 11/26/2024] [Indexed: 03/04/2025] Open
Abstract
Heart failure is rapidly increasing and is a growing burden on human health and the economy in the world. The functional role of mRNA regulation in the pathogenesis of heart failure remains to be elucidated. Carbon catabolite repression 4-negative on TATA-less complex is a multisubunit protein complex that deadenylates mRNA, a process of exonuclease-mediated degradation of mRNA poly(A) tail. Here we show the cardiac protective roles of deadenylase subunit CNOT6L against cardiac stress. After 2 weeks of transverse aortic constriction (TAC)-induced pressure overload, expression of CNOT6L deadenylase subunit was significantly upregulated in the mouse hearts. When CNOT6L gene was genetically deleted, the mice exhibited marked decline of left ventricular contractility and enhancement of fibrosis at 2 weeks after TAC. Transcriptome analyses elucidated that CNOT6L targets tenascin-C mRNA, which stimulates tissue fibrosis and inflammation. CNOT6L deletion markedly upregulated tenascin-C expression in cardiac fibroblasts. Poly(A) tail length and luciferase reporter analyses revealed that CNOT6L catalyzes deadenylation of tenascin-C mRNA likely through interaction with the cis-element in its 3'-untranslated region. Double knockout of tenascin-C and CNOT6L ameliorated cardiac fibrosis and dysfunction in single CNOT6 knockout mice under TAC or chronic infusion of angiotensin II. Thus, CNOT6L deadenylase prevents the progression of heart failure through downregulation of the expression of tenascin-C in cardiac fibroblasts, implicating a potential therapeutic strategy of targeting mRNA deadenylation. SIGNIFICANCE STATEMENT: To our knowledge, this study provides the first evidence that posttranscriptional regulation of tenascin-C expression in cardiac fibroblasts, including cell-type-specific roles of CNOT6L-mediated mRNA deadenylation, is crucial to maintain heart functions against pressure overload stress or angiotensin II-induced hypertension, implicating a potential therapeutic strategy of targeting mRNA deadenylation.
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Affiliation(s)
- Teruki Sato
- Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan; Department of Cardiovascular Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Tomokazu Yamaguchi
- Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan
| | - Takafumi Minato
- Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan
| | - Midori Hoshizaki
- Laboratory of Medical Infection System, Research Institute of Nozaki Tokushukai Hospital, Daito City, Osaka, Japan
| | - Ayaha Yamamoto
- Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan; Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
| | - Masahiro Morita
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Suita, Osaka, Japan
| | - Toru Suzuki
- Division of RNA and Gene Regulation, Institute of Medical Science, The University of Tokyo, Minato-ku, Japan
| | - Yasushi Fujio
- Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
| | - Yumiko Imai
- Laboratory of Medical Infection System, Research Institute of Nozaki Tokushukai Hospital, Daito City, Osaka, Japan
| | - Yutaka Suzuki
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Tadashi Yamamoto
- Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
| | - Hiroyuki Watanabe
- Department of Cardiovascular Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Keiji Kuba
- Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan.
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6
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Zhang J, Yang S, Chen X, Zhang F, Guo S, Wu C, Wang T, Wang H, Lu S, Qiao C, Sheng X, Liu S, Zhang X, Luo H, Li Q, Wu J. Aidi injection inhibits the migration and invasion of gefitinib-resistant lung adenocarcinoma cells by regulating the PLAT/FAK/AKT pathway. Chin Med 2025; 20:2. [PMID: 39754146 PMCID: PMC11699780 DOI: 10.1186/s13020-024-01054-1] [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: 10/14/2024] [Accepted: 12/26/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND With extended gefitinib treatment, the therapeutic effect in some non-small cell lung cancer (NSCLC) patients declined with the development of drug resistance. Aidi injection (ADI) is utilized in various cancers as a traditional Chinese medicine prescription. This study explores the molecular mechanism by which ADI, when combined with gefitinib, attenuates gefitinib resistance in PC9GR NSCLC cells. METHODS In vitro and in vivo pharmacological experiments were conducted in PC9GR cells and NSG mice with PC9GR cell-derived tumors, respectively. The molecular mechanism of ADI was further studied using whole-transcriptome sequencing technology. Bioinformatics and molecular biology methods were employed to validate the critical targets of ADI. RESULTS Firstly, ADI treatment alone and combined with gefitinib significantly inhibited the proliferation, migration, and invasion of PC9GR cells. Then, whole-transcriptome sequencing and bioinformatics analysis revealed that PLAT is a key target for the increased efficacy of ADI combined with gefitinib. Additionally, ADI downregulates the expression of PLAT, TNC, ITGB3, p-AKT, p-PI3K, and p-FAK. ADI inhibits the migration and invasion of PC9GR cells by regulating the PLAT/FAK/AKT pathway. CONCLUSIONS Aidi injection inhibits the migration and invasion of gefitinib-resistant lung adenocarcinoma cells by regulating the PLAT/FAK/AKT pathway. This study provides essential evidence for elucidating the mechanism of ADI in synergistic therapy for lung cancer.
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Affiliation(s)
- Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Siyun Yang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaodong Chen
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Fanqin Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Chao Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Tieshan Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Haojia Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shan Lu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Chuanqi Qiao
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaoguang Sheng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shuqi Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Hua Luo
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, People's Republic of China.
| | - Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
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7
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Zhang W, Liu Z, Wang K, Zhang L, Liu S, He K, Wang H, Wang J, Wang Y, Yang Y, Zhang X, Wu H. Quantitative proteomic landscape of the pathophysiology of adhesive arachnoiditis and its clinical significance: Structure and mechanism of TNC and RANBP1 proteins. Int J Biol Macromol 2025; 287:138444. [PMID: 39662555 DOI: 10.1016/j.ijbiomac.2024.138444] [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: 10/09/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024]
Abstract
The pathophysiological mechanism of adhesive arachnoiditis (AA) is complex, involving the interaction of multiple proteins. In recent years, the development of quantitative proteomics technology has provided a new perspective to reveal its pathological mechanism. The main objective of this study was to reveal the changes of protein expression profiles in arachnoid tissue of patients with AA. Proteomic analysis of arachnoid tissue samples was performed by high-throughput mass spectrometry. Bioinformatics tools were used to process and analyze the data and screen out 712 differentially expressed proteins (DEPs). Specially, 2 hub DEPs (TNC and RANBP1) were found as potential diagnostic markers. The expression levels of TNC and RANBP1 proteins were significantly up-regulated in patients with AA. TNC protein played a key role in inflammation and extracellular matrix remodeling, while RANBP1 was involved in cytoplasmic transport and cell cycle regulation. The abnormal expression and modification of these two proteins were closely related to the pathophysiological process of the disease. Immunoinfiltration analysis found the pathological process of AA were related to the infiltration of memory B cells, activated NK cells and CD8(+) T cells. Additonally, weighted gene co-expression network analysis (WGCNA) showed the organization of the arachnoid proteome into a network of 28 biologically meaningful modules of co-expressed proteins. Of these, 2 modules were positively correlated to AA phenotypes. This study shows a distinct proteomic landscape of AA and non-adhesive arachnoiditis (nAA). These findings also provide valuable insights into the molecular changes associated with potential mechanisms underlying AA.
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Affiliation(s)
- Weikang Zhang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Zhenlei Liu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Kai Wang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Lei Zhang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Shaocheng Liu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Kun He
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - He Wang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Junyi Wang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Yaobin Wang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Yuhua Yang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Xiangyu Zhang
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China
| | - Hao Wu
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun street No.45, Xicheng, Beijing, China.
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8
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Jahnke L, Enzmann V. Extracellular Matrix Gene Expression Patterns in Retinal Wound Healing: A Comparative Study Between Mouse and Zebrafish Laser Injury Models. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1468:213-217. [PMID: 39930198 DOI: 10.1007/978-3-031-76550-6_35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
Fibrosis is an outcome of irregular wound healing, manifesting as heightened scar formation marked by substantial extracellular matrix (ECM) accumulation, persistent inflammation, and gradual tissue or organ restructuring. This condition disrupts the normal tissue architecture, impairing organ function. Herein, the pivotal role of fibrosis in retinal repair mechanisms is compared in mice and zebrafish in responses to laser-induced injury. Our focus spans the intricate interplay between the gene regulation of ECM-involved protagonists and the dynamic development of fibrotic scars. We observed differential gene expression shifts and evaluated the effects of the fibrosis inhibitor pirfenidone (PFD) in the mouse model. These insights into retinal repair mechanisms contribute to a comprehensive understanding, guiding future therapeutic strategies for vision preservation.
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Affiliation(s)
- Laura Jahnke
- Department of Ophthalmology, University Hospital of Bern, University of Bern, Bern, Switzerland
- Department of BioMedical Research, University of Bern, Bern, Switzerland
| | - Volker Enzmann
- Department of Ophthalmology, University Hospital of Bern, University of Bern, Bern, Switzerland.
- Department of BioMedical Research, University of Bern, Bern, Switzerland.
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9
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Aughton K, Hattersley J, Coupland SE, Kalirai H. Revealing the structural microenvironment of high metastatic risk uveal melanomas following decellularisation. Sci Rep 2024; 14:26811. [PMID: 39500968 PMCID: PMC11538295 DOI: 10.1038/s41598-024-78171-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/29/2024] [Indexed: 11/08/2024] Open
Abstract
Uveal melanoma (UM) is a rare aggressive intraocular tumour that spreads most commonly to the liver in tumours with loss of one copy of chromosome 3 (HR-M3); current treatments for metastatic disease remain largely ineffective. Pre-clinical research is increasingly using three-dimensional models that better recapitulate the tumour microenvironment (TME). One aspect of the TME is the acellular extracellular matrix (ECM) that influences cell proliferation, migration and response to therapy. Although commercial matrices are used in culture, the composition and biochemical properties may not be representative of the tumour ECM in vivo. This study identifies UM metastatic risk specific ECM proteins by developing methodology for decellularisation of low- and high- metastatic risk tissue samples (LR-D3 vs. HR-M3). Proteomic analysis revealed a matrisome signature of 34 core ECM and ECM-associated proteins upregulated in HR-M3 UM. Combining additional UM secretome and whole cell iTRAQ proteomic datasets revealed enriched GO and KEGG pathways including 'regulating ECM binding' and 'PI3K/Akt signalling'. Structural analyses of decellularised matrices revealed microarchitecture of differing fibre density and expression differences in collagen 4, collagen 6A1 and nidogen 1, between metastatic risk groups. This approach is a powerful tool for the generation of ECM matrices relevant to high metastatic risk UM.
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Affiliation(s)
- Karen Aughton
- Liverpool Ocular Oncology Research Group, Department of Eye and Vision Science, Institute of Life Course and Medical Science, University of Liverpool, 3rd Floor William Henry Duncan Building, West Derby Street, Liverpool, L7 8TX, UK.
| | - Joshua Hattersley
- Liverpool Ocular Oncology Research Group, Department of Eye and Vision Science, Institute of Life Course and Medical Science, University of Liverpool, 3rd Floor William Henry Duncan Building, West Derby Street, Liverpool, L7 8TX, UK
| | - Sarah E Coupland
- Liverpool Ocular Oncology Research Group, Department of Eye and Vision Science, Institute of Life Course and Medical Science, University of Liverpool, 3rd Floor William Henry Duncan Building, West Derby Street, Liverpool, L7 8TX, UK
- Liverpool Clinical Laboratories, Liverpool University Hospital Foundation Trust, Liverpool, UK
| | - Helen Kalirai
- Liverpool Ocular Oncology Research Group, Department of Eye and Vision Science, Institute of Life Course and Medical Science, University of Liverpool, 3rd Floor William Henry Duncan Building, West Derby Street, Liverpool, L7 8TX, UK
- Liverpool Clinical Laboratories, Liverpool University Hospital Foundation Trust, Liverpool, UK
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10
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Qaisar R. The emerging roles of necroptosis in skeletal muscle health and disease. Pflugers Arch 2024; 476:1645-1651. [PMID: 39037477 DOI: 10.1007/s00424-024-02994-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 07/15/2024] [Accepted: 07/16/2024] [Indexed: 07/23/2024]
Abstract
Necroptosis is a regulated form of cell death with implications in various physiological and pathological processes in multiple tissues. However, the relevant findings from post-mitotic tissues, such as skeletal muscle, are scarce. This review summarizes the potential contributions of necroptosis to skeletal muscle health and diseases. It first discusses the physiological roles of necroptosis in muscle regeneration and development. It then summarizes the contributions of necroptosis to the pathogenesis of multiple muscle diseases, including muscular dystrophies, inflammatory myopathies, cachexia, and neuromuscular disorders. Lastly, it unravels the gaps in our understanding and therapeutic challenges of inhibiting necroptosis as a potential intervention for muscle diseases. Specifically, the findings from the transgenic animal models and the use of pharmacological inhibitors of necroptosis are discussed with relevance to improving the structure and/or function of skeletal muscle in various diseases. Recent developments from experimental animal models and clinical data are presented to discuss the roles of necroptosis in skeletal muscle health and diseases.
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Affiliation(s)
- Rizwan Qaisar
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates.
- Space Medicine Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates.
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11
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Loreti M, Cecchini A, Kaufman CD, Stamenkovic C, Renero A, Nicoletti C, Kervadec A, Guarnaccia G, Mayer D, Colas A, Lorenzo Puri P, Sacco A. Tenascin-C from the tissue microenvironment promotes muscle stem cell self-renewal through Annexin A2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.29.620732. [PMID: 39554125 PMCID: PMC11565721 DOI: 10.1101/2024.10.29.620732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Skeletal muscle tissue self-repair occurs through the finely timed activation of resident muscle stem cells (MuSC). Following perturbation, MuSC exit quiescence, undergo myogenic commitment, and differentiate to regenerate the injured muscle. This process is coordinated by signals present in the tissue microenvironment, however the precise mechanisms by which the microenvironment regulates MuSC activation are still poorly understood. Here, we identified Tenascin-C (TnC), an extracellular matrix (ECM) glycoprotein, as a key player in promoting of MuSC self-renewal and function. We show that fibro-adipogenic progenitors (FAPs) are the primary cellular source of TnC during muscle repair, and that MuSC sense TnC signaling through cell the surface receptor Annexin A2. We provide in vivo evidence that TnC is required for efficient muscle repair, as mice lacking TnC exhibit a regeneration phenotype of premature aging. We propose that the decline of TnC in physiological aging contributes to inefficient muscle regeneration in aged muscle. Taken together, our results highlight the pivotal role of TnC signaling during muscle repair in healthy and aging skeletal muscle.
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Affiliation(s)
- Mafalda Loreti
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
- Current affiliation: J&J, 3880 Murphy Canyon Rd, San Diego, CA 92123, USA
| | - Alessandra Cecchini
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Collin D. Kaufman
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Cedomir Stamenkovic
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Alma Renero
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
- Current affiliation: University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Chiara Nicoletti
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Anais Kervadec
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
- Current affiliation: Avidity Biosciences, Inc., 10578 Science Center Drive Suite 125, San Diego, CA 92121, USA
| | - Gabriele Guarnaccia
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Daphne Mayer
- Rice University, 6100 Main St, Huston, TX 77005, USA
| | - Alexandre Colas
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Pier Lorenzo Puri
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
| | - Alessandra Sacco
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA
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12
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Eun K, Kim AY, Ryu S. Matricellular proteins in immunometabolism and tissue homeostasis. BMB Rep 2024; 57:400-416. [PMID: 38919018 PMCID: PMC11444987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/11/2023] [Accepted: 04/25/2024] [Indexed: 06/27/2024] Open
Abstract
Matricellular proteins are integral non-structural components of the extracellular matrix. They serve as essential modulators of immunometabolism and tissue homeostasis, playing critical roles in physiological and pathological conditions. These extracellular matrix proteins including thrombospondins, osteopontin, tenascins, the secreted protein acidic and rich in cysteine (SPARC) family, the Cyr61, CTGF, NOV (CCN) family, and fibulins have multi-faceted functions in regulating immune cell functions, metabolic pathways, and tissue homeostasis. They are involved in immune-metabolic regulation and influence processes such as insulin signaling, adipogenesis, lipid metabolism, and immune cell function, playing significant roles in metabolic disorders such as obesity and diabetes. Furthermore, their modulation of tissue homeostasis processes including cellular adhesion, differentiation, migration, repair, and regeneration is instrumental for maintaining tissue integrity and function. The importance of these proteins in maintaining physiological equilibrium is underscored by the fact that alterations in their expression or function often coincide with disease manifestation. This review contributes to our growing understanding of these proteins, their mechanisms, and their potential therapeutic applications. [BMB Reports 2024; 57(9): 400-416].
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Affiliation(s)
- Kyoungjun Eun
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
| | - Ah Young Kim
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
| | - Seungjin Ryu
- Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea
- Institute of Natural Medicine, College of Medicine, Hallym Unviersity, Chuncheon 24252, Korea
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul 06974, Korea
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13
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Omori K, Takada A, Toyomasu Y, Tawara I, Shintoku C, Imanaka-Yoshida K, Sakuma H, Nomoto Y. Expression of Tenascin-C Is Upregulated in the Early Stages of Radiation Pneumonitis/Fibrosis in a Novel Mouse Model. Curr Issues Mol Biol 2024; 46:9674-9685. [PMID: 39329927 PMCID: PMC11430349 DOI: 10.3390/cimb46090575] [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: 07/25/2024] [Revised: 08/26/2024] [Accepted: 08/30/2024] [Indexed: 09/28/2024] Open
Abstract
The lung is a major dose-limiting organ for radiation therapy (RT) for cancer in the thoracic region, and the clarification of radiation-induced lung damage (RILD) is important. However, there have been few reports containing a detailed comparison of radiographic images with the pathological findings of radiation pneumonitis (RP)/radiation fibrosis (RF). We recently reported the upregulated expression of tenascin-C (TNC), an inflammation-associated extracellular matrix molecule, in surgically resected lung tissue, and elevated serum levels were elevated in a RILD patient. Therefore, we have developed a novel mouse model of partial lung irradiation and studied it with special attention paid to the computed tomography (CT) images and immunohistological findings. The right lungs of mice (BALB/c) were irradiated locally at 30 Gy/1fr, and the following two groups were created. In Group 1, sequential CT was performed to confirm the time-dependent changes in RILD. In Group 2, the CT images and histopathological findings of the lung were compared. RP findings were detected histologically at 16 weeks after irradiation; they were also observed on the CT images from 20 weeks. The immunostaining of TNC was observed before the appearance of RP on the CT images. The findings suggest that TNC could be an inflammatory marker preceding lung fibrosis.
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Affiliation(s)
- Kazuki Omori
- Department of Radiology, Mie University Hospital, Tsu 514-8507, Mie, Japan; (K.O.); (Y.T.); (H.S.); (Y.N.)
| | - Akinori Takada
- Department of Radiology, Mie University Hospital, Tsu 514-8507, Mie, Japan; (K.O.); (Y.T.); (H.S.); (Y.N.)
| | - Yutaka Toyomasu
- Department of Radiology, Mie University Hospital, Tsu 514-8507, Mie, Japan; (K.O.); (Y.T.); (H.S.); (Y.N.)
| | - Isao Tawara
- Department of Hematology and Oncology, Mie University Hospital, Tsu 514-8507, Mie, Japan;
| | - Chihiro Shintoku
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (C.S.); (K.I.-Y.)
| | - Kyoko Imanaka-Yoshida
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan; (C.S.); (K.I.-Y.)
| | - Hajime Sakuma
- Department of Radiology, Mie University Hospital, Tsu 514-8507, Mie, Japan; (K.O.); (Y.T.); (H.S.); (Y.N.)
| | - Yoshihito Nomoto
- Department of Radiology, Mie University Hospital, Tsu 514-8507, Mie, Japan; (K.O.); (Y.T.); (H.S.); (Y.N.)
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14
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Fujita M, Sasada M, Iyoda T, Fukai F. Involvement of Matricellular Proteins in Cellular Senescence: Potential Therapeutic Targets for Age-Related Diseases. Int J Mol Sci 2024; 25:6591. [PMID: 38928297 PMCID: PMC11204155 DOI: 10.3390/ijms25126591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Senescence is a physiological and pathological cellular program triggered by various types of cellular stress. Senescent cells exhibit multiple characteristic changes. Among them, the characteristic flattened and enlarged morphology exhibited in senescent cells is observed regardless of the stimuli causing the senescence. Several studies have provided important insights into pro-adhesive properties of cellular senescence, suggesting that cell adhesion to the extracellular matrix (ECM), which is involved in characteristic morphological changes, may play pivotal roles in cellular senescence. Matricellular proteins, a group of structurally unrelated ECM molecules that are secreted into the extracellular environment, have the unique ability to control cell adhesion to the ECM by binding to cell adhesion receptors, including integrins. Recent reports have certified that matricellular proteins are closely involved in cellular senescence. Through this biological function, matricellular proteins are thought to play important roles in the pathogenesis of age-related diseases, including fibrosis, osteoarthritis, intervertebral disc degeneration, atherosclerosis, and cancer. This review outlines recent studies on the role of matricellular proteins in inducing cellular senescence. We highlight the role of integrin-mediated signaling in inducing cellular senescence and provide new therapeutic options for age-related diseases targeting matricellular proteins and integrins.
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Affiliation(s)
- Motomichi Fujita
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Chiba, Japan
| | - Manabu Sasada
- Clinical Research Center in Hiroshima, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8551, Japan
| | - Takuya Iyoda
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigaku-Doori, Sanyo-Onoda 756-0884, Yamaguchi, Japan
| | - Fumio Fukai
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Chiba, Japan
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15
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Dhaouadi S, Bouhaouala-Zahar B, Orend G. Tenascin-C targeting strategies in cancer. Matrix Biol 2024; 130:1-19. [PMID: 38642843 DOI: 10.1016/j.matbio.2024.04.002] [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: 12/20/2023] [Revised: 04/13/2024] [Accepted: 04/14/2024] [Indexed: 04/22/2024]
Abstract
Tenascin-C (TNC) is a matricellular and multimodular glycoprotein highly expressed under pathological conditions, especially in cancer and chronic inflammatory diseases. Since a long time TNC is considered as a promising target for diagnostic and therapeutic approaches in anti-cancer treatments and was already extensively targeted in clinical trials on cancer patients. This review provides an overview of the current most advanced strategies used for TNC detection and anti-TNC theranostic approaches including some advanced clinical strategies. We also discuss novel treatment protocols, where targeting immune modulating functions of TNC could be center stage.
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Affiliation(s)
- Sayda Dhaouadi
- Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia
| | - Balkiss Bouhaouala-Zahar
- Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia; Faculté de Médecine de Tunis, Université Tunis el Manar, Tunis, Tunisia
| | - Gertraud Orend
- INSERM U1109, The Tumor Microenvironment laboratory, Université Strasbourg, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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16
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Park JY, Kim HJ, Chae JR, Cho YL, Kang WJ. Preclinical evaluation of an 18F-labeled Tenascin-C aptamer for PET imaging of atherosclerotic plaque in mouse models of atherosclerosis. Biochem Biophys Res Commun 2024; 703:149650. [PMID: 38377941 DOI: 10.1016/j.bbrc.2024.149650] [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: 01/27/2024] [Accepted: 02/06/2024] [Indexed: 02/22/2024]
Abstract
Tenascin-C is an extracellular matrix glycoprotein strongly expressed in coronary atherosclerotic plaque. Aptamers are single-stranded oligonucleotides that bind to specific target molecules with high affinity. This study hypothesized that tenascin-C expression at atherosclerotic plaque in vivo could be detected by tenascin-C specific aptamers using positron emission tomography (PET). This paper reports the radiosynthesis of a fluorine-18 (18F)-labeled tenascin-C aptamer for the biodistribution and PET imaging of the tenascin-C expression in apolipoprotein E-deficient (ApoE-/-) mice. The aortas ApoE-/- mice showed significantly increased positive areas of Oil red O staining than control C57BL/6 mice, and tenascin-C expression was detected in foam cells accumulated in the subendothelial lesions of ApoE-/- mice. The ex vivo biodistribution of the 18F-labeled tenascin-C aptamer showed significantly increased uptake at the aorta of ApoE-/- mice, and ex vivo autoradiography of aorta revealed the high accumulation of the 18F-labeled tenascin-C aptamer in the atherosclerotic lesions of ApoE-/- mice, which was consistent with the location of the atherosclerotic plaques detected by Oil red O staining. PET imaging of the 18F-labeled tenascin-C aptamer revealed a significantly higher mean standardized uptake in the aorta of the ApoE-/- mice than the control C57BL/6 mice. These data highlight the potential use of tenascin-C aptamer to diagnose atherosclerotic lesions in vivo.
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Affiliation(s)
- Jun Young Park
- Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Hyun Jeong Kim
- Department of Nuclear Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, 363 Dongbaekjukjeon-daero, Giheung-gu, Yongin, 16995, Republic of Korea
| | - Ju Ri Chae
- Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Ye Lim Cho
- Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Won Jun Kang
- Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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17
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Chen J, Zhao L, Zhang L, Luo Y, Jiang Y, H P. The identification of signature genes and their relationship with immune cell infiltration in age-related macular degeneration. Mol Biol Rep 2024; 51:339. [PMID: 38393419 DOI: 10.1007/s11033-023-08969-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 11/26/2023] [Indexed: 02/25/2024]
Abstract
BACKGROUND Age-related macular degeneration (AMD) is a prevalent source of visual impairment among the elderly population, and its incidence has risen in tandem with the increasing longevity of humans. Despite the progress made with anti-VEGF therapy, clinical outcomes have proven to be unsatisfactory. METHOD We obtained differentially expressed genes (DEGs) of AMD patients and healthy controls from the GEO database. GO and KEGG analyses were used to enrich the DEGs. Weighted gene coexpression network analysis (WGCNA) was used to identify modules related to AMD. SVM, random forest, and least absolute shrinkage and selection operator (LASSO) were employed to screen hub genes. Gene set enrichment analysis (GSEA) was used to explore the pathways in which these hub genes were enriched. CIBERSORT was utilized to analyze the relationship between the hub genes and immune cell infiltration. Finally, Western blotting and RT‒PCR were used to explore the expression of hub genes in AMD mice. RESULTS We screened 1084 DEGs in GSE29801, of which 496 genes were upregulated. These 1084 DEGs were introduced into the WGCNA, and 94 genes related to AMD were obtained. Seventy-nine overlapping genes were obtained by the Venn plot. These 79 genes were introduced into three machine-learning methods to screen the hub genes, and the genes identified by the three methods were TNC, FAP, SREBF1, and TGF-β2. We verified their diagnostic function in the GSE29801 and GSE103060 datasets. Then, the hub gene co-enrichment pathways were obtained by GO and KEGG analyses. CIBERSORT analysis showed that these hub genes were associated with immune cell infiltration. Finally, we found increased expression of TNC, FAP, SREBF1, and TGF-β2 mRNA and protein in the retinas of AMD mice. CONCLUSION We found that four hub genes, namely, FAP, TGF-β2, SREBF1, and TNC, have diagnostic significance in patients with AMD and are related to immune cell infiltration. Finally, we determined that the mRNA and protein expression of these hub genes was upregulated in the retinas of AMD mice.
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Affiliation(s)
- Jinquan Chen
- Department of Ophthalmology, The Tongnan District People's Hospital, Chongqing, China
| | - Long Zhao
- Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Longbin Zhang
- Department of Ophthalmology, The Tongnan District People's Hospital, Chongqing, China
| | - Yiling Luo
- Department of Ophthalmology, The Tongnan District People's Hospital, Chongqing, China
| | - Yuling Jiang
- Department of Ophthalmology, The Tongnan District People's Hospital, Chongqing, China
| | - Peng H
- Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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18
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Major G, Simcock J, Kumar A, Kleffmann T, Woodfield TBF, Lim KS. Comprehensive Matrisome Profiling of Human Adipose Tissue for Soft Tissue Reconstruction. Adv Biol (Weinh) 2024; 8:e2300448. [PMID: 37953659 DOI: 10.1002/adbi.202300448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/14/2023] [Indexed: 11/14/2023]
Abstract
For effective translation of research from tissue engineering and regenerative medicine domains, the cell-instructive extracellular matrix (ECM) of specific tissues must be accurately realized. As adipose tissue is gaining traction as a biomaterial for soft tissue reconstruction, with highly variable clinical outcomes obtained, a quantitative investigation of the adipose tissue matrisome is overdue. In this study, the human adipose tissue matrisome is profiled using quantitative sequential windowed acquisition of all theoretical fragment ion spectra - mass spectrometry (SWATH-MS) proteomics across a cohort of 13 fat-grafting patients, to provide characterization of ECM proteins within the tissue, and to understand human population variation. There are considerable differences in the expression of matrisome proteins across the patient cohort, with age and lipoaspirate collection technique contributing to the greatest variation across the core matrisome. A high abundance of basement membrane proteins (collagen IV and heparan sulfate proteoglycan) is detected, as well as fibrillar collagens I and II, reflecting the hierarchical structure of the tissue. This study provides a comprehensive proteomic evaluation of the adipose tissue matrisome and contributes to an enhanced understanding of the influence of the matrisome in adipose-related pathologies by providing a healthy reference cohort and details an experimental pipeline that can be further exploited for future biomaterial development.
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Affiliation(s)
- Gretel Major
- Department of Orthopaedic Surgery and Musculoskeletal Medicine, Centre for Bioengineering & Nanomedicine, University of Otago, Christchurch, 8011, New Zealand
| | - Jeremy Simcock
- Department of Surgery, University of Otago, Christchurch, 8011, New Zealand
| | - Abhishek Kumar
- Centre for Protein Research, Research Infrastructure Centre, University of Otago, Dunedin, 9054, New Zealand
| | - Torsten Kleffmann
- Centre for Protein Research, Research Infrastructure Centre, University of Otago, Dunedin, 9054, New Zealand
| | - Tim B F Woodfield
- Department of Orthopaedic Surgery and Musculoskeletal Medicine, Centre for Bioengineering & Nanomedicine, University of Otago, Christchurch, 8011, New Zealand
| | - Khoon S Lim
- Department of Orthopaedic Surgery and Musculoskeletal Medicine, Centre for Bioengineering & Nanomedicine, University of Otago, Christchurch, 8011, New Zealand
- Light-Activated Biomaterials Group, School of Medical Science, University of Sydney, Sydney, NSW, 2006, Australia
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19
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Ostrowska-Lesko M, Rajtak A, Moreno-Bueno G, Bobinski M. Scientific and clinical relevance of non-cellular tumor microenvironment components in ovarian cancer chemotherapy resistance. Biochim Biophys Acta Rev Cancer 2024; 1879:189036. [PMID: 38042260 DOI: 10.1016/j.bbcan.2023.189036] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 11/24/2023] [Accepted: 11/25/2023] [Indexed: 12/04/2023]
Abstract
The tumor microenvironment (TME) components play a crucial role in cancer cells' resistance to chemotherapeutic agents. This phenomenon is exceptionally fundamental in patients with ovarian cancer (OvCa), whose outcome depends mainly on their response to chemotherapy. Until now, most reports have focused on the role of cellular components of the TME, while less attention has been paid to the stroma and other non-cellular elements of the TME, which may play an essential role in the therapy resistance. Inhibiting these components could help define new therapeutic targets and potentially restore chemosensitivity. The aim of the present article is both to summarize the knowledge about non-cellular components of the TME in the development of OvCa chemoresistance and to suggest targeting of non-cellular elements of the TME as a valuable strategy to overcome chemoresistance and to develop new therapeutic strategies in OvCA patients.
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Affiliation(s)
- Marta Ostrowska-Lesko
- Chair and Department of Toxicology, Medical University of Lublin, 8b Jaczewskiego Street, 20-090 Lublin, Poland.
| | - Alicja Rajtak
- 1st Chair and Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Poland
| | - Gema Moreno-Bueno
- Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Sols-Morreale' (IIBm-CISC), Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Spain; Fundación MD Anderson Internacional (FMDA), Spain.
| | - Marcin Bobinski
- 1st Chair and Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Poland.
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20
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Dominic S, Baba KSSS, Sreedevi NN, Sanober A, Rajasekhar L, Khan SA, Mohammed N, Bhaskar MV, Mohan IK. Clinical Utility of Pro-inflammatory Oligomeric Glycoprotein Tenascin-C in the Diagnosis of Seropositive and Seronegative Rheumatoid Arthritis. Indian J Clin Biochem 2024; 39:110-117. [PMID: 38223014 PMCID: PMC10784432 DOI: 10.1007/s12291-022-01086-0] [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: 10/06/2021] [Accepted: 08/17/2022] [Indexed: 10/14/2022]
Abstract
Owing to limited usefulness of Rheumatoid Factor and anti-CCP in rheumatoid arthritis, there is a need to identify a more sensitive and specific biomarker to detect rheumatoid arthritis (RA), particularly seronegative RA cases. Tenascin-C is an extracellular matrix glycoprotein, which has been implicated in the pathophysiology of RA. The objective of our study was to evaluate the diagnostic utility of serum Tenascin-C in seropositive and seronegative rheumatoid arthritis patients. We conducted a cross-sectional case control study. Sixty patients who fulfilled the ACR 2010 criteria for rheumatoid arthritis were included in the study. Thirty patients were found to be positive for RF and/or anti-CCP and 30 were negative for both RF and anti-CCP. Thirty age and gender-matched healthy subjects were taken as controls. Serum Tenascin-C was measured by quantitative sandwich enzyme immunoassay technique. The mean serum concentration of Tenascin-C in controls, seronegative and seropositive cases was 0.66 ng/ml, 20.54 ng/ml and 23.42 ng/ml, respectively. Tenascin-C levels were significantly higher in RA cases compared to controls (p < 0.0001). There was no significant difference in Tenascin-C between seropositive and seronegative cases (p = 0.603). ROC curve analysis showed a sensitivity of 96.6% and specificity of 100% with AUC of 0.98 at 2.21 ng/ml as cut-off value for diagnosing RA. Tenascin-C is elevated in both seronegative and seropositive RA, which indicates that it can be used as a sensitive marker for RA. The addition of Tenascin-C to the existing RF and anti-CCP may help in identifying a large number of patients with RA, particularly seronegative rheumatoid arthritis cases.
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Affiliation(s)
- Sachin Dominic
- Department of Biochemistry, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500082 India
| | - K. S. S. Sai Baba
- Department of Biochemistry, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500082 India
| | - N. N. Sreedevi
- Department of Biochemistry, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500082 India
| | - Arshi Sanober
- Department of Biochemistry, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500082 India
| | - Liza Rajasekhar
- Department of Clinical Immunology and Rheumatology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500082 India
| | - Siraj Ahmed Khan
- Department of Biochemistry, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500082 India
| | - Noorjahan Mohammed
- Department of Biochemistry, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500082 India
| | - M. Vijaya Bhaskar
- Department of Biochemistry, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500082 India
| | - Iyyapu Krishna Mohan
- Department of Biochemistry, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana 500082 India
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21
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Abedsaeidi M, Hojjati F, Tavassoli A, Sahebkar A. Biology of Tenascin C and its Role in Physiology and Pathology. Curr Med Chem 2024; 31:2706-2731. [PMID: 37021423 DOI: 10.2174/0929867330666230404124229] [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: 07/18/2022] [Revised: 01/25/2023] [Accepted: 02/10/2023] [Indexed: 04/07/2023]
Abstract
Tenascin-C (TNC) is a multimodular extracellular matrix (ECM) protein hexameric with several molecular forms (180-250 kDa) produced by alternative splicing at the pre-mRNA level and protein modifications. The molecular phylogeny indicates that the amino acid sequence of TNC is a well-conserved protein among vertebrates. TNC has binding partners, including fibronectin, collagen, fibrillin-2, periostin, proteoglycans, and pathogens. Various transcription factors and intracellular regulators tightly regulate TNC expression. TNC plays an essential role in cell proliferation and migration. Unlike embryonic tissues, TNC protein is distributed over a few tissues in adults. However, higher TNC expression is observed in inflammation, wound healing, cancer, and other pathological conditions. It is widely expressed in a variety of human malignancies and is recognized as a pivotal factor in cancer progression and metastasis. Moreover, TNC increases both pro-and anti-inflammatory signaling pathways. It has been identified as an essential factor in tissue injuries such as damaged skeletal muscle, heart disease, and kidney fibrosis. This multimodular hexameric glycoprotein modulates both innate and adaptive immune responses regulating the expression of numerous cytokines. Moreover, TNC is an important regulatory molecule that affects the onset and progression of neuronal disorders through many signaling pathways. We provide a comprehensive overview of the structural and expression properties of TNC and its potential functions in physiological and pathological conditions.
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Affiliation(s)
- Malihehsadat Abedsaeidi
- Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Farzaneh Hojjati
- Division of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Amin Tavassoli
- Division of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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22
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Campos A, Burgos-Ravanal R, Lobos-González L, Huilcamán R, González MF, Díaz J, Verschae AC, Acevedo JP, Carrasco M, Sepúlveda F, Jeldes E, Varas-Godoy M, Leyton L, Quest AF. Caveolin-1-dependent tenascin C inclusion in extracellular vesicles is required to promote breast cancer cell malignancy. Nanomedicine (Lond) 2023; 18:1651-1668. [PMID: 37929694 DOI: 10.2217/nnm-2023-0143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2023] Open
Abstract
Background: Elevated expression of CAV1 in breast cancer increases tumor progression. Extracellular vesicles (EVs) from CAV1-expressing MDA-MB-231 breast cancer cells contain Tenascin C (TNC), but the relevance of TNC remained to be defined. Methods: EVs were characterized by nanotracking analysis, microscopy and western blotting. The uptake of EVs by cells was studied using flow cytometry. The effects of EVs on breast cancer cells were tested in migration, invasion, colony formation and in vivo assays. Results: EVs were taken up by cells; however, only those containing TNC promoted invasiveness. In vivo, EVs lacking TNC ceased to promote tumor growth. Conclusion: CAV1 and TNC contained in breast cancer cell-derived EVs were identified as proteins that favor progression of breast cancer.
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Affiliation(s)
- America Campos
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, Scotland
| | - Renato Burgos-Ravanal
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - Lorena Lobos-González
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Santiago, 7610615, Chile
| | - Ricardo Huilcamán
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - María Fernanda González
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - Jorge Díaz
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - Albano Cáceres Verschae
- Laboratorio de Biología Celular del Cáncer, CEBICEM, Universidad San Sebastián, Santiago, 7510157, Chile
- Department of Oncology/Pathology, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Juan Pablo Acevedo
- Center of Interventional Medicine for Precision & Advanced Cellular Therapy (IMPACT), Santiago, 8331150, Chile
| | - Macarena Carrasco
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
| | - Francisca Sepúlveda
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Santiago, 7610615, Chile
| | - Emanuel Jeldes
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, Scotland
| | - Manuel Varas-Godoy
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
- Laboratorio de Biología Celular del Cáncer, CEBICEM, Universidad San Sebastián, Santiago, 7510157, Chile
| | - Lisette Leyton
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - Andrew Fg Quest
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
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23
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Domaingo A, Jokesch P, Schweiger A, Gschwandtner M, Gerlza T, Koch M, Midwood KS, Kungl AJ. Chemokine Binding to Tenascin-C Influences Chemokine-Induced Immune Cell Migration. Int J Mol Sci 2023; 24:14694. [PMID: 37834140 PMCID: PMC10572825 DOI: 10.3390/ijms241914694] [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: 08/31/2023] [Revised: 09/15/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Tenascin-C (TNC) is a complex glycoprotein of the extracellular matrix (ECM) involved in a plethora of (patho-)physiological processes, such as oncogenesis and inflammation. Since chemokines play an essential role in both disease processes, we have investigated here the binding of TNC to some of the key chemokines, namely CCL2, CCL26, CXCL8, CXCL10, and CXCL12. Thereby, a differential chemokine-TNC binding pattern was observed, with CCL26 exhibiting the highest and CCL2 the lowest affinity for TNC. Heparan sulfate (HS), another member of the ECM, proved to be a similarly high-affinity ligand of TNC, with a Kd value of 730 nM. Chemokines use glycosa-minoglycans such as HS as co-receptors to induce immune cell migration. Therefore, we assumed an influence of TNC on immune cell chemotaxis due to co-localization within the ECM. CCL26- and CCL2-induced mobilization experiments of eosinophils and monocytes, respectively, were thus performed in the presence and the absence of TNC. Pre-incubation of the immune cells with TNC resulted in a 3.5-fold increase of CCL26-induced eosinophil chemotaxis, whereas a 1.3-fold de-crease in chemotaxis was observed when monocytes were pre-incubated with CCL2. As both chemokines have similar HS binding but different TNC binding affinities, we speculate that TNC acts as an attenuator in monocyte and as an amplifier in eosinophil mobilization by impeding CCL2 from binding to HS on the one hand, and by reinforcing CCL26 to bind to HS on the other hand.
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Affiliation(s)
- Alissa Domaingo
- Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, Schubertstr. 1, 8010 Graz, Austria
| | - Philipp Jokesch
- Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, Schubertstr. 1, 8010 Graz, Austria
| | - Alexandra Schweiger
- Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, Schubertstr. 1, 8010 Graz, Austria
| | - Martha Gschwandtner
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Tanja Gerlza
- Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, Schubertstr. 1, 8010 Graz, Austria
| | - Manuel Koch
- Institute for Dental Research and Oral Musculoskeletal Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Cologne, Germany
| | - Kim S. Midwood
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Andreas J. Kungl
- Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz, Schubertstr. 1, 8010 Graz, Austria
- Antagonis Biotherapeutics GmbH, Strasserhofweg 77a, 8045 Graz, Austria
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24
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Zheng Y, Zhong G, He C, Li M. Targeted splicing therapy: new strategies for colorectal cancer. Front Oncol 2023; 13:1222932. [PMID: 37664052 PMCID: PMC10470845 DOI: 10.3389/fonc.2023.1222932] [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: 05/15/2023] [Accepted: 08/07/2023] [Indexed: 09/05/2023] Open
Abstract
RNA splicing is the process of forming mature mRNA, which is an essential phase necessary for gene expression and controls many aspects of cell proliferation, survival, and differentiation. Abnormal gene-splicing events are closely related to the development of tumors, and the generation of oncogenic isoform in splicing can promote tumor progression. As a main process of tumor-specific splicing variants, alternative splicing (AS) can promote tumor progression by increasing the production of oncogenic splicing isoforms and/or reducing the production of normal splicing isoforms. This is the focus of current research on the regulation of aberrant tumor splicing. So far, AS has been found to be associated with various aspects of tumor biology, including cell proliferation and invasion, resistance to apoptosis, and sensitivity to different chemotherapeutic drugs. This article will review the abnormal splicing events in colorectal cancer (CRC), especially the tumor-associated splicing variants arising from AS, aiming to offer an insight into CRC-targeted splicing therapy.
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Affiliation(s)
| | | | - Chengcheng He
- Department of Gastroenterology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
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25
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Sumioka T, Matsumoto KI, Reinach PS, Saika S. Tenascins and osteopontin in biological response in cornea. Ocul Surf 2023; 29:131-149. [PMID: 37209968 DOI: 10.1016/j.jtos.2023.05.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/01/2023] [Accepted: 05/16/2023] [Indexed: 05/22/2023]
Abstract
The structural composition, integrity and regular curvature of the cornea contribute to the maintenance of its transparency and vision. Disruption of its integrity caused by injury results in scarring, inflammation and neovascularization followed by losses in transparency. These sight compromising effects is caused by dysfunctional corneal resident cell responses induced by the wound healing process. Upregulation of growth factors/cytokines and neuropeptides affect development of aberrant behavior. These factors trigger keratocytes to first transform into activated fibroblasts and then to myofibroblasts. Myofibroblasts express extracellular matrix components for tissue repair and contract the tissue to facilitate wound closure. Proper remodeling following primary repair is critical for restoration of transparency and visual function. Extracellular matrix components contributing to the healing process are divided into two groups; a group of classical tissue structural components and matrix macromolecules that modulate cell behaviors/activities besides being integrated into the matrix structure. The latter components are designated as matricellular proteins. Their functionality is elicited through mechanisms which modulate the scaffold integrity, cell behaviors, activation/inactivation of either growth factors or cytoplasmic signaling regulation. We discuss here the functional roles of matricellular proteins in mediating injury-induced corneal tissue repair. The roles are described of major matricellular proteins, which include tenascin C, tenascin X and osteopontin. Focus is directed towards dealing with their roles in modulating individual activities of wound healing-related growth factors, e. g., transforming growth factor β (TGF β). Modulation of matricellular protein functions could encompass a potential novel strategy to improve the outcome of injury-induced corneal wound healing.
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Affiliation(s)
- Takayoshi Sumioka
- Department of Ophthalmology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, 641-0012, Japan.
| | - Ken-Ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, 89-1 Enya-cho, Izumo, 693-8501, Japan
| | - Peter Sol Reinach
- Department of Biological. Sciences SUNY Optometry, New York, NY, 10036, USA
| | - Shizuya Saika
- Department of Ophthalmology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, 641-0012, Japan
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26
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Chen CH, Chen SH, Chen SH, Chuang ADC, T G D, Chen JP. Hyaluronic acid/platelet rich plasma-infused core-shell nanofiber membrane to prevent postoperative tendon adhesion and promote tendon healing. Int J Biol Macromol 2023; 231:123312. [PMID: 36669628 DOI: 10.1016/j.ijbiomac.2023.123312] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023]
Abstract
An anti-adhesive barrier membrane incorporating hyaluronic acid (HA) can reduce fibroblasts attachment and impart lubrication effect for smooth tendon gliding during management of post-surgical tendon adhesion. On the other hand, as numerous growth factors are required during tendon recovery, growth factors released by platelets in platelet-rich plasma (PRP) can provide beneficial therapeutic effects to facilitate tendon recovery post tendon injury. Furthermore, PRP is reported to be associated with anti-inflammatory properties for suppressing postoperative adhesion. Toward this end, we fabricate core-shell nanofiber membranes (NFM) with HA/PRP-infused core and polycaprolactone shell in this study. Different NFM with 100 % (H-P), 75 % (HP31-P), 50 % (HP11-P) and 25 % (H31-P) HA in the core was fabricated through coaxial electrospinning and analyzed through microscopic, pore size, mechanical, as well as HA and growth factor release studies. In vitro study with fibroblasts indicates the NFM can act as a barrier to prevent cell penetration and reduce cell attachment/focal adhesion, in addition to promoting tenocyte migration in tendon healing. In vivo studies in a rabbit flexor tendon rupture model indicates the HP11-P NFM shows improved efficacy over H-P NFM and control in reducing tendon adhesion formation and inflammation, while promoting tendon healing, from functional assays and histological analysis.
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Affiliation(s)
- Chih-Hao Chen
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Keelung, Keelung 20401, Taiwan; Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Kwei-San, Taoyuan 33305, Taiwan
| | - Shih-Hsien Chen
- Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan
| | - Shih-Heng Chen
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Kwei-San, Taoyuan 33305, Taiwan
| | - Andy Deng-Chi Chuang
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Keelung, Keelung 20401, Taiwan
| | - Darshan T G
- Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan
| | - Jyh-Ping Chen
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Kwei-San, Taoyuan 33305, Taiwan; Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Kwei-San, Taoyuan 33305, Taiwan; Research Center for Food and Cosmetic Safety, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33302, Taiwan; Department of Materials Engineering, Ming Chi University of Technology, Tai-Shan, New Taipei City 24301, Taiwan.
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Martins-da-Silva A, Baroni M, Salomão KB, das Chagas PF, Bonfim-Silva R, Geron L, Cruzeiro GAV, da Silva WA, Corrêa CAP, Carlotti CG, de Paula Queiroz RG, Marie SKN, Brandalise SR, Yunes JA, Scrideli CA, Valera ET, Tone LG. Clinical Prognostic Implications of Wnt Hub Genes Expression in Medulloblastoma. Cell Mol Neurobiol 2023; 43:813-826. [PMID: 35366170 PMCID: PMC11415171 DOI: 10.1007/s10571-022-01217-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 03/22/2022] [Indexed: 11/03/2022]
Abstract
Medulloblastoma is the most common type of pediatric malignant primary brain tumor, and about one-third of patients die due to disease recurrence and most survivors suffer from long-term side effects. MB is clinically, genetically, and epigenetically heterogeneous and subdivided into at least four molecular subgroups: WNT, SHH, Group 3, and Group 4. We evaluated common differentially expressed genes between a Brazilian RNA-seq GSE181293 dataset and microarray GSE85217 dataset cohort of pediatric MB samples using bioinformatics methodology in order to identify hub genes of the molecular subgroups based on PPI network construction, survival and functional analysis. The main finding was the identification of five hub genes from the WNT subgroup that are tumor suppressors, and whose lower expression is related to a worse prognosis for MB patients. Furthermore, the common genes correlated with the five tumor suppressors participate in important pathways and processes for tumor initiation and progression, as well as development and differentiation, and some of them control cell stemness and pluripotency. These genes have not yet been studied within the context of MB, representing new important elements for investigation in the search for therapeutic targets, prognostic markers or for understanding of MB biology.
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Affiliation(s)
- Andrea Martins-da-Silva
- Department of Pediatrics, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil.
| | - Mirella Baroni
- Department of Pediatrics, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Karina Bezerra Salomão
- Department of Pediatrics, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Pablo Ferreira das Chagas
- Department of Genetics, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Ricardo Bonfim-Silva
- Department of Surgery and Anatomy, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Lenisa Geron
- Department of Genetics, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Gustavo Alencastro Veiga Cruzeiro
- Department of Pediatrics, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
- Department of Pediatric Oncology, Harvard Medical School - Dana-Farber Cancer Institute, Boston, MA, USA
| | - Wilson Araújo da Silva
- Department of Genetics, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Carolina Alves Pereira Corrêa
- Department of Pediatrics, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Carlos Gilberto Carlotti
- Department of Surgery and Anatomy, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Rosane Gomes de Paula Queiroz
- Department of Pediatrics, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | | | | | | | - Carlos Alberto Scrideli
- Department of Pediatrics, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
- Department of Genetics, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Luiz Gonzaga Tone
- Department of Pediatrics, University Hospital - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
- Department of Genetics, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
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Cheng L, Wang D, Wang Z, Li H, Wang G, Wu Z, Xu M, Yan S, Zhan H, Wang H, Zhang X, Liang T, Wei C, Zhang F, Zheng W, Yu X, Li Y. Proteomics Landscape Mapping of Organ-Resolved Behçet's Disease Using In-Depth Plasma Proteomics for Identifying Hyaluronic Binding Protein 2 Expression Associated With Vascular Involvement. Arthritis Rheumatol 2023; 75:424-437. [PMID: 36122191 DOI: 10.1002/art.42348] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 08/19/2022] [Accepted: 09/07/2022] [Indexed: 01/14/2023]
Abstract
OBJECTIVE This study was undertaken to elucidate the pathogenesis and heterogeneity of Behçet's disease (BD) involving different organs using in-depth proteomics to identify the biomarkers for clinical assessment and treatment of patients with BD. METHODS We measured the expression levels of proteins in plasma samples from 98 patients with BD and from 31 healthy controls using our in-depth proteomics platform with a data-independent acquisition mass spectrometer and antibody microarray. We performed bioinformatics analyses of the biologic processes and signaling pathways that were changed in the BD group and constructed a proteomics landscape of organ-resolved BD pathogenesis. We then validated the biomarkers of disease severity and the vascular subset in an independent cohort of 108 BD patients and 29 healthy controls using an enzyme-linked immunosorbent assay. RESULTS The BD group had 220 differentially expressed proteins, which discriminated between BD patients (88.6%) and healthy controls (95.5%). The bioinformatics analyses revealed different biologic processes associated with BD pathogeneses, including complement activation, wound healing, angiogenesis, and leukocyte-mediated immunity. Furthermore, the constructed proteomics landscape of organ-resolved BD identified proteomics features of BD associated with different organs and protein targets that could be used for the development of therapeutic treatment. Hyaluronic binding protein 2, tenascin, and serpin A3 were validated as potential biomarkers for the clinical assessment of vascular BD and treatment targets. CONCLUSION Our results provide valuable insight into the pathogenesis of organ-resolved BD in terms of proteomics characteristics and potential biomarkers for clinical assessment and potential therapies for vascular BD.
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Affiliation(s)
- Linlin Cheng
- Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Dongxue Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Zhimian Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, and Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Haolong Li
- Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Guibin Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Ziyan Wu
- Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Meng Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Songxin Yan
- Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Haoting Zhan
- Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hongye Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Xiaomei Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Te Liang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Chundi Wei
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, and Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Wenjie Zheng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, and Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Xiaobo Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Yongzhe Li
- Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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Abstract
Tenascin-C is a large extracellular matrix glycoprotein with complex, not yet fully unveiled roles. Its context- and structure-dependent modus operandi renders tenascin-C a puzzling protein. Since its discovery ∼40 years ago, research into tenascin-C biology continues to reveal novel functions, the most recent of all being its immunomodulatory activity, especially its role in infection, which is just now beginning to emerge. Here, we explore the role of tenascin-C in the immune response to viruses, including SARS-CoV-2 and HIV-1. Recently, tenascin-C has emerged as a biomarker of disease severity during COVID-19 and other viral infections, and we highlight relevant RNA sequencing and proteomic analyses that suggest a correlation between tenascin-C levels and disease severity. Finally, we ask what the function of this protein during viral replication is and propose tenascin-C as an intercellular signal of inflammation shuttled to distal sites via exosomes, a player in the repair and remodeling of infected and damaged tissues during severe infectious disease, as well as a ligand for specific pathogens with distinct implications for the host.
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Affiliation(s)
- Lorena Zuliani-Alvarez
- 1QBI Coronavirus Research Group, San Francisco, California,2Quantitative Biosciences Institute, University of California, San Francisco, California,3Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California
| | - Anna M. Piccinini
- 4School of Pharmacy, University of Nottingham, Nottingham, United Kingdom
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Kiss A, Nadasy GL, Fees A, Arnold Z, Aykac I, Dostal C, Szabó GT, Szabó PL, Szekeres M, Pokreisz P, Hunyady L, Podesser BK. Alterations in Coronary Resistance Artery Network Geometry in Diabetes and the Role of Tenascin C. Rev Cardiovasc Med 2023; 24:6. [PMID: 39076867 PMCID: PMC11270457 DOI: 10.31083/j.rcm2401006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 11/01/2022] [Accepted: 11/11/2022] [Indexed: 07/31/2024] Open
Abstract
Background Geometrical alterations in the coronary resistance artery network and the potential involvement of Tenascin C (TNC) extracellular matrix protein were investigated in diabetic and control mice. Methods Diabetes was induced by streptozotocin (STZ) injections (n = 7-11 animals in each group) in Tenascin C KO (TNC KO) mice and their Wild type (A/J) littermates. After 16-18 weeks the heart was removed and the whole subsurface network of the left coronary artery was prepared (down to branches of 40 μ m outer diameter), in situ pressure-perfused and studied using video-microscopy. Outer and inner diameters, wall thicknesses and bifurcation angles were measured on whole network pictures reconstructed into collages at 1.7 μ m pixel resolutions. Results Diabetes induced abnormal morphological alterations including trifurcations, sharp bends of larger branches, and branches directed retrogradely (p < 0.001 by the χ 2 test). Networks of TNC KO mice tended to form early divisions producing parallelly running larger branches (p < 0.001 by the χ 2 probe). Networks of coronary resistance arteries were substantially more abundant in 100-180 μ m components, appearing in 2-5 mm flow distance from orifice in diabetes. This was accompanied by thickening of the wall of larger arterioles ( > 220 μ m) and thinning of the wall of smaller (100-140 μ m) arterioles (p < 0.001). Blood flow should cover larger distances in diabetic networks, but interestingly STZ-induced diabetes did not generate further geometrical changes in TNC KO mice. Conclusions Diabetes promotes hypertrophic and hypotrophic vascular remodeling and induces vasculogenesis at well defined, specific positions of the coronary vasculature. TNC plays a pivotal role in the formation of coronary network geometry, and TNC deletion causes parallel fragmentation preventing diabetes-induced abnormal vascular morphologies.
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Affiliation(s)
- Attila Kiss
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Gyorgy L Nadasy
- Department of Physiology, Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary
| | | | - Zsuzsanna Arnold
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Ibrahim Aykac
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Christopher Dostal
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Gábor T Szabó
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Petra Lujza Szabó
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Maria Szekeres
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 1088 Budapest, Hungary
| | - Peter Pokreisz
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Laszlo Hunyady
- Department of Physiology, Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary
| | - Bruno K Podesser
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
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31
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Matrix protein Tenascin-C promotes kidney fibrosis via STAT3 activation in response to tubular injury. Cell Death Dis 2022; 13:1044. [PMID: 36522320 PMCID: PMC9755308 DOI: 10.1038/s41419-022-05496-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/29/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022]
Abstract
Accumulating evidence indicates that the extracellular matrix (ECM) is not only a consequence of fibrosis, but also contributes to the progression of fibrosis, by creating a profibrotic microenvironment. Tenascin-C (TNC) is an ECM glycoprotein that contains multiple functional domains. We showed that following kidney injury, TNC was markedly induced in fibrotic areas in the kidney from both mouse models and humans with kidney diseases. Genetically deletion of TNC in mice significantly attenuated unilateral ureteral obstruction-induced kidney fibrosis. Further studies showed that TNC promoted the proliferation of kidney interstitial cells via STAT3 activation. TNC-expressing cells in fibrotic kidney were activated fibroblast 2 (Act.Fib2) subpopulation, according to a previously generated single nucleus RNA-seq dataset profiling kidney of mouse UUO model at day 14. To identify and characterize TNC-expressing cells, we generated a TNC-promoter-driven CreER2-IRES-eGFP knock-in mouse line and found that the TNC reporter eGFP was markedly induced in cells around injured tubules that had lost epithelial markers, suggesting TNC was induced in response to epithelium injury. Most of the eGFP-positive cells were both NG2 and PDGFRβ positive. These cells did not carry markers of progenitor cells or macrophages. In conclusion, this study provides strong evidence that matrix protein TNC contributes to kidney fibrosis. TNC pathway may serve as a potential therapeutic target for interstitial fibrosis and the progression of chronic kidney disease.
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Kong Ho S, Leu HB, Wu CC, Yeh HI, Yin WH, Lin TH, Chang KC, Wang JH, Tseng WK, Chen JW, Wu YW. The prognostic significance of the presence of tenascin-C in patients with stable coronary heart disease. Clin Chim Acta 2022; 535:68-74. [PMID: 35963306 DOI: 10.1016/j.cca.2022.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/29/2022] [Accepted: 08/01/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND We investigated the prognostic value of tenascin-C in patients with stable coronary heart disease. METHODS A total of 666 patients were enrolled and followed for 72 months. The primary outcome was a composite of cardiac events. The secondary outcomes were all-cause death, cardiovascular death, acute myocardial infarction (AMI), and heart failure hospitalization. RESULTS The area under the curve of tenascin-C to discriminate the occurrence of composite cardiac events was 70 % (95 % CI: 64.2 % to 75.8 %), and the corresponding optimal cutoff value was 19.91 ng/ml. A higher concentration of tenascin-C was associated with a greater risk of composite cardiac events (P trend < 0.001). Similar results were observed in all-cause death, AMI, and heart failure hospitalization. CONCLUSION Tenascin-C was found to be an independent predictor of total cardiovascular events in patients with stable coronary heart disease at 72 months, and also for all-cause death, AMI, and heart failure hospitalization.
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Affiliation(s)
- Sing Kong Ho
- Cardiology Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Hsin-Bang Leu
- Institute of Clinical Medicine and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan; Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chau-Chung Wu
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Medical Education & Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hung-I Yeh
- Cardiovascular Division, Department of Internal Medicine, MacKay Memorial Hospital, Mackay Medical College, New Taipei City, Taiwan
| | - Wei-Hsian Yin
- Division of Cardiology, Heart Center, Cheng-Hsin General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tsung-Hsien Lin
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kuan-Cheng Chang
- Division of Cardiovascular Medicine, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Ji-Hung Wang
- Department of Cardiology, Buddhist Tzu-Chi General Hospital, Tzu-Chi University, Hualien, Taiwan
| | - Wei-Kung Tseng
- Department of Medical Imaging and Radiological Sciences, I-Shou University, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Jaw-Wen Chen
- Institute of Clinical Medicine and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan; Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Yen-Wen Wu
- Cardiology Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Graduate Institute of Medicine, Yuan Ze University, Taoyuan, Taiwan
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33
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Gholipour A, Shakerian F, Zahedmehr A, Oveisee M, Maleki M, Mowla SJ, Malakootian M. Tenascin-C as a noninvasive biomarker of coronary artery disease. Mol Biol Rep 2022; 49:9267-9273. [PMID: 35941419 DOI: 10.1007/s11033-022-07760-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 06/25/2022] [Accepted: 06/29/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Coronary artery disease (CAD), is the leading cause of mortality and morbidity worldwide. Tenascin-C (TNC) with high expression levels in inflammatory and cardiovascular diseases, leads to the rupture of atherosclerotic plaques. The origin of plaque destabilization can be associated to endothelial dysfunction. Given the high prevalence of CAD, finding valuable biomarkers for its early detection is of great interest. Using serum samples from patients with CAD and individuals without CAD, we assessed the efficacy of TNC expression levels in serum exosomes and during endothelial cell differentiation as a noninvasive biomarker of CAD. METHODS TNC expression was analyzed using the RNA-sequencing data sets of 6 CAD and 6 normal samples of blood exosomes and endothelial differentiation transitions. Additionally, TNC expression was investigated in the serum samples of patients with CAD and individuals without CAD via qRT-PCR. ROC curve analysis was employed to test the suitability of TNC expression alterations as a CAD biomarker. RESULTS TNC exhibited higher expression in the exosomes of the CAD samples than in those of the non-CAD samples. During endothelial differentiation, TNC expression was upregulated and then consistently downregulated in mature endothelial cells. Moreover, TNC was significantly upregulated in the serum of the CAD group (P = 0.02), with an AUC of 0.744 for the expression level (95% confidence interval, 0.582 to 0.907; P = 0.011). Hence its expression level can be discriminated CAD from non-CAD samples. DISCUSSION Our study is the first to confirm that altered TNC expression is associated with pathological CAD conditions in Iranian patients. The expression of TNC is involved in endothelial differentiation and CAD development. Accordingly, TNC can serve as a valuable noninvasive biomarker with potential application in CAD diagnosis.
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Affiliation(s)
- Akram Gholipour
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Farshad Shakerian
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
- Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Zahedmehr
- Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maziar Oveisee
- Orthopedic Department, Bam University of Medical Sciences, Bam, Kerman, Iran
- Clinical Research Center, Pastor Educational Hospital, Bam University of Medical Sciences, Bam, Kerman, Iran
| | - Majid Maleki
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Javad Mowla
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Mahshid Malakootian
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Yilmaz A, Loustau T, Salomé N, Poilil Surendran S, Li C, Tucker RP, Izzi V, Lamba R, Koch M, Orend G. Advances on the roles of tenascin-C in cancer. J Cell Sci 2022; 135:276631. [PMID: 36102918 PMCID: PMC9584351 DOI: 10.1242/jcs.260244] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The roles of the extracellular matrix molecule tenascin-C (TNC) in health and disease have been extensively reviewed since its discovery over 40 years ago. Here, we will describe recent insights into the roles of TNC in tumorigenesis, angiogenesis, immunity and metastasis. In addition to high levels of expression in tumors, and during chronic inflammation, and bacterial and viral infection, TNC is also expressed in lymphoid organs. This supports potential roles for TNC in immunity control. Advances using murine models with engineered TNC levels were instrumental in the discovery of important functions of TNC as a danger-associated molecular pattern (DAMP) molecule in tissue repair and revealed multiple TNC actions in tumor progression. TNC acts through distinct mechanisms on many different cell types with immune cells coming into focus as important targets of TNC in cancer. We will describe how this knowledge could be exploited for cancer disease management, in particular for immune (checkpoint) therapies.
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Affiliation(s)
- Alev Yilmaz
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Thomas Loustau
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Nathalie Salomé
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Suchithra Poilil Surendran
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Chengbei Li
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Richard P. Tucker
- University of California at Davis 4 Department of Cell Biology and Human Anatomy , , 95616 Davis, CA , USA
| | - Valerio Izzi
- University of Oulu 5 Faculty of Biochemistry and Molecular Medicine , , FI-90014 Oulu , Finland
- University of Oulu 6 Faculty of Medicine , , FI-90014 Oulu , Finland
| | - Rijuta Lamba
- University of Oulu 5 Faculty of Biochemistry and Molecular Medicine , , FI-90014 Oulu , Finland
- University of Oulu 6 Faculty of Medicine , , FI-90014 Oulu , Finland
| | - Manuel Koch
- Institute for Dental Research and Oral Musculoskeletal Research, Center for Biochemistry, Center for Molecular Medicine Cologne (CMMC) 7 , Faculty of Medicine and , Joseph-Stelzmann-Str. 52, 50931 Cologne , Germany
- University Hospital Cologne, University of Cologne 7 , Faculty of Medicine and , Joseph-Stelzmann-Str. 52, 50931 Cologne , Germany
| | - Gertraud Orend
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
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Yu G, Corn PG, Shen P, Song JH, Lee YC, Lin SC, Pan J, Agarwal SK, Panaretakis T, Pacifici M, Logothetis CJ, Yu-Lee LY, Lin SH. Retinoic Acid Receptor Activation Reduces Metastatic Prostate Cancer Bone Lesions by Blocking the Endothelial-to-Osteoblast Transition. Cancer Res 2022; 82:3158-3171. [PMID: 35802768 PMCID: PMC9444986 DOI: 10.1158/0008-5472.can-22-0170] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 05/11/2022] [Accepted: 07/06/2022] [Indexed: 02/05/2023]
Abstract
Metastatic prostate cancer in the bone induces bone-forming lesions that contribute to progression and therapy resistance. Prostate cancer-induced bone formation originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Current strategies targeting prostate cancer-induced bone formation are lacking. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces prostate cancer-induced bone formation. Treatment with palovarotene, an RARγ agonist being tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited EC-to-OSB transition and osteoblast mineralization in vitro and decreased tumor-induced bone formation and tumor growth in several osteogenic prostate cancer models, and similar effects were observed with the pan-RAR agonist all-trans-retinoic acid (ATRA). Knockdown of RARα, β, or γ isoforms in ECs blocked BMP4-induced EC-to-OSB transition and osteoblast mineralization, indicating a role for all three isoforms in prostate cancer-induced bone formation. Furthermore, treatment with palovarotene or ATRA reduced plasma Tenascin C, a factor secreted from EC-OSB cells, which may be used to monitor treatment response. Mechanistically, BMP4-activated pSmad1 formed a complex with RAR in the nucleus of ECs to activate EC-to-OSB transition. RAR activation by palovarotene or ATRA caused pSmad1 degradation by recruiting the E3-ubiquitin ligase Smad ubiquitination regulatory factor1 (Smurf1) to the nuclear pSmad1/RARγ complex, thus blocking EC-to-OSB transition. Collectively, these findings suggest that palovarotene can be repurposed to target prostate cancer-induced bone formation to improve clinical outcomes for patients with bone metastasis. SIGNIFICANCE This study provides mechanistic insights into how RAR agonists suppress prostate cancer-induced bone formation and offers a rationale for developing RAR agonists for prostate cancer bone metastasis therapy. See related commentary by Bhowmick and Bhowmick, p. 2975.
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Affiliation(s)
- Guoyu Yu
- Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030
| | - Paul G. Corn
- Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030
| | - Pengfei Shen
- Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030
| | - Jian H. Song
- Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030
| | - Yu-Chen Lee
- Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030
| | - Song-Chang Lin
- Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030
| | - Jing Pan
- Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030
| | - Sandeep K. Agarwal
- Department of Medicine, Section of Immunology Allergy & Rheumatology, Baylor College of Medicine; Houston, Texas 77030
| | - Theocharis Panaretakis
- Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030
| | - Maurizio Pacifici
- Translational Research Program in Pediatric Orthopaedics, The Children’s Hospital of Philadelphia; Philadelphia
| | - Christopher J. Logothetis
- Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030
| | - Li-Yuan Yu-Lee
- Department of Medicine, Section of Immunology Allergy & Rheumatology, Baylor College of Medicine; Houston, Texas 77030,Co-Corresponding authors: Dr. Sue-Hwa Lin, Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: 713-794-1559; Fax: 713-834-6084; ; Dr. Li-yuan Yu-Lee, Department of Medicine, Section of Immunology Allergy & Rheumatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: 713-798-4770;
| | - Sue-Hwa Lin
- Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030,Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center; Houston, Texas 77030,The University of Texas Graduate School of Biomedical Sciences at Houston; Houston, Texas.,Co-Corresponding authors: Dr. Sue-Hwa Lin, Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: 713-794-1559; Fax: 713-834-6084; ; Dr. Li-yuan Yu-Lee, Department of Medicine, Section of Immunology Allergy & Rheumatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: 713-798-4770;
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Toyomasu Y, Matsui K, Omori K, Takada A, Imanaka-Yoshida K, Tawara I, Shimamoto A, Takao M, Kobayashi H, Tomaru A, Fujimoto H, Kobayashi T, Sakuma H, Nomoto Y. Tenascin C in radiation-induced lung damage: Pathological expression and serum level elevation. Thorac Cancer 2022; 13:2904-2907. [PMID: 36047568 PMCID: PMC9575110 DOI: 10.1111/1759-7714.14624] [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: 06/30/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 11/29/2022] Open
Abstract
Radiation‐induced lung damage (RILD) is a critical problem in lung cancer radiotherapy, and it is difficult to predict its severity. Although no biomarkers for RILD have been established, tenascin C (TNC) is an extracellular matrix glycoprotein involved in the remodeling of damaged tissues and has been implicated in inflammation and fibrosis. We report the unique case of a 36‐year‐old man with adenocarcinoma of the lung, Union for International Cancer Control stage IIIB, who was treated with radiotherapy before lung surgery. The surgical specimen showed histopathological expression of TNC in the region where radiation pneumonitis was observed radiographically. Serum TNC levels were elevated after radiotherapy. In this case, TNC is suggested to be implicated in RILD and may be a potential candidate as a biomarker for the onset and severity of the condition.
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Affiliation(s)
| | - Kenta Matsui
- Department of Pathology and Matrix Biology, Mie University, Tsu, Japan
| | - Kazuki Omori
- Department of Radiology, Mie University, Tsu, Japan
| | | | | | - Isao Tawara
- Department of Hematology and Oncology, Mie University, Tsu, Japan
| | | | - Motoshi Takao
- Department of Thoracic Surgery, Mie University, Tsu, Japan
| | | | - Atsushi Tomaru
- Department of Respiratory Medicine, Mie University, Tsu, Japan
| | - Hajime Fujimoto
- Department of Respiratory Medicine, Mie University, Tsu, Japan
| | - Tetsu Kobayashi
- Department of Respiratory Medicine, Mie University, Tsu, Japan
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37
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Fu Z, Zhu G, Luo C, Chen Z, Dou Z, Chen Y, Zhong C, Su S, Liu F. Matricellular protein tenascin C: Implications in glioma progression, gliomagenesis, and treatment. Front Oncol 2022; 12:971462. [PMID: 36033448 PMCID: PMC9413079 DOI: 10.3389/fonc.2022.971462] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/25/2022] [Indexed: 11/24/2022] Open
Abstract
Matricellular proteins are nonstructural extracellular matrix components that are expressed at low levels in normal adult tissues and are upregulated during development or under pathological conditions. Tenascin C (TNC), a matricellular protein, is a hexameric and multimodular glycoprotein with different molecular forms that is produced by alternative splicing and post-translational modifications. Malignant gliomas are the most common and aggressive primary brain cancer of the central nervous system. Despite continued advances in multimodal therapy, the prognosis of gliomas remains poor. The main reasons for such poor outcomes are the heterogeneity and adaptability caused by the tumor microenvironment and glioma stem cells. It has been shown that TNC is present in the glioma microenvironment and glioma stem cell niches, and that it promotes malignant properties, such as neovascularization, proliferation, invasiveness, and immunomodulation. TNC is abundantly expressed in neural stem cell niches and plays a role in neurogenesis. Notably, there is increasing evidence showing that neural stem cells in the subventricular zone may be the cells of origin of gliomas. Here, we review the evidence regarding the role of TNC in glioma progression, propose a potential association between TNC and gliomagenesis, and summarize its clinical applications. Collectively, TNC is an appealing focus for advancing our understanding of gliomas.
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Affiliation(s)
- Zaixiang Fu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ganggui Zhu
- Department of Neurosurgery, Hangzhou First People’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chao Luo
- Department of Neurosurgery, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Zihang Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhangqi Dou
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yike Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chen Zhong
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Su
- Department of Neurosurgery, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Fuyi Liu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Fuyi Liu,
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38
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Tenascin-C in fibrosis in multiple organs: Translational implications. Semin Cell Dev Biol 2022; 128:130-136. [PMID: 35400564 PMCID: PMC10119770 DOI: 10.1016/j.semcdb.2022.03.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/17/2022] [Accepted: 03/14/2022] [Indexed: 12/28/2022]
Abstract
Systemic sclerosis (SSc, scleroderma) is a complex disease with a pathogenic triad of autoimmunity, vasculopathy, and fibrosis involving the skin and multiple internal organs [1]. Because fibrosis accounts for as much as 45% of all deaths worldwide and appears to be increasing in prevalence [2], understanding its pathogenesis and progression is an urgent scientific challenge. Fibroblasts and myofibroblasts are the key effector cells executing physiologic tissue repair on one hand, and pathological fibrogenesis leading to chronic fibrosing conditions on the other. Recent studies identify innate immune signaling via toll-like receptors (TLRs) as a key driver of persistent fibrotic response in SSc. Repeated injury triggers the in-situ generation of "damage-associated molecular patterns" (DAMPs) or danger signals. Sensing of these danger signals by TLR4 on resident cells elicits potent stimulatory effects on fibrotic gene expression and myofibroblast differentiation triggering the self-limited tissue repair response to self-sustained pathological fibrosis characteristic of SSc. Our unbiased survey for DAMPs associated with SSc identified extracellular matrix glycoprotein tenascin-C as one of the most highly up-regulated ECM proteins in SSc skin and lung biopsies [3,4]. Furthermore, tenascin C is responsible for driving sustained fibroblasts activation, thereby progression of fibrosis [3]. This review summarizes recent studies examining the regulation and complex functional role of tenascin C, presenting tenascin-TLR4 axis in pathological fibrosis, and novel anti-fibrotic approaches targeting their signaling.
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Kwong AM, Luke PPW, Bhattacharjee RN. Carbon monoxide mechanism of protection against renal ischemia and reperfusion injury. Biochem Pharmacol 2022; 202:115156. [PMID: 35777450 DOI: 10.1016/j.bcp.2022.115156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 12/20/2022]
Abstract
Carbon monoxide is quickly moving past its historic label as a molecule once feared, to a therapeutic drug that modulates inflammation. The development of carbon monoxide releasing molecules and utilization of heme oxygenase-1 inducers have shown carbon monoxide to be a promising therapy in reducing renal ischemia and reperfusion injury and other inflammatory diseases. In this review, we will discuss the developments and application of carbon monoxide releasing molecules in renal ischemia and reperfusion injury, and transplantation. We will review the anti-inflammatory mechanisms of carbon monoxide in respect to mitigating apoptosis, suppressing dendritic cell maturation and signalling, inhibiting toll-like receptor activation, promoting anti-inflammatory responses, and the effects on renal vasculature.
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Affiliation(s)
- Aaron M Kwong
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Patrick P W Luke
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Surgery, London Health Sciences Centre, Canada; Matthew Mailing Centre for Translational Transplantation Studies, Canada.
| | - Rabindra N Bhattacharjee
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Surgery, London Health Sciences Centre, Canada; Matthew Mailing Centre for Translational Transplantation Studies, Canada.
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40
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Tucker RP, Degen M. Revisiting the Tenascins: Exploitable as Cancer Targets? Front Oncol 2022; 12:908247. [PMID: 35785162 PMCID: PMC9248440 DOI: 10.3389/fonc.2022.908247] [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: 03/30/2022] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
For their full manifestation, tumors require support from the surrounding tumor microenvironment (TME), which includes a specific extracellular matrix (ECM), vasculature, and a variety of non-malignant host cells. Together, these components form a tumor-permissive niche that significantly differs from physiological conditions. While the TME helps to promote tumor progression, its special composition also provides potential targets for anti-cancer therapy. Targeting tumor-specific ECM molecules and stromal cells or disrupting aberrant mesenchyme-cancer communications might normalize the TME and improve cancer treatment outcome. The tenascins are a family of large, multifunctional extracellular glycoproteins consisting of four members. Although each have been described to be expressed in the ECM surrounding cancer cells, tenascin-C and tenascin-W are currently the most promising candidates for exploitability and clinical use as they are highly expressed in various tumor stroma with relatively low abundance in healthy tissues. Here, we review what is known about expression of all four tenascin family members in tumors, followed by a more thorough discussion on tenascin-C and tenascin-W focusing on their oncogenic functions and their potential as diagnostic and/or targetable molecules for anti-cancer treatment purposes.
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Affiliation(s)
- Richard P. Tucker
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Martin Degen
- Laboratory for Oral Molecular Biology, Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland
- *Correspondence: Martin Degen,
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41
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Lepucki A, Orlińska K, Mielczarek-Palacz A, Kabut J, Olczyk P, Komosińska-Vassev K. The Role of Extracellular Matrix Proteins in Breast Cancer. J Clin Med 2022; 11:jcm11051250. [PMID: 35268340 PMCID: PMC8911242 DOI: 10.3390/jcm11051250] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/16/2022] [Accepted: 02/22/2022] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix is a structure composed of many molecules, including fibrillar (types I, II, III, V, XI, XXIV, XXVII) and non-fibrillar collagens (mainly basement membrane collagens: types IV, VIII, X), non-collagenous glycoproteins (elastin, laminin, fibronectin, thrombospondin, tenascin, osteopontin, osteonectin, entactin, periostin) embedded in a gel of negatively charged water-retaining glycosaminoglycans (GAGs) such as non-sulfated hyaluronic acid (HA) and sulfated GAGs which are linked to a core protein to form proteoglycans (PGs). This highly dynamic molecular network provides critical biochemical and biomechanical cues that mediate the cell–cell and cell–matrix interactions, influence cell growth, migration and differentiation and serve as a reservoir of cytokines and growth factors’ action. The breakdown of normal ECM and its replacement with tumor ECM modulate the tumor microenvironment (TME) composition and is an essential part of tumorigenesis and metastasis, acting as key driver for malignant progression. Abnormal ECM also deregulate behavior of stromal cells as well as facilitating tumor-associated angiogenesis and inflammation. Thus, the tumor matrix modulates each of the classically defined hallmarks of cancer promoting the growth, survival and invasion of the cancer. Moreover, various ECM-derived components modulate the immune response affecting T cells, tumor-associated macrophages (TAM), dendritic cells and cancer-associated fibroblasts (CAF). This review article considers the role that extracellular matrix play in breast cancer. Determining the detailed connections between the ECM and cellular processes has helped to identify novel disease markers and therapeutic targets.
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Affiliation(s)
- Arkadiusz Lepucki
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.L.); (K.O.)
| | - Kinga Orlińska
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.L.); (K.O.)
| | - Aleksandra Mielczarek-Palacz
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland; (A.M.-P.); (J.K.)
| | - Jacek Kabut
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland; (A.M.-P.); (J.K.)
| | - Pawel Olczyk
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.L.); (K.O.)
- Correspondence:
| | - Katarzyna Komosińska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland;
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Laboratory evidence on a direct correlation between acute central serous chorioretinopathy and tenascin C, metalloprotein 1, BAX, BCL2, subfatin and asprosin. J Fr Ophtalmol 2022; 45:314-322. [PMID: 35123814 DOI: 10.1016/j.jfo.2021.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 11/23/2022]
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43
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Loustau T, Abou-Faycal C, Erne W, zur Wiesch PA, Ksouri A, Imhof T, Mörgelin M, Li C, Mathieu M, Salomé N, Crémel G, Dhaouadi S, Bouhaouala-Zahar B, Koch M, Orend G. Modulating tenascin-C functions by targeting the MAtrix REgulating MOtif, “MAREMO”. Matrix Biol 2022; 108:20-38. [DOI: 10.1016/j.matbio.2022.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/31/2022] [Accepted: 02/23/2022] [Indexed: 12/11/2022]
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44
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Chelluboina B, Chokkalla AK, Mehta SL, Morris-Blanco KC, Bathula S, Sankar S, Park JS, Vemuganti R. Tenascin-C induction exacerbates post-stroke brain damage. J Cereb Blood Flow Metab 2022; 42:253-263. [PMID: 34689646 PMCID: PMC9122520 DOI: 10.1177/0271678x211056392] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The role of tenascin-C (TNC) in ischemic stroke pathology is not known despite its prognostic association with cerebrovascular diseases. Here, we investigated the effect of TNC knockdown on post-stroke brain damage and its putative mechanism of action in adult mice of both sexes. Male and female C57BL/6 mice were subjected to transient middle cerebral artery occlusion and injected (i.v.) with either TNC siRNA or a negative (non-targeting) siRNA at 5 min after reperfusion. Motor function (beam walk and rotarod tests) was assessed between days 1 and 14 of reperfusion. Infarct volume (T2-MRI), BBB damage (T1-MRI with contrast), and inflammatory markers were measured at 3 days of reperfusion. The TNC siRNA treated cohort showed significantly curtailed post-stroke TNC protein expression, motor dysfunction, infarction, BBB damage, and inflammation compared to the sex-matched negative siRNA treated cohort. These results demonstrate that the induction of TNC during the acute period after stroke might be a mediator of post-ischemic inflammation and secondary brain damage independent of sex.
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Affiliation(s)
- Bharath Chelluboina
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Anil K Chokkalla
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA.,Cellular and Molecular Pathology Graduate Program, University of Wisconsin, Madison, WI, USA
| | - Suresh L Mehta
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | | | | | - Sneha Sankar
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Jin Soo Park
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA
| | - Raghu Vemuganti
- Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA.,Cellular and Molecular Pathology Graduate Program, University of Wisconsin, Madison, WI, USA.,William S. Middleton Veterans Administration Hospital, Madison, WI, USA
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45
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Keller KE, Peters DM. Pathogenesis of glaucoma: Extracellular matrix dysfunction in the trabecular meshwork-A review. Clin Exp Ophthalmol 2022; 50:163-182. [PMID: 35037377 DOI: 10.1111/ceo.14027] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/19/2021] [Accepted: 11/26/2021] [Indexed: 12/11/2022]
Abstract
The trabecular meshwork regulates aqueous humour outflow from the anterior chamber of the eye. It does this by establishing a tunable outflow resistance, defined by the interplay between cells and their extracellular matrix (ECM) milieu, and the molecular interactions between ECM proteins. During normal tissue homeostasis, the ECM is remodelled and trabecular cell behaviour is modified, permitting increased aqueous fluid outflow to maintain intraocular pressure (IOP) within a relatively narrow physiological pressure. Dysfunction in the normal homeostatic process leads to increased outflow resistance and elevated IOP, which is a primary risk factor for glaucoma. This review delineates some of the changes in the ECM that lead to gross as well as some more subtle changes in the structure and function of the ECM, and their impact on trabecular cell behaviour. These changes are discussed in the context of outflow resistance and glaucoma.
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Affiliation(s)
- Kate E Keller
- Casey Eye Institute, Oregon Health &Science University, Portland, Oregon, USA
| | - Donna M Peters
- Department of Pathology & Laboratory Medicine, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin, USA
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46
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Popova NV, Jücker M. The Functional Role of Extracellular Matrix Proteins in Cancer. Cancers (Basel) 2022; 14:238. [PMID: 35008401 PMCID: PMC8750014 DOI: 10.3390/cancers14010238] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 02/04/2023] Open
Abstract
The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells.
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Affiliation(s)
- Nadezhda V. Popova
- Laboratory of Receptor Cell Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, 117997 Moscow, Russia;
| | - Manfred Jücker
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
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47
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Li Y, Xu Z, Wu L, Liang X, Zhao L, Liu F, Wang F. Tenascin-C predicts IVIG non-responsiveness and coronary artery lesions in kawasaki disease in a Chinese cohort. Front Pediatr 2022; 10:979026. [PMID: 36582508 PMCID: PMC9792982 DOI: 10.3389/fped.2022.979026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES To assess the predictive value of tenascin-C (TN-C) for intravenous immunoglobulin (IVIG) non-responsiveness and coronary artery lesions (CALs) development at the acute stage of Kawasaki disease, and to build novel scoring systems for identifying IVIG non-responsiveness and CALs. METHODS A total of 261 patients in acute-stage Kawasaki disease were included. Serum samples before IVIG initiation were collected and TN-C expression levels were measured using an enzyme-linked immunosorbent assay. In addition to TN-C, another fifteen clinical and laboratory parameters collected before treatment were compared between IVIG responsive and non-responsive groups, and between groups with and without CALs. Multiple logistic regression analyses were performed to construct new scoring systems for the prediction of IVIG non-responsiveness and CALs development. RESULTS IVIG non-responsive group (n = 51) had significantly higher TN-C level compared to IVIG responsive group (n = 210) (15.44 vs. 12.38 IU/L, P < 0.001). A novel scoring system composed of TN-C, total bilirubin, serum sodium and albumin was established to predict IVIG non-responsiveness. Patients with a total score ≥ 2 points were classified as high-risk cases. With the sensitivity of 78.4% and specificity of 73.8%, the efficiency of our scoring system for predicting IVIG non-responsiveness was comparable to the Kobayashi system. Consistently, the group developing CALs at the acute stage (n = 42) had significantly higher TN-C level compared to the group without CALs (n = 219) (19.76 vs. 12.10 IU/L, P < 0.001). A new scoring system showed that patients with elevated TN-C, platelet count ≥ 450 × 109/L, and delayed initial infusion of IVIG had a higher risk of developing CALs. Individuals with a total score ≥ 3 points were classified as high-risk cases. The sensitivity and specificity of the novel simple system for predicting CALs development were 83.3% and 74.0%, respectively, yielding a better efficiency than the Harada score. CONCLUSION Elevated TN-C appeared to be an independent risk factor for both IVIG non-responsiveness and CALs in Chinese children with KD. Our scoring systems containing TN-C is simple and efficient in the early identification of high-risk KD cases that could benefit from more individualized medications.
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Affiliation(s)
- Yujie Li
- Department of Cardiology, Children's Hospital of Fudan University, Shanghai, China
| | - Ziqing Xu
- Department of Cardiology, Children's Hospital of Fudan University, Shanghai, China
| | - Lin Wu
- Department of Cardiology, Children's Hospital of Fudan University, Shanghai, China
| | - Xuecun Liang
- Department of Cardiology, Children's Hospital of Fudan University, Shanghai, China
| | - Lu Zhao
- Department of Cardiology, Children's Hospital of Fudan University, Shanghai, China
| | - Fang Liu
- Department of Cardiology, Children's Hospital of Fudan University, Shanghai, China
| | - Feng Wang
- Department of Cardiology, Children's Hospital of Fudan University, Shanghai, China
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van Lith SAM, Raavé R. Targets in nuclear medicine imaging: Past, present and future. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00069-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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49
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Nagel F, Schaefer AK, Gonçalves IF, Acar E, Oszwald A, Kaiser P, Kain R, Trescher K, Eilenberg WH, Brostjan C, Santer D, Kiss A, Podesser BK. OUP accepted manuscript. Interact Cardiovasc Thorac Surg 2022; 34:841-848. [PMID: 35137102 PMCID: PMC9070497 DOI: 10.1093/icvts/ivac018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/18/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Felix Nagel
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
- Department of Cardiac Surgery, University Hospital St. Pölten, Karl Landsteiner University, St. Pölten, Austria
| | - Anne-Kristin Schaefer
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - Inês Fonseca Gonçalves
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - Eylem Acar
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - Andre Oszwald
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Philipp Kaiser
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - Renate Kain
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Karola Trescher
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
- Department of Cardiac Surgery, University Hospital St. Pölten, Karl Landsteiner University, St. Pölten, Austria
| | - Wolf H Eilenberg
- Department of Vascular Surgery, Medical University of Vienna, Vienna, Austria
| | - Christine Brostjan
- Department of Vascular Surgery, Medical University of Vienna, Vienna, Austria
| | - David Santer
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
- Department of Cardiac Surgery, University Hospital Basel, Basel, Switzerland
| | - Attila Kiss
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - Bruno K Podesser
- Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
- Department of Cardiac Surgery, University Hospital St. Pölten, Karl Landsteiner University, St. Pölten, Austria
- Corresponding author. Ludwig Boltzmann Institute for Cardiovascular Research, Center for Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, Leitstelle 1Q, 1090 Vienna, Austria. Tel: +43-140400-52210; fax: +43-140400-52290; e-mail: (B.K. Podesser)
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50
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Xu Y, Li N, Gao J, Shang D, Zhang M, Mao X, Chen R, Zheng J, Shan Y, Chen M, Xie Q, Hao CM. Elevated Serum Tenascin-C Predicts Mortality in Critically Ill Patients With Multiple Organ Dysfunction. Front Med (Lausanne) 2021; 8:759273. [PMID: 34901073 PMCID: PMC8661593 DOI: 10.3389/fmed.2021.759273] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Multiple organ dysfunction is a complex and lethal clinical feature with heterogeneous causes and is usually characterized by tissue injury of multiple organs. Tenascin-C (TNC) is a matricellular protein that is rarely expressed in most of the adult tissues, but re-induced following injury. This study aimed to evaluate serum TNC in predicting mortality in critically ill patients with multiple organ dysfunction. Methods: Adult critically ill patients with at least two organs dysfunction and an increase of Sequential Organ Failure Assess (SOFA) score ≥ 2 points within 7 days were prospectively enrolled into two independent cohorts. The emergency (derivation) cohort was a consecutive series and the patients were from Emergency Department. The inpatient (validation) cohort was a convenience series and the patients were from medical wards. Their serum samples at the first 24 h after enrollment were collected and subjected to TNC measurement using ELISA. The association between serum TNC level and 28-day all-cause mortality was investigated, and then the predictive value of serum TNC was analyzed. Results: A total of 110 patients with a median age of 64 years (53, 73) were enrolled in the emergency cohort. Compared to the survivors, serum TNC in the non-survivors was significantly higher (467.7 vs. 197.5 ng/ml, p < 0.001). Multivariate logistic regression analysis revealed that the association between serum TNC and 28-day mortality was independent of sepsis or critical illness scores such as SOFA, Acute Physiology and Chronic Health Evaluation (APACHE II), and Simplified Acute Physiology Score (SAPS II), respectively (p < 0.001 for each). The area under receiver operating characteristic curve of serum TNC for predicting mortality was 0.803 (0.717-0.888) (p < 0.001), similar with SOFA 0.808 (0.725-0.891), APACHE II 0.762 (0.667-0.857), and SAPS II 0.779 (0.685-0.872). The optimal cut-off value of serum TNC was 298.2 ng/ml. Kaplan-Meier analysis showed that the survival of patients with serum TNC ≥ 300 ng/ml was significantly worse than that of patients with serum TNC < 300 ng/ml. This result was validated in the inpatient cohort. The sensitivity and specificity of serum TNC ≥ 300 ng/ml for predicting mortality were 74.3 and 74.7% in the emergency cohort, and 63.0 and 70.1% in the inpatient cohort, respectively. Conclusion: Serum TNC was associated with mortality in critically ill patients with multiple organ dysfunction, and would be used as a prognostic tool for predicting mortality in this population.
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Affiliation(s)
- Yunyu Xu
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Nanyang Li
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiamin Gao
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, China
| | - Da Shang
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Min Zhang
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaoyi Mao
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ruiying Chen
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jianming Zheng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Ying Shan
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, China
| | - Mingquan Chen
- Department of Emergency, Huashan Hospital, Fudan University, Shanghai, China
| | - Qionghong Xie
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chuan-Ming Hao
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
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