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Okuyama T, Tsuno T, Inoue R, Fukushima S, Kyohara M, Matsumura A, Miyashita D, Nishiyama K, Takano Y, Togashi Y, Meguro-Horike M, Horike SI, Kin T, Shapiro AJ, Yanagisawa H, Terauchi Y, Shirakawa J. The matricellular protein Fibulin-5 regulates β-cell proliferation in an autocrine/paracrine manner. iScience 2025; 28:111856. [PMID: 39995864 PMCID: PMC11848788 DOI: 10.1016/j.isci.2025.111856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 11/20/2024] [Accepted: 01/17/2025] [Indexed: 02/26/2025] Open
Abstract
The matricellular protein Fibulin-5 (Fbln5) is a secreted protein that is essential for elastic fiber formation, and pancreatic islets are usually surrounded by the extracellular matrix (ECM), which includes elastic fibers. However, much uncertainty remains regarding the function of the ECM and its components in β-cells. Here, we describe the role of Fbln5 in β-cell replication. Fbln5 expression was increased upon glucose stimulation in β-cells of mouse and human islets. β-Cell-specific Fbln5-knockout (βFbln5KO) mice exhibit significantly reduced β-cell proliferation in vivo but not in vitro. Secreted extracellular Fbln5 enhances β-cell replication. Fbln5-deficient β-cells exhibit the downregulated expression of the gene encoding Polo-like kinase 1 (PLK1), which is accompanied by ERK-mediated FoxM1 nuclear export. These data suggest that Fbln5 is secreted from β-cells in response to glucose and plays important roles in the appropriate maintenance of β-cell functions in an autocrine or paracrine manner.
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Affiliation(s)
- Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takahiro Tsuno
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Ryota Inoue
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Setsuko Fukushima
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Anzu Matsumura
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kuniyuki Nishiyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
| | - Yusuke Takano
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Makiko Meguro-Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Shin-ichi Horike
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Japan
| | - Tatsuya Kin
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - A.M. James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Jun Shirakawa
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan
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Bian X, Yin S, Yin X, Fang T, Wang Y, Yang S, Jiang X, Xue Y, Ye F, Zhang L. Clinical and Biological Significances of FBLN5 in Gastric Cancer. Cancers (Basel) 2023; 15:553. [PMID: 36672502 PMCID: PMC9856449 DOI: 10.3390/cancers15020553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/07/2023] [Accepted: 01/15/2023] [Indexed: 01/18/2023] Open
Abstract
Abnormal FBLN5 expression levels are related to various cancer types. This study is the first to explore its clinical and biological significances in gastric cancer (GC). We used The Cancer Genome Atlas-GC (TCGA-GC) and Gene Expression Omnibus (GEO) databases to identify the differential expression of FBLN5, and its association with clinical pathological characteristics was analyzed. A Kaplan-Meier plotter was used to calculate the impact of FBLN5 on GC patient prognosis, and the biological functions of FBLN5 were analyzed. In addition, we constructed a GC tissue microarray, and performed an immunohistochemical staining of FBLN5 to verify our findings. Western blotting was conducted simultaneously to confirm that FBLN5 was overexpressed in GC. We found that the high level of FBLN5 mRNA in GC was associated with a poor prognosis. High FBLN5 expression levels were significantly correlated with INFc and N3 lymph node metastasis. Univariate and multivariate analyses showed that FBLN5 expression levels and lymph node metastasis rate were independent risk factors related to GC patient prognosis, which can be combined to construct a nomogram to serve patients. Therefore, we believe that FBLN5 is significantly related to the poor prognosis of GC patients. FBLN5 is a valuable prognostic indicator to evaluate the prognosis of GC.
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Affiliation(s)
- Xiulan Bian
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
| | - Shengjie Yin
- Department of Medical Oncology, Municipal Hospital of Chifeng, Chifeng 024000, China
| | - Xin Yin
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150086, China
| | - Tianyi Fang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150086, China
| | - Yufei Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150086, China
| | - Shuo Yang
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
| | - Xinju Jiang
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
| | - Yingwei Xue
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150086, China
| | - Fei Ye
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
| | - Lei Zhang
- Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin 150086, China
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Suzuki Y, Oinaka H, Nakajima H, Nampei M, Kawakita F, Miura Y, Yasuda R, Toma N, Suzuki H. Plasma Fibulin-5 Levels as an Independent Predictor of a Poor Outcome after an Aneurysmal Subarachnoid Hemorrhage. Int J Mol Sci 2022; 23:ijms232315184. [PMID: 36499510 PMCID: PMC9740042 DOI: 10.3390/ijms232315184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/27/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) is a poor-outcome disease with a delayed neurological exacerbation. Fibulin-5 (FBLN5) is one of matricellular proteins, some of which have been involved in SAH pathologies. However, no study has investigated FBLN5's roles in SAH. This study was aimed at examining the relationships between serially measured plasma FBLN5 levels and neurovascular events or outcomes in 204 consecutive aneurysmal SAH patients, including 77 patients (37.7%) with poor outcomes (90-day modified Rankin Scale 3-6). Plasma FBLN5 levels were not related to angiographic vasospasm, delayed cerebral ischemia, and delayed cerebral infarction, but elevated levels were associated with severe admission clinical grades, any neurological exacerbation and poor outcomes. Receiver-operating characteristic curves indicated that the most reasonable cut-off values of plasma FBLN5, in order to differentiate 90-day poor from good outcomes, were obtained from analyses at days 4-6 for all patients (487.2 ng/mL; specificity, 61.4%; and sensitivity, 62.3%) and from analyses at days 7-9 for only non-severe patient (476.8 ng/mL; specificity, 66.0%; and sensitivity, 77.8%). Multivariate analyses revealed that the plasma FBLN5 levels were independent determinants of the 90-day poor outcomes in both all patients' and non-severe patients' analyses. These findings suggest that the delayed elevation of plasma FBLN5 is related to poor outcomes, and that FBLN5 may be a new molecular target to reveal a post-SAH pathophysiology.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Hidenori Suzuki
- Correspondence: ; Tel.: +81-59-232-1111; Fax: +81-59-231-5212
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Brewitz L, Onisko BC, Schofield CJ. Combined proteomic and biochemical analyses redefine the consensus sequence requirement for epidermal growth factor-like domain hydroxylation. J Biol Chem 2022; 298:102129. [PMID: 35700824 PMCID: PMC9293771 DOI: 10.1016/j.jbc.2022.102129] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 11/16/2022] Open
Abstract
Epidermal growth factor-like domains (EGFDs) have important functions in cell-cell signaling. Both secreted and cell surface human EGFDs are subject to extensive modifications, including aspartate and asparagine residue C3-hydroxylations catalyzed by the 2-oxoglutarate oxygenase aspartate/asparagine-β-hydroxylase (AspH). Although genetic studies show AspH is important in human biology, studies on its physiological roles have been limited by incomplete knowledge of its substrates. Here, we redefine the consensus sequence requirements for AspH-catalyzed EGFD hydroxylation based on combined analysis of proteomic mass spectrometric data and mass spectrometry-based assays with isolated AspH and peptide substrates. We provide cellular and biochemical evidence that the preferred site of EGFD hydroxylation is embedded within a disulfide-bridged macrocycle formed of 10 amino acid residues. This definition enabled the identification of previously unassigned hydroxylation sites in three EGFDs of human fibulins as AspH substrates. A non-EGFD containing protein, lymphocyte antigen-6/plasminogen activator urokinase receptor domain containing protein 6B (LYPD6B) was shown to be a substrate for isolated AspH, but we did not observe evidence for LYPD6B hydroxylation in cells. AspH-catalyzed hydroxylation of fibulins is of particular interest given their important roles in extracellular matrix dynamics. In conclusion, these results lead to a revision of the consensus substrate requirements for AspH and expand the range of observed and potential AspH-catalyzed hydroxylation in cells, which will enable future study of the biological roles of AspH.
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Affiliation(s)
- Lennart Brewitz
- Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, United Kingdom.
| | | | - Christopher J Schofield
- Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, Oxford, United Kingdom.
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Zhang X, Alanazi YF, Jowitt TA, Roseman AM, Baldock C. Elastic Fibre Proteins in Elastogenesis and Wound Healing. Int J Mol Sci 2022; 23:4087. [PMID: 35456902 PMCID: PMC9027394 DOI: 10.3390/ijms23084087] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/31/2022] [Accepted: 04/03/2022] [Indexed: 12/30/2022] Open
Abstract
As essential components of our connective tissues, elastic fibres give tissues such as major blood vessels, skin and the lungs their elasticity. Their formation is complex and co-ordinately regulated by multiple factors. In this review, we describe key players in elastogenesis: fibrillin-1, tropoelastin, latent TGFβ binding protein-4, and fibulin-4 and -5. We summarise their roles in elastogenesis, discuss the effect of their mutations on relevant diseases, and describe their interactions involved in forming the elastic fibre network. Moreover, we look into their roles in wound repair for a better understanding of their potential application in tissue regeneration.
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Affiliation(s)
- Xinyang Zhang
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; (X.Z.); (T.A.J.)
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK;
| | - Yasmene F. Alanazi
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Thomas A. Jowitt
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; (X.Z.); (T.A.J.)
| | - Alan M. Roseman
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK;
| | - Clair Baldock
- Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; (X.Z.); (T.A.J.)
- School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK;
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Li X, Zhong S, Sun Y, Huang X, Li Y, Wang L, Wu Y, Yang M, Yuan HX, Liu J, Zang S. Integration analysis identifies the role of metallothionein in the progression from hepatic steatosis to steatohepatitis. Front Endocrinol (Lausanne) 2022; 13:951093. [PMID: 36329886 PMCID: PMC9622801 DOI: 10.3389/fendo.2022.951093] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD), a metabolic disorder that develops from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), has become an epidemic of chronic liver dysfunction worldwide. However, mechanisms that govern the transition from NAFL to NASH have not been fully elucidated. METHODS Gene expression profile data of NAFLD liver tissues were obtained from Gene Expression Omnibus (GEO), including three microarray datasets with 60 NAFL and 44 NASH patients. Integrative differentially expressed genes (DEGs) between NAFL and NASH patients were identified using robust rank aggregation (RRA) analysis. Hub genes were identified combined with gene ontology functional annotation and protein-protein interaction network construction and validated using a sequencing dataset. Huh-7 cells with palmitate-induced lipid overload and NAFLD-diet mouse model of different stages were used to verify our findings. RESULTS RRA analysis determined 70 robust DEGs between NAFL and NASH. The most robustly upregulated genes were SPP1, AKR1B10, CHST9, and ANXA2, while the most robustly downregulated DEGs were SNORD94, SCARNA10, SNORA20, and MT1M. Cellular response to zinc ion (GO: 0071294) ranked first in GO analysis of downregulated genes, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment showed that mineral absorption (hsa04978) was significantly enriched. The involvement of the metallothionein pathway was further validated by the decrease of Mt1 expression during NAFL to NASH progression in NAFLD mice and the protection from lipotoxicity in liver cells by overexpressing MT1M. CONCLUSIONS Our integrated analysis identified novel gene signatures and provided comprehensive molecular mechanisms underlying the transition from NAFL to NASH. Metallothionein might be a potential intervention target for NAFLD progression.
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Affiliation(s)
- Xiaoya Li
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Shaoping Zhong
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yifan Sun
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Xinmei Huang
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Yue Li
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Lihong Wang
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Yueyue Wu
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Min Yang
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Hai-Xin Yuan
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Jun Liu
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
- *Correspondence: Shufei Zang, ; Jun Liu,
| | - Shufei Zang
- Department of Endocrinology of Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
- *Correspondence: Shufei Zang, ; Jun Liu,
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Hassanein SS, Abdel-Mawgood AL, Ibrahim SA. EGFR-Dependent Extracellular Matrix Protein Interactions Might Light a Candle in Cell Behavior of Non-Small Cell Lung Cancer. Front Oncol 2021; 11:766659. [PMID: 34976811 PMCID: PMC8714827 DOI: 10.3389/fonc.2021.766659] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/23/2021] [Indexed: 12/14/2022] Open
Abstract
Lung cancer remains the leading cause of cancer-related death and is associated with a poor prognosis. Lung cancer is divided into 2 main types: the major in incidence is non-small cell lung cancer (NSCLC) and the minor is small cell lung cancer (SCLC). Although NSCLC progression depends on driver mutations, it is also affected by the extracellular matrix (ECM) interactions that activate their corresponding signaling molecules in concert with integrins and matrix metalloproteinases (MMPs). These signaling molecules include cytoplasmic kinases, small GTPases, adapter proteins, and receptor tyrosine kinases (RTKs), particularly the epidermal growth factor receptor (EGFR). In NSCLC, the interplay between ECM and EGFR regulates ECM stiffness, angiogenesis, survival, adhesion, migration, and metastasis. Furthermore, some tumor-promoting ECM components (e.g., glycoproteins and proteoglycans) enhance activation of EGFR and loss of PTEN. On the other hand, other tumor-suppressing glycoproteins and -proteoglycans can inhibit EGFR activation, suppressing cell invasion and migration. Therefore, deciphering the molecular mechanisms underlying EGFR and ECM interactions might provide a better understanding of disease pathobiology and aid in developing therapeutic strategies. This review critically discusses the crosstalk between EGFR and ECM affecting cell behavior of NSCLC, as well as the involvement of ECM components in developing resistance to EGFR inhibition.
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Affiliation(s)
- Sarah Sayed Hassanein
- Biotechnology Program, Basic and Applied Sciences (BAS) Institute, Egypt-Japan University of Science and Technology (E-JUST), Alexandria, Egypt
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Ahmed Lotfy Abdel-Mawgood
- Biotechnology Program, Basic and Applied Sciences (BAS) Institute, Egypt-Japan University of Science and Technology (E-JUST), Alexandria, Egypt
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Rippa AL, Alpeeva EV, Vasiliev AV, Vorotelyak EA. Alveologenesis: What Governs Secondary Septa Formation. Int J Mol Sci 2021; 22:ijms222212107. [PMID: 34829987 PMCID: PMC8618598 DOI: 10.3390/ijms222212107] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 12/30/2022] Open
Abstract
The simplification of alveoli leads to various lung pathologies such as bronchopulmonary dysplasia and emphysema. Deep insight into the process of emergence of the secondary septa during development and regeneration after pneumonectomy, and into the contribution of the drivers of alveologenesis and neo-alveolarization is required in an efficient search for therapeutic approaches. In this review, we describe the formation of the gas exchange units of the lung as a multifactorial process, which includes changes in the actomyosin cytoskeleton of alveocytes and myofibroblasts, elastogenesis, retinoic acid signaling, and the contribution of alveolar mesenchymal cells in secondary septation. Knowledge of the mechanistic context of alveologenesis remains incomplete. The characterization of the mechanisms that govern the emergence and depletion of αSMA will allow for an understanding of how the niche of fibroblasts is changing. Taking into account the intense studies that have been performed on the pool of lung mesenchymal cells, we present data on the typing of interstitial fibroblasts and their role in the formation and maintenance of alveoli. On the whole, when identifying cell subpopulations in lung mesenchyme, one has to consider the developmental context, the changing cellular functions, and the lability of gene signatures.
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9
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Murine AGM single-cell profiling identifies a continuum of hemogenic endothelium differentiation marked by ACE. Blood 2021; 139:343-356. [PMID: 34517413 DOI: 10.1182/blood.2020007885] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 08/19/2021] [Indexed: 11/20/2022] Open
Abstract
In vitro generation and expansion of hematopoietic stem cells (HSCs) holds great promise for the treatment of any ailment that relies on bone marrow or blood transplantation. To achieve this, it is essential to resolve the molecular and cellular pathways that govern HSC formation in the embryo. HSCs first emerge in the aorta-gonad-mesonephros region (AGM) where a rare subset of endothelial cells, hemogenic endothelium (HE), undergoes an endothelial-to-hematopoietic transition (EHT). Here, we present full-length single-cell-RNA-sequencing of the EHT process with a focus on HE and dorsal aorta niche cells. By using Runx1b and Gfi1/1b transgenic reporter mouse models to isolate HE, we uncovered that the pre-HE to HE continuum is specifically marked by Angiotensin-I converting enzyme (ACE) expression. We established that HE cells begin to enter the cell cycle near the time of EHT initiation when their morphology still resembles endothelial cells. We further demonstrated that RUNX1 AGM niche cells consist of vascular smooth muscle cells and PDGFRa+ mesenchymal cells and can functionally support hematopoiesis. Overall, our study provides new insights into HE differentiation towards HSC and the role of AGM RUNX1+ niche cells in this process. Our expansive scRNA-seq datasets represents a powerful resource to investigate these processes further.
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10
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Oxidative Stress Mediates Vascular Tortuosity. Antioxidants (Basel) 2021; 10:antiox10060926. [PMID: 34200411 PMCID: PMC8228074 DOI: 10.3390/antiox10060926] [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: 04/15/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 11/17/2022] Open
Abstract
Vascular tortuosity is associated with various disorders and is being increasingly detected through advances in imaging techniques. The underlying mechanisms for vascular tortuosity, however, remain unclear. Here, we tested the hypothesis that oxidative stress mediates the generation of tortuous vessels. We used the bilateral common carotid artery (CCA) ligation model to induce vascular tortuosity. Both young and adult rats showed basilar artery tortuous morphological changes one month after bilateral CCA ligation. These tortuous changes were permanent but more pronounced in the adult rats. Microarray and real-time PCR analysis revealed that these tortuous changes were accompanied by the induction of oxidative stress-related genes. Moreover, the indicated model in rabbits showed that tortuous morphological changes to the basilar artery were suppressed by antioxidant treatment. These results are highly suggestive of the significance of oxidative stress in the development of vascular tortuosity. Although further studies will be needed to elucidate the possible mechanisms by which oxidative stress enhances vascular tortuosity, our study also points toward possible prophylaxis and treatment for vascular tortuosity.
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11
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Meng LH, Chen YX. Lipid accumulation and protein modifications of Bruch's membrane in age-related macular degeneration. Int J Ophthalmol 2021; 14:766-773. [PMID: 34012894 DOI: 10.18240/ijo.2021.05.19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 02/26/2021] [Indexed: 12/26/2022] Open
Abstract
Age-related macular degeneration (AMD) is a progressive retinal disease, which is the leading cause of blindness in western countries. There is an urgency to establish new therapeutic strategies that could prevent or delay the progression of AMD more efficiently. Until now, the pathogenesis of AMD has remained unclear, limiting the development of the novel therapy. Bruch's membrane (BM) goes through remarkable changes in AMD, playing a significant role during the disease course. The main aim of this review is to present the crucial processes that occur at the level of BM, with special consideration of the lipid accumulation and protein modifications. Besides, some therapies targeted at these molecules and the construction of BM in tissue engineering of retinal pigment epithelium (RPE) cells transplantation were listed. Hopefully, this review may provide a reference for researchers engaged in pathogenesis or management on AMD.
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Affiliation(s)
- Li-Hui Meng
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.,Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - You-Xin Chen
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.,Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
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12
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Role of Fibulins in Embryonic Stage Development and Their Involvement in Various Diseases. Biomolecules 2021; 11:biom11050685. [PMID: 34063320 PMCID: PMC8147605 DOI: 10.3390/biom11050685] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 12/24/2022] Open
Abstract
The extracellular matrix (ECM) plays an important role in the evolution of early metazoans, as it provides structural and biochemical support to the surrounding cells through the cell–cell and cell–matrix interactions. In multi-cellular organisms, ECM plays a pivotal role in the differentiation of tissues and in the development of organs. Fibulins are ECM glycoproteins, found in a variety of tissues associated with basement membranes, elastic fibers, proteoglycan aggregates, and fibronectin microfibrils. The expression profile of fibulins reveals their role in various developmental processes such as elastogenesis, development of organs during the embryonic stage, tissue remodeling, maintenance of the structural integrity of basement membrane, and elastic fibers, as well as other cellular processes. Apart from this, fibulins are also involved in the progression of human diseases such as cancer, cardiac diseases, congenital disorders, and chronic fibrotic disorders. Different isoforms of fibulins show a dual role of tumor-suppressive and tumor-promoting activities, depending on the cell type and cellular microenvironment in the body. Knockout animal models have provided deep insight into their role in development and diseases. The present review covers details of the structural and expression patterns, along with the role of fibulins in embryonic development and disease progression, with more emphasis on their involvement in the modulation of cancer diseases.
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Becker J, Schwoch S, Zelent C, Sitte M, Salinas G, Wilting J. Transcriptome Analysis of Hypoxic Lymphatic Endothelial Cells Indicates Their Potential to Contribute to Extracellular Matrix Rearrangement. Cells 2021; 10:cells10051008. [PMID: 33923324 PMCID: PMC8145299 DOI: 10.3390/cells10051008] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/12/2021] [Accepted: 04/14/2021] [Indexed: 12/27/2022] Open
Abstract
Lymphedema (LE) affects millions of people worldwide. It is a chronic progressive disease with massive development of fibrosclerosis when untreated. There is no pharmacological treatment of lymphedema. The disease is associated with swelling of the interstitium of the affected organ, mostly arm or leg, impressive development of adipose tissue, fibrosis and sclerosis with accumulation of huge amounts of collagen, and Papillomatosis cutis. Malnutrition and reduced oxygenation of the affected tissues is a hallmark of lymphedema. Here, we investigated if the hypoxia of lymphatic endothelial cells (LECs) might contribute to fibrosis. We applied RNASeq and qPCR to study the concordant changes of the exome of three human foreskin-derived LEC isolates after 4 days of hypoxia (1% O2) vs. normoxia (21% O2). Of the approximately 16,000 genes expressed in LECs, 162 (1%) were up- or down-regulated by hypoxia. Of these, 21 genes have important functions in the production or modification of the extracellular matrix (ECM). In addition to the down-regulation of elastin, we found up-regulation of druggable enzymes and regulators such as the long non-coding RNA H19, inter-alpha-trypsin inhibitor heavy chain family member 5 (ITIH5), lysyl-oxidase (LOX), prolyl 4-hydroxylase subunit alpha 1 (P4HA1), procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2), and others that are discussed in the paper. Initial lymphatics do not produce a continuous basement membrane; however, our study shows that hypoxic LECs have an unexpectedly high ability to alter the ECM.
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Affiliation(s)
- Jürgen Becker
- Department of Anatomy and Cell Biology, University Medical School Göttingen, 37075 Göttingen, Germany; (J.B.); (S.S.); (C.Z.)
| | - Sonja Schwoch
- Department of Anatomy and Cell Biology, University Medical School Göttingen, 37075 Göttingen, Germany; (J.B.); (S.S.); (C.Z.)
| | - Christina Zelent
- Department of Anatomy and Cell Biology, University Medical School Göttingen, 37075 Göttingen, Germany; (J.B.); (S.S.); (C.Z.)
| | - Maren Sitte
- NGS-Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Center Göttingen, 37075 Göttingen, Germany; (M.S.); (G.S.)
| | - Gabriela Salinas
- NGS-Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Center Göttingen, 37075 Göttingen, Germany; (M.S.); (G.S.)
| | - Jörg Wilting
- Department of Anatomy and Cell Biology, University Medical School Göttingen, 37075 Göttingen, Germany; (J.B.); (S.S.); (C.Z.)
- Correspondence:
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Yuan R, Li Y, Yang B, Jin Z, Xu J, Shao Z, Miao H, Ren T, Yang Y, Li G, Song X, Hu Y, Wang X, Huang Y, Liu Y. LOXL1 exerts oncogenesis and stimulates angiogenesis through the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis in ICC. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:797-810. [PMID: 33614230 PMCID: PMC7868718 DOI: 10.1016/j.omtn.2021.01.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023]
Abstract
Aberrant expression of lysyl oxidase-like 1 (LOXL1) reportedly leads to fibrous diseases. Recent studies have revealed its role in cancers. In this study, we observed an elevated level of LOXL1 in the tissues and sera of patients with intrahepatic cholangiocarcinoma (ICC) compared with levels in nontumor tissues and sera of unaffected individuals. Overexpression of LOXL1 in RBE and 9810 cell lines promoted cell proliferation, colony formation, and metastasis in vivo and in vitro and induced angiogenesis. In contrast, depletion of LOXL1 showed the opposite effects. We further showed that LOXL1 interacted with fibulin 5 (FBLN5), which regulates angiogenesis, through binding to the αvβ3 integrin in an arginine-glycine-aspartic (Arg-Gly-Asp) domain-dependent mechanism and enhanced the focal adhesion kinase (FAK)-mitogen-activated protein kinase (MAPK) signaling pathway inside vascular endothelial cells. Our findings shed light on the molecular mechanism underlying LOXL1 regulation of angiogenesis in ICC development and indicate that the LOXL1-FBLN5/αvβ3 integrin/FAK-MAPK axis might be the critical pathological link leading to angiogenesis in ICC.
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Affiliation(s)
- Ruiyan Yuan
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Bo Yang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Department of Surgery, First Affiliated Hospital of Wenzhou Medical University, Baixiang Road, Wenzhou 325000, China
| | - Zhaohui Jin
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jiacheng Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China
| | - Ziyu Shao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Huijie Miao
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Tai Ren
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yang Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Guoqiang Li
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiaoling Song
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yunping Hu
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xu’an Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
| | - Ying Huang
- State Key Laboratory of Oncogenes and Related Genes, Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
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Gharesouran J, Hosseinzadeh H, Ghafouri-Fard S, Jabbari Moghadam Y, Ahmadian Heris J, Jafari-Rouhi AH, Taheri M, Rezazadeh M. New insight into clinical heterogeneity and inheritance diversity of FBLN5-related cutis laxa. Orphanet J Rare Dis 2021; 16:51. [PMID: 33509220 PMCID: PMC7845118 DOI: 10.1186/s13023-021-01696-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 01/18/2021] [Indexed: 12/21/2022] Open
Abstract
Background FBLN5-related cutis laxa (CL) is a rare disorder that involves elastic fiber-enriched tissues and is characterized by lax skin and variable systemic involvement such as pulmonary emphysema, arterial involvement, inguinal hernias, hollow viscus diverticula and pyloric stenosis. This type of CL follows mostly autosomal recessive (AR) and less commonly autosomal dominant patterns of inheritance. Results In this study, we detected a novel homozygous missense variant in exon 6 of FBLN5 gene (c.G544C, p.A182P) by using whole exome sequencing in a consanguineous Iranian family with two affected members. Our twin patients showed some of the clinical manifestation of FBLN5-related CL but they did not present pulmonary complications, gastrointestinal and genitourinary abnormalities. The notable thing about this monozygotic twin sisters is that only one of them showed ventricular septal defect, suggesting that this type of CL has intrafamilial variability. Co-segregation analysis showed the patients’ parents and relatives were heterozygous for detected variation suggesting AR form of the CL. In silico prediction tools showed that this mutation is pathogenic and 3D modeling of the normal and mutant protein revealed relative structural alteration of fibulin-5 suggesting that the A182P can contribute to the CL phenotype via the combined effect of lack of protein function and partly misfolding-associated toxicity. Conclusion We underlined the probable roles and functions of the involved domain of fibulin-5 and proposed some possible mechanisms involved in AR form of FBLN5-related CL. However, further functional studies and subsequent clinical and molecular investigations are needed to confirm our findings.
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Affiliation(s)
- Jalal Gharesouran
- Molecular Genetics Division, GMG Center, Tabriz, Iran.,Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Hosseinzadeh
- Molecular Genetics Division, GMG Center, Tabriz, Iran.,Division of Medical Genetics, Tabriz Children's Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yalda Jabbari Moghadam
- Department of Otorhinolaryngology, School of Medicine, Sina Medical Research and Training Hospital, Children Medical Research and Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Pediatrics, School of Medicine, Children Medical Research and Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Rezazadeh
- Department of Medical Genetics, Tabriz University of Medical Sciences, Tabriz, Iran.
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Safka Brozkova D, Stojkovic T, Haberlová J, Mazanec R, Windhager R, Fernandes Rosenegger P, Hacker S, Züchner S, Kochański A, Leonard-Louis S, Francou B, Latour P, Senderek J, Seeman P, Auer-Grumbach M. Demyelinating Charcot-Marie-Tooth neuropathy associated with FBLN5 mutations. Eur J Neurol 2020; 27:2568-2574. [PMID: 32757322 DOI: 10.1111/ene.14463] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 07/29/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND PURPOSE Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 whilst point mutations in PMP22 and other genes are rare causes. Recently, FBLN5 mutations have been reported in CMT1 families. METHODS Individuals with FBLN5-associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients' visits at our centres or primary care sites. RESULTS Nineteen CMT1 families containing 38 carriers of three different FBLN5 missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the common PMP22 duplication, individuals with FBLN5 variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits. CONCLUSIONS Our study confirms the relevance of FBLN5 mutations in CMT1. It is proposed to include FBLN5 in the genetic work-up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement. FBLN5-associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme.
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Affiliation(s)
- D Safka Brozkova
- DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - T Stojkovic
- Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, Institut de Myologie, APHP, G-H Pitié-Salpêtrière, Paris, France
| | - J Haberlová
- DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - R Mazanec
- Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - R Windhager
- Department of Orthopaedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - P Fernandes Rosenegger
- Department of Orthopaedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - S Hacker
- Department of Orthopaedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
| | - S Züchner
- Dr John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - A Kochański
- Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - S Leonard-Louis
- Unité de Pathologie Neuromusculaire, Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, APHP, G-H Pitié-Salpêtrière, Paris, France
| | - B Francou
- Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, APHP, Hôpital Kremlin-Bicêtre, Paris, France
| | - P Latour
- Service de Biochimie et Biologie Moléculaire Grand Est, CHU de Lyon, GH Est, Bron, France
| | - J Senderek
- Department of Neurology, Friedrich-Baur-Institute, LMU Munich, Munich, Germany
| | - P Seeman
- DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - M Auer-Grumbach
- Department of Orthopaedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria
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17
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Acat M, Sengoren Dikis O, Us Dulger S, Akbay E, Karakaya E, Haskul I, Chousein EG. Fibulins: a new biomarker for pulmonary thromboembolism? Aging Male 2020; 23:556-563. [PMID: 30632874 DOI: 10.1080/13685538.2018.1542674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Fibulin-1, -2, -4, and -5 have important role in several vascular diseases. We aimed to investigate if fibulin-4 and -5 can be used as a biomarker for pulmonary thromboembolism (PTE). METHODS This is a prospective case control study. Thirthy patients diagnosed with PTE and 31 in the control group. Data on demographic characteristics, length of hospital stay, blood cell counts, troponin and BNP levels, arterial blood gases, radiological reports, indication for thromboembolitic treatment, intensive care unit (ICU) requirement, and loss of life were recorded for the patients group. Serum Fibulin-4 and Fibulin-5 levels were measured. RESULTS Fibulin 4 levels correlated positively with female gender (p < .01, r = 0.433). Positive results were found in 14 (46.7%) patients for PESI.0.1; in 7 (23.3%) patients for D-dimer; in 7 (23.3%) patients for troponin-I; in 7(23.3%) patients for BNP. Median values for Fibulin 4 level were significantly higher in patients positive for BNP. Fibulin-5 level was found to be correlated with the presence of embolism (p = .041, r = 0.263). CONCLUSIONS Fibulin-4 and -5 have been shown to be relevant to cardiovascular biology and diseases. Experimental studies and observations in humans show that they may play a role in several cardiovascular diseases particularly pulmonary embolism.
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Affiliation(s)
- Murat Acat
- Department of Pulmonary Diseases, Karabuk University, Karabuk Training and Research Hospital, Karabuk, Turkey
| | - Ozlem Sengoren Dikis
- Department of Pulmonary Diseases, Health Sciences University Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Seyhan Us Dulger
- Department of Pulmonary Diseases, Health Sciences University Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey
| | - Ertan Akbay
- Department of Cardiology Diseases, Karabuk University, Karabuk Training and Research Hospital, Karabuk, Turkey
| | - Ekrem Karakaya
- Department of Pulmonary Diseases, Karabuk University, Karabuk Training and Research Hospital, Karabuk, Turkey
| | - Ismail Haskul
- Department of Biochemistry, Karabuk University, Karabuk Training and Research Hospital, Karabuk, Turkey
| | - Efsun Gonca Chousein
- Department of Pulmonary Diseases, Health Sciences University Yedikule Training and Research Hospital, Istanbul, Turkey
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Boezio GL, Bensimon-Brito A, Piesker J, Guenther S, Helker CS, Stainier DY. Endothelial TGF-β signaling instructs smooth muscle cell development in the cardiac outflow tract. eLife 2020; 9:57603. [PMID: 32990594 PMCID: PMC7524555 DOI: 10.7554/elife.57603] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 09/09/2020] [Indexed: 12/14/2022] Open
Abstract
The development of the cardiac outflow tract (OFT), which connects the heart to the great arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) cells. Defects in OFT development can lead to severe malformations, including aortic aneurysms, which are frequently associated with impaired TGF-β signaling. To better understand the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the TGF-β receptor Alk5 and found a strikingly specific dilation of the OFT: alk5-/- OFTs exhibit increased EC numbers as well as extracellular matrix (ECM) and SMC disorganization. Surprisingly, endothelial-specific alk5 overexpression in alk5-/- rescues the EC, ECM, and SMC defects. Transcriptomic analyses reveal downregulation of the ECM gene fibulin-5, which when overexpressed in ECs ameliorates OFT morphology and function. These findings reveal a new requirement for endothelial TGF-β signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.
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Affiliation(s)
- Giulia Lm Boezio
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Anabela Bensimon-Brito
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Janett Piesker
- Scientific Service Group Microscopy, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Stefan Guenther
- Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Christian Sm Helker
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Didier Yr Stainier
- Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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19
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Livingstone I, Uversky VN, Furniss D, Wiberg A. The Pathophysiological Significance of Fibulin-3. Biomolecules 2020; 10:E1294. [PMID: 32911658 PMCID: PMC7563619 DOI: 10.3390/biom10091294] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/03/2020] [Accepted: 09/04/2020] [Indexed: 02/07/2023] Open
Abstract
Fibulin-3 (also known as EGF-containing fibulin extracellular matrix protein 1 (EFEMP1)) is a secreted extracellular matrix glycoprotein, encoded by the EFEMP1 gene that belongs to the eight-membered fibulin protein family. It has emerged as a functionally unique member of this family, with a diverse array of pathophysiological associations predominantly centered on its role as a modulator of extracellular matrix (ECM) biology. Fibulin-3 is widely expressed in the human body, especially in elastic-fibre-rich tissues and ocular structures, and interacts with enzymatic ECM regulators, including tissue inhibitor of metalloproteinase-3 (TIMP-3). A point mutation in EFEMP1 causes an inherited early-onset form of macular degeneration called Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). EFEMP1 genetic variants have also been associated in genome-wide association studies with numerous complex inherited phenotypes, both physiological (namely, developmental anthropometric traits) and pathological (many of which involve abnormalities of connective tissue function). Furthermore, EFEMP1 expression changes are implicated in the progression of numerous types of cancer, an area in which fibulin-3 has putative significance as a therapeutic target. Here we discuss the potential mechanistic roles of fibulin-3 in these pathologies and highlight how it may contribute to the development, structural integrity, and emergent functionality of the ECM and connective tissues across a range of anatomical locations. Its myriad of aetiological roles positions fibulin-3 as a molecule of interest across numerous research fields and may inform our future understanding and therapeutic approach to many human diseases in clinical settings.
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Affiliation(s)
- Imogen Livingstone
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford OX3 7LD, UK; (I.L.); (D.F.)
| | - Vladimir N. Uversky
- Laboratory of New Methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Pushchino 142290, Moscow Region, Russia;
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Dominic Furniss
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford OX3 7LD, UK; (I.L.); (D.F.)
- Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Akira Wiberg
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford OX3 7LD, UK; (I.L.); (D.F.)
- Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
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20
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Ma Z, Mao C, Jia Y, Fu Y, Kong W. Extracellular matrix dynamics in vascular remodeling. Am J Physiol Cell Physiol 2020; 319:C481-C499. [PMID: 32579472 DOI: 10.1152/ajpcell.00147.2020] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Vascular remodeling is the adaptive response to various physiological and pathophysiological alterations that are closely related to aging and vascular diseases. Understanding the mechanistic regulation of vascular remodeling may be favorable for discovering potential therapeutic targets and strategies. The extracellular matrix (ECM), including matrix proteins and their degradative metalloproteases, serves as the main component of the microenvironment and exhibits dynamic changes during vascular remodeling. This process involves mainly the altered composition of matrix proteins, metalloprotease-mediated degradation, posttranslational modification of ECM proteins, and altered topographical features of the ECM. To date, adequate studies have demonstrated that ECM dynamics also play a critical role in vascular remodeling in various diseases. Here, we review these related studies, summarize how ECM dynamics control vascular remodeling, and further indicate potential diagnostic biomarkers and therapeutic targets in the ECM for corresponding vascular diseases.
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Affiliation(s)
- Zihan Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Chenfeng Mao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Yiting Jia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Yi Fu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
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Gene Expression Profiling of the Extracellular Matrix Signature in Macrophages of Different Activation Status: Relevance for Skin Wound Healing. Int J Mol Sci 2019; 20:ijms20205086. [PMID: 31615030 PMCID: PMC6829210 DOI: 10.3390/ijms20205086] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 10/03/2019] [Accepted: 10/11/2019] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix (ECM) provides structural support for tissue architecture and is a major effector of cell behavior during skin repair and inflammation. Macrophages are involved in all stages of skin repair but only limited knowledge exists about macrophage-specific expression and regulation of ECM components. In this study, we used transcriptome profiling and bioinformatic analysis to define the unique expression of ECM-associated genes in cultured macrophages. Characterization of the matrisome revealed that most genes were constitutively expressed and that several genes were uniquely regulated upon interferon gamma (IFNγ) and dexamethasone stimulation. Among those core matrisome and matrisome-associated components transforming growth factor beta (TGFβ)-induced, matrix metalloproteinase 9 (MMP9), elastin microfibril interfacer (EMILIN)-1, netrin-1 and gliomedin were also present within the wound bed at time points that are characterized by profound macrophage infiltration. Hence, macrophages are a source of ECM components in vitro as well as during skin wound healing, and identification of these matrisome components is a first step to understand the role and therapeutic value of ECM components in macrophages and during wound healing.
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22
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Recent updates on the molecular network of elastic fiber formation. Essays Biochem 2019; 63:365-376. [PMID: 31395654 DOI: 10.1042/ebc20180052] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/12/2019] [Accepted: 07/26/2019] [Indexed: 12/20/2022]
Abstract
Elastic fibers confer elasticity and recoiling to tissues and organs and play an essential role in induction of biochemical responses in a cell against mechanical forces derived from the microenvironment. The core component of elastic fibers is elastin (ELN), which is secreted as the monomer tropoelastin from elastogenic cells, and undergoes self-aggregation, cross-linking and deposition on to microfibrils, and assemble into insoluble ELN polymers. For elastic fibers to form, a microfibril scaffold (primarily formed by fibrillin-1 (FBN1)) is required. Numerous elastic fiber-associated proteins are involved in each step of elastogenesis and they instruct and/or facilitate the elastogenesis processes. In this review, we designated five proteins as key molecules in elastic fiber formation, including ELN, FBN1, fibulin-4 (FBLN4), fibulin-5 (FBLN5), and latent TGFβ-binding protein-4 (LTBP4). ELN and FBN1 serve as building blocks for elastic fibers. FBLN5, FBLN4 and LTBP4 have been demonstrated to play crucial roles in elastogenesis through knockout studies in mice. Using these molecules as a platform and expanding the elastic fiber network through the generation of an interactome map, we provide a concise review of elastogenesis with a recent update as well as discuss various biological functions of elastic fiber-associated proteins beyond elastogenesis in vivo.
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Xu H, Chen S, Zhang H, Zou Y, Zhao J, Yu J, Le S, Cui J, Jiang L, Wu J, Xia J. Network-based analysis reveals novel gene signatures in the peripheral blood of patients with sporadic nonsyndromic thoracic aortic aneurysm. J Cell Physiol 2019; 235:2478-2491. [PMID: 31489966 DOI: 10.1002/jcp.29152] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 08/23/2019] [Indexed: 12/11/2022]
Abstract
Thoracic aortic aneurysm (TAA), a serious cardiovascular disease that causes morbidity and mortality worldwide. At present, few biomarkers can accurately diagnose the appearance of TAA before dissection or rupture. Our research has the intention to investigate the developing applicable biomarkers for TAA promising clinically diagnostic biomarkers or probable regulatory targets for TAA. In our research, we built correlation networks utilizing the expression profile of peripheral blood mononuclear cell obtained from a public microarray data set (GSE9106). Furthermore, we chose the turquoise module, which has the strongest significance with TAA and was further analyzed. Fourteen genes that overlapped with differentially expressed proteins in the medial aortic layer were obtained. Subsequently, we verified the results applying quantitative polymerase chain reaction (Q-PCR) to our clinical specimen. In general, the Q-PCR results coincide with the majority of the expression profile. Fascinatingly, a notable change occurred in CLU, DES, MYH10, and FBLN5. In summary, using weighted gene coexpression analysis, our study indicates that CLU, DES, MYH10, and FBLN5 were identified and validated to be related to TAA and might be candidate biomarkers or therapeutic targets for TAA.
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Affiliation(s)
- Heng Xu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shanshan Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hao Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yanqiang Zou
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jing Zhao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jizhang Yu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sheng Le
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jikai Cui
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lang Jiang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jie Wu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Mori H, Yamada H, Toyama K, Takahashi K, Akama T, Inoue T, Nakamura T. Developmental and age-related changes to the elastic lamina of Bruch’s membrane in mice. Graefes Arch Clin Exp Ophthalmol 2018; 257:289-301. [DOI: 10.1007/s00417-018-4184-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 10/10/2018] [Accepted: 11/09/2018] [Indexed: 01/28/2023] Open
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Roles of short fibulins, a family of matricellular proteins, in lung matrix assembly and disease. Matrix Biol 2018; 73:21-33. [DOI: 10.1016/j.matbio.2018.02.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/26/2017] [Accepted: 02/01/2018] [Indexed: 12/19/2022]
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Extracellular Interactions between Fibulins and Transforming Growth Factor (TGF)-β in Physiological and Pathological Conditions. Int J Mol Sci 2018; 19:ijms19092787. [PMID: 30227601 PMCID: PMC6163299 DOI: 10.3390/ijms19092787] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 12/25/2022] Open
Abstract
Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell–matrix interactions, including thrombospondins, SPARC (Secreted Protein Acidic and Rich in Cystein), tenascins, osteopontin, periostin, and fibulins. Fibulin family members consist of eight ECM glycoproteins characterized by a tandem array of calcium-binding epidermal growth factor-like modules and a common C-terminal domain. Fibulins not only participate in structural integrity of basement membrane and elastic fibers, but also serve as mediators for cellular processes and tissue remodeling as they are highly upregulated during embryonic development and certain disease processes, especially at the sites of epithelial–mesenchymal transition (EMT). Emerging studies have indicated a close relationship between fibulins and TGF-β signaling, but each fibulin plays a different role in a context-dependent manner. In this review, regulatory interactions between fibulins and TGF-β signaling are discussed. Understanding biological roles of fibulins in TGF-β regulation may introduce new insights into the pathogenesis of some human diseases.
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Fibulin-5 promotes airway smooth muscle cell proliferation and migration via modulating Hippo-YAP/TAZ pathway. Biochem Biophys Res Commun 2017; 493:985-991. [PMID: 28942149 DOI: 10.1016/j.bbrc.2017.09.105] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 09/19/2017] [Indexed: 01/27/2023]
Abstract
Asthma is a common chronic disease mainly occurs from childhood. Increased airway smooth muscle mass is involved in the pathogenesis of asthma. Fibulin-5 was upregulated in the lung tissues of patients with COPD and idiopathic pulmonary fibrosis. This study aimed to investigate Fibulin-5 expression in asthmatic patients and the effect and mechanism of Fibulin-5 on the proliferation and migration of airway smooth muscle cells (ASMCs). The expression of Fibulin-5, YAP, and TAZ in the induced sputum of 38 asthmatic children (19 mild and 19 moderate asthmatics) and 19 healthy controls was determined. The effects and mechanisms of Fibulin-5 on the proliferation and migration of ASMCs were analyzed through upregulating Fibulin-5. We found compared with healthy controls, the expression of Fibulin-5, YAP, and TAZ was increased in the induced sputum of asthmatic children and much higher in moderate asthmatics. Fibulin-5 overexpression promoted the proliferation and migration of ASMCs, upregulated the expression of YAP and TAZ, and reduced the levels of p-YAP and p-TAZ. YAP inhibitor (Peptide 17) abrogated the proliferation and migration of ASMCs induced by Fibulin-5 overexpression in a dose-dependent manner. Additionally, Fibulin-5 overexpression enhanced its binding capacity of β1 integrin, and β1 integrin blocking antibody partly reversed the effect of Fibulin-5 overexpression on the levels of YAP and TAZ. In conclusion, Fibulin-5 expression is correlated with the pathogenesis of childhood asthma. It may function at least partly through binding to β1 integrin and modulating Hippo-YAP/TAZ pathway to promote the proliferation and migration of ASMCs.
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Halabi CM, Broekelmann TJ, Lin M, Lee VS, Chu ML, Mecham RP. Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries. SCIENCE ADVANCES 2017; 3:e1602532. [PMID: 28508064 PMCID: PMC5415335 DOI: 10.1126/sciadv.1602532] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 02/28/2017] [Indexed: 06/07/2023]
Abstract
Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4's suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissue-specific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly.
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Affiliation(s)
- Carmen M. Halabi
- Division of Nephrology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Thomas J. Broekelmann
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Michelle Lin
- Division of Nephrology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Vivian S. Lee
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Mon-Li Chu
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Robert P. Mecham
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Orriols M, Varona S, Aguiló S, Galán M, Martínez González J, Rodríguez C. [Inflammation inhibits vascular fibulin-5 expression: Involvement of transcription factor SOX9]. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2016; 28:271-280. [PMID: 27692634 DOI: 10.1016/j.arteri.2016.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 05/27/2016] [Accepted: 06/03/2016] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Fibulin-5 (FBLN5) is an elastogenic protein critically involved in extracellular matrix (ECM) remodelling, a key process in abdominal aortic aneurysm (AAA). However, the possible contribution of FBLN5 to AAA development has not been addressed. METHODS Expression levels were determined by real-time PCR and Western blot in human abdominal aorta from patients with AAA or healthy donors, as well as in human aortic vascular smooth muscle cells (VSMC). Lentiviral transduction, transient transfections, and chromatin immunoprecipitation (ChIP) assays were also performed. RESULTS The expression of FBLN5 in human AAA was significantly lower than in healthy donors. FBLN5 mRNA and protein levels and their secretion to the extracellular environment were down-regulated in VSMC exposed to inflammatory stimuli. Interestingly, FBLN5 transcriptional activity was inhibited by TNFα and lipopolysaccharide (LPS), and depends on a SOX response element. In fact, SOX9 expression was reduced in VMSC induced by inflammatory mediators and in human AAA, and correlated with that of FBLN5. Furthermore, SOX9 over-expression limited the reduction of FBLN5 expression induced by cytokines in VSMC. Finally, it was observed that SOX9 interacts with FBLN5 promoter, and that this binding was reduced upon TNFα exposure. CONCLUSIONS FBLN5 downregulation in human AAA could contribute to extracellular matrix remodelling induced by the inflammatory component of the disease.
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Affiliation(s)
- Mar Orriols
- Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España
| | - Saray Varona
- Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España
| | - Silvia Aguiló
- Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España
| | - María Galán
- Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España
| | | | - Cristina Rodríguez
- Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona, España.
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Topalovski M, Hagopian M, Wang M, Brekken RA. Hypoxia and Transforming Growth Factor β Cooperate to Induce Fibulin-5 Expression in Pancreatic Cancer. J Biol Chem 2016; 291:22244-22252. [PMID: 27531748 DOI: 10.1074/jbc.m116.730945] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Indexed: 12/17/2022] Open
Abstract
The deposition of extracellular matrix (ECM) is a defining feature of pancreatic ductal adenocarcinoma (PDA), where ECM signaling can promote cancer cell survival and epithelial plasticity programs. However, ECM signaling can also limit PDA tumor growth by producing cytotoxic levels of reactive oxygen species. For example, excess fibronectin stimulation of α5β1 integrin on stromal cells in PDA results in reduced angiogenesis and increased tumor cell apoptosis because of oxidative stress. Fibulin-5 (Fbln5) is a matricellular protein that blocks fibronectin-integrin interaction and thus directly limits ECM-driven reactive oxygen species production and supports PDA progression. Compared with normal pancreatic tissue, Fbln5 is expressed abundantly in the stroma of PDA; however, the mechanisms underlying the stimulation of Fbln5 expression in PDA are undefined. Using in vitro and in vivo approaches, we report that hypoxia triggers Fbln5 expression in a TGF-β- and PI3K-dependent manner. Pharmacologic inhibition of TGF-β receptor, PI3K, or protein kinase B (AKT) was found to block hypoxia-induced Fbln5 expression in mouse embryonic fibroblasts and 3T3 fibroblasts. Moreover, tumor-associated fibroblasts from mouse PDA were also responsive to TGF-β receptor and PI3K/AKT inhibition with regard to suppression of Fbln5. In genetically engineered mouse models of PDA, therapy-induced hypoxia elevated Fbln5 expression, whereas pharmacologic inhibition of TGF-β signaling reduced Fbln5 expression. These findings offer insight into the signaling axis that induces Fbln5 expression in PDA and a potential strategy to block its production.
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Affiliation(s)
- Mary Topalovski
- From the Hamon Center for Therapeutic Oncology Research, Cancer Biology Graduate Program
| | | | - Miao Wang
- From the Hamon Center for Therapeutic Oncology Research
| | - Rolf A Brekken
- From the Hamon Center for Therapeutic Oncology Research, Cancer Biology Graduate Program, Division of Surgical Oncology, Department of Surgery, and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593
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Chan W, Ismail H, Mayaki D, Sanchez V, Tiedemann K, Davis EC, Hussain SNA. Fibulin-5 Regulates Angiopoietin-1/Tie-2 Receptor Signaling in Endothelial Cells. PLoS One 2016; 11:e0156994. [PMID: 27304216 PMCID: PMC4909301 DOI: 10.1371/journal.pone.0156994] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 05/23/2016] [Indexed: 11/24/2022] Open
Abstract
Background Fibulin-5 is an extracellular matrix glycoprotein that plays critical roles in vasculogenesis and embryonic development. Deletion of Fibulin-5 in mice results in enhanced skin vascularization and upregulation of the angiogenesis factor angiopoietin-1 (Ang-1), suggesting that Fibulin-5 functions as an angiogenesis inhibitor. In this study, we investigate the inhibitory effects of Fibulin-5 on Ang-1/TIE-2 receptor pathway signaling and cell survival in human endothelial cells. Methodology/Principal Findings Recombinant wild-type and RGE-mutant Fibulin-5 proteins were generated through stable transfection of HEK293 and CHO cells, respectively. In vitro solid phase binding assays using pure proteins revealed that wild-type Fibulin-5 does not bind to Ang-1 or TIE-2 proteins but strongly binds to heparin. Binding assays using human umbilical vein endothelial cells (HUVECs) indicated that wild-type Fibulin-5 strongly binds to cells but RGE-mutant Fibulin-5, which is incapable of binding to integrins, does not. Pre-incubation of HUVECs for 1 hr with Fibulin-5 significantly increased caspase 3/7 activity, ERK1/2 phosphorylation, and expressions of the transcription factor early growth response 1 (EGR1) and the dual-specificity phosphatase 5 (DUSP5). Fibulin-5 also strongly attenuated Ang-1-induced TIE-2 and AKT phosphorylation, decreased Ang-1-induced expressions of the transcription factors Inhibitor of DNA Binding 1 (ID1) and Kruppel-like Factor 2 (KLF2), and reversed the inhibitory effect of Ang-1 on serum deprivation-induced cytotoxicity and caspase 3/7 activity. Conclusion/Significance We conclude that Fibulin-5 strongly binds to the endothelial cell surface through heparin-sulfate proteoglycans and possibly integrins and that it exerts strong anti-angiogenic effects by reducing endothelial cell viability and interfering with the signaling pathways of the Ang-1/TIE-2 receptor axis.
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Affiliation(s)
- Wilson Chan
- Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada
| | - Hodan Ismail
- Translational Research in Respiratory Diseases, McGill University Health Centre, and Meakins-Christie Laboratories, Department of Medicine, McGill University, Montréal, QC, Canada
| | - Dominique Mayaki
- Translational Research in Respiratory Diseases, McGill University Health Centre, and Meakins-Christie Laboratories, Department of Medicine, McGill University, Montréal, QC, Canada
| | - Veronica Sanchez
- Translational Research in Respiratory Diseases, McGill University Health Centre, and Meakins-Christie Laboratories, Department of Medicine, McGill University, Montréal, QC, Canada
| | - Kerstin Tiedemann
- Faculty of Dentistry, McGill University and Shriners Hospital for Children, Montréal, QC, Canada
| | - Elaine C. Davis
- Department of Anatomy and Cell Biology, McGill University, Montréal, QC, Canada
| | - Sabah N. A. Hussain
- Translational Research in Respiratory Diseases, McGill University Health Centre, and Meakins-Christie Laboratories, Department of Medicine, McGill University, Montréal, QC, Canada
- * E-mail:
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Lambert NG, ElShelmani H, Singh MK, Mansergh FC, Wride MA, Padilla M, Keegan D, Hogg RE, Ambati BK. Risk factors and biomarkers of age-related macular degeneration. Prog Retin Eye Res 2016; 54:64-102. [PMID: 27156982 DOI: 10.1016/j.preteyeres.2016.04.003] [Citation(s) in RCA: 249] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 04/01/2016] [Accepted: 04/12/2016] [Indexed: 02/03/2023]
Abstract
A biomarker can be a substance or structure measured in body parts, fluids or products that can affect or predict disease incidence. As age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, much research and effort has been invested in the identification of different biomarkers to predict disease incidence, identify at risk individuals, elucidate causative pathophysiological etiologies, guide screening, monitoring and treatment parameters, and predict disease outcomes. To date, a host of genetic, environmental, proteomic, and cellular targets have been identified as both risk factors and potential biomarkers for AMD. Despite this, their use has been confined to research settings and has not yet crossed into the clinical arena. A greater understanding of these factors and their use as potential biomarkers for AMD can guide future research and clinical practice. This article will discuss known risk factors and novel, potential biomarkers of AMD in addition to their application in both academic and clinical settings.
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Affiliation(s)
- Nathan G Lambert
- Ambati Lab, John A. Moran Eye Center, 65 Mario Capecchi Drive, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT, USA.
| | - Hanan ElShelmani
- Ocular Development and Neurobiology Research Group, Zoology Department, School of Natural Sciences, University of Dublin, Trinity College, Dublin 2, Ireland.
| | - Malkit K Singh
- Ambati Lab, John A. Moran Eye Center, 65 Mario Capecchi Drive, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT, USA.
| | - Fiona C Mansergh
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
| | - Michael A Wride
- Ocular Development and Neurobiology Research Group, Zoology Department, School of Natural Sciences, University of Dublin, Trinity College, Dublin 2, Ireland.
| | - Maximilian Padilla
- Ambati Lab, John A. Moran Eye Center, 65 Mario Capecchi Drive, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT, USA.
| | - David Keegan
- Mater Misericordia Hospital, Eccles St, Dublin 7, Ireland.
| | - Ruth E Hogg
- Centre for Experimental Medicine, Institute of Clinical Science Block A, Grosvenor Road, Belfast, Co.Antrim, Northern Ireland, UK.
| | - Balamurali K Ambati
- Ambati Lab, John A. Moran Eye Center, 65 Mario Capecchi Drive, Salt Lake City, UT, USA; Department of Ophthalmology & Visual Sciences, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT, USA.
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Hu L, Dong MX, Zhao H, Xu GH, Qin XY. Fibulin-5: a novel biomarker for evaluating severity and predicting prognosis in patients with acute intracerebral haemorrhage. Eur J Neurol 2016; 23:1195-201. [PMID: 27106135 DOI: 10.1111/ene.13013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 03/01/2016] [Indexed: 12/20/2022]
Affiliation(s)
- L. Hu
- Department of Neurology; the First Affiliated Hospital of Chongqing Medical University; Chongqing China
- Department of Neurology; the Fifth People's Hospital of Chongqing; Chongqing China
| | - M.-X. Dong
- Department of Neurology; the First Affiliated Hospital of Chongqing Medical University; Chongqing China
| | - H. Zhao
- Department of Neurology; the First Affiliated Hospital of Chongqing Medical University; Chongqing China
| | - G.-H. Xu
- Department of Neurology; the First Affiliated Hospital of Chongqing Medical University; Chongqing China
| | - X.-Y. Qin
- Department of Neurology; the First Affiliated Hospital of Chongqing Medical University; Chongqing China
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Orriols M, Varona S, Martí-Pàmies I, Galán M, Guadall A, Escudero JR, Martín-Ventura JL, Camacho M, Vila L, Martínez-González J, Rodríguez C. Down-regulation of Fibulin-5 is associated with aortic dilation: role of inflammation and epigenetics. Cardiovasc Res 2016; 110:431-42. [DOI: 10.1093/cvr/cvw082] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 04/14/2016] [Indexed: 01/04/2023] Open
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Topalovski M, Brekken RA. Matrix control of pancreatic cancer: New insights into fibronectin signaling. Cancer Lett 2015; 381:252-8. [PMID: 26742464 DOI: 10.1016/j.canlet.2015.12.027] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 12/18/2015] [Accepted: 12/19/2015] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease that resists most current therapies. A defining characteristic of PDA is an intense fibrotic response that promotes tumor cell invasion and chemoresistance. Efforts to understand the complex relationship between the tumor and its extracellular network and to therapeutically perturb tumor-stroma interactions are ongoing. Fibronectin (FN), a provisional matrix protein abundant in PDA stroma but not normal tissues, supports metastatic spread and chemoresistance of this deadly disease. FN also supports angiogenesis, which is required for even hypovascular tumors such as PDA to develop and progress. Targeting components of the tumor stroma, such as FN, can effectively reduce tumor growth and spread while also enhancing delivery of chemotherapy. Here, we review the molecular mechanisms by which FN drives angiogenesis, metastasis and chemoresistance in PDA. In light of these new findings, we also discuss therapeutic strategies to inhibit FN signaling.
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Affiliation(s)
- Mary Topalovski
- Hamon Center for Therapeutic Oncology Research and the Division of Surgical Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Rolf A Brekken
- Hamon Center for Therapeutic Oncology Research and the Division of Surgical Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Departments of Surgery and Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
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Preis M, Schneiderman J, Koren B, Ben-Yosef Y, Levin-Ashkenazi D, Shapiro S, Cohen T, Blich M, Israeli-Amit M, Sarnatzki Y, Gershtein D, Shofti R, Lewis BS, Shaul Y, Flugelman MY. Co-expression of fibulin-5 and VEGF165 increases long-term patency of synthetic vascular grafts seeded with autologous endothelial cells. Gene Ther 2015; 23:237-46. [PMID: 26588709 DOI: 10.1038/gt.2015.104] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 10/12/2015] [Accepted: 10/15/2015] [Indexed: 12/30/2022]
Abstract
Small caliber synthetic vascular grafts are commonly used for bypass surgery and dialysis access sites but have high failure rates because of neointima formation and thrombosis. Seeding synthetic grafts with endothelial cells (ECs) provides a biocompatible surface that may prevent graft failure. However, EC detachment following exposure to blood flow still remains a major obstacle in the development of biosynthetic grafts. We tested the hypothesis that induced expression by the seeded EC, of vascular endothelial growth factor165 (VEGF165) and of fibulin-5, an extracellular matrix glycoprotein that has a crucial role in elastin fiber organization and increase EC adherence to surfaces, may improve long-term graft patency. Autologous ECs were isolated from venous segments, and were transduced with retroviral vectors expressing fibulin-5 and VEGF165. The modified cells were seeded on expanded polytetrafluoroethylene (ePTFE) grafts and implanted in a large animal model. Three months after transplantation, all grafts seeded with modified EC were patent on a selective angiography, whereas only a third of the control grafts were patent. Similar results were shown at 6 months. Thus, seeding ePTFE vascular grafts with genetically modified EC improved long-term small caliber graft patency. The biosynthetic grafts may provide a novel therapeutic modality for patients with peripheral vascular disease and patients requiring vascular access for hemodialysis.
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Affiliation(s)
- M Preis
- Institute of Hematology, Lady Davis Carmel Medical Center, Haifa, Israel
| | - J Schneiderman
- Department of Vascular Surgery, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - B Koren
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.,MultiGene Vascular Systems Ltd, Haifa, Israel
| | - Y Ben-Yosef
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.,MultiGene Vascular Systems Ltd, Haifa, Israel
| | - D Levin-Ashkenazi
- The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
| | - S Shapiro
- Immunology Research Unit, Lady Davis Carmel Medical Center, Haifa, Israel
| | - T Cohen
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.,MultiGene Vascular Systems Ltd, Haifa, Israel
| | - M Blich
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel
| | - M Israeli-Amit
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.,MultiGene Vascular Systems Ltd, Haifa, Israel
| | - Y Sarnatzki
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.,MultiGene Vascular Systems Ltd, Haifa, Israel
| | - D Gershtein
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.,MultiGene Vascular Systems Ltd, Haifa, Israel
| | - R Shofti
- The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
| | - B S Lewis
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.,MultiGene Vascular Systems Ltd, Haifa, Israel.,The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
| | - Y Shaul
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - M Y Flugelman
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel.,MultiGene Vascular Systems Ltd, Haifa, Israel.,The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
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Regeneration of elastic fibers by three-dimensional culture on a collagen scaffold and the addition of latent TGF-β binding protein 4 to improve elastic matrix deposition. Biomaterials 2015; 72:29-37. [DOI: 10.1016/j.biomaterials.2015.08.036] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 08/17/2015] [Accepted: 08/18/2015] [Indexed: 11/23/2022]
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Wang M, Topalovski M, Toombs JE, Wright CM, Moore ZR, Boothman DA, Yanagisawa H, Wang H, Witkiewicz A, Castrillon DH, Brekken RA. Fibulin-5 Blocks Microenvironmental ROS in Pancreatic Cancer. Cancer Res 2015; 75:5058-69. [PMID: 26577699 DOI: 10.1158/0008-5472.can-15-0744] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 08/15/2015] [Indexed: 12/16/2022]
Abstract
Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5-integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase-dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell-ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease.
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Affiliation(s)
- Miao Wang
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas
| | - Mary Topalovski
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas
| | - Jason E Toombs
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas
| | - Christopher M Wright
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas
| | - Zachary R Moore
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - David A Boothman
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Hiromi Yanagisawa
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas
| | - Huamin Wang
- Department of Pathology, UT MD Anderson Cancer Center, Houston, Texas
| | | | | | - Rolf A Brekken
- Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas. Department of Surgery, UT Southwestern Medical Center, Dallas, Texas. Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas.
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Winship A, Cuman C, Rainczuk K, Dimitriadis E. Fibulin-5 is upregulated in decidualized human endometrial stromal cells and promotes primary human extravillous trophoblast outgrowth. Placenta 2015; 36:1405-11. [PMID: 26506560 DOI: 10.1016/j.placenta.2015.10.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 09/25/2015] [Accepted: 10/12/2015] [Indexed: 01/01/2023]
Abstract
Interactions between the highly invasive trophoblasts and the maternal uterine decidual extracellular matrix (ECM) are crucial in the determination of a successful pregnancy. Fibulin-5 (FBLN5) is a member of the fibulin family that alters cell adhesive and invasive properties and is expressed in human villous cytotrophoblasts. We aimed to determine the expression and immunolocalization of FBLN5 in human first trimester decidua and examine the effect of FBLN5 in trophoblast invasion in vitro using a first trimester placental villous outgrowth assay. We demonstrated that FBLN5 mRNA expression is upregulated in response to cAMP-mediated decidualization of primary human endometrial stromal cells, although FBLN5 itself does not enhance decidualization. We reported for the first time, FBLN5 protein production in first trimester decidual cells and also co-localization to HLAG-positive EVTs in first trimester decidua. Consequently, we investigated the effects of exogenous FBLN5 on placental villous outgrowth in vitro and demonstrated that FBLN5 promotes EVT migration/invasion. This is the first study to identify FBLN5 in decidualized human endometrial stromal cells, first trimester decidua and EVT and determine a functional role for FBLN5 in human EVTs, suggesting that decidual and or EVT-derived FBLN5 regulates EVT invasion and placentation in women.
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Affiliation(s)
- Amy Winship
- Embryo Implantation Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
| | - Carly Cuman
- Embryo Implantation Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Medicine, Monash University, Clayton, VIC, Australia
| | - Katarzyna Rainczuk
- Embryo Implantation Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Evdokia Dimitriadis
- Embryo Implantation Laboratory, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia; Department of Molecular and Translational Medicine, Monash University, Clayton, VIC, Australia.
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Tang JC, Liu JH, Liu XL, Liang X, Cai XJ. Effect of fibulin-5 on adhesion, migration and invasion of hepatocellular carcinoma cells via an integrin-dependent mechanism. World J Gastroenterol 2015; 21:11127-11140. [PMID: 26494967 PMCID: PMC4607910 DOI: 10.3748/wjg.v21.i39.11127] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 07/08/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the role of fibulin-5 (FBLN-5) as a suppressor of hepatocellular carcinoma (HCC) cell metastasis via integrin.
METHODS: The expression of FBLN-5 was determined by immunohistochemistry in 140 HCC samples and matched normal tissues, and was further confirmed by RT-PCR and Western blot analyses in various cell lines. Recombinant FBLN-5 was expressed in Escherichia coli BL21(DE3), purified and used in cell attachment assays. Expression of a specific plasmid or a specific siRNA in HCC cells resulted in the overexpression or knockdown of FBLN-5, respectively. Further, the migration and invasion of HCC cells were investigated using the Boyden chamber and transwell assays. The concentration of secreted matrix metalloproteinase 7 (MMP-7) was determined using ELISA.
RESULTS: FBLN-5 expression was found to be downregulated in HCC. Its expression was significantly correlated with advanced tumor metastasis; this was indicative of poor 5-year overall survival. Recombinant full-length human FBLN-5 promoted the attachment of HCC cells via integrins: it inhibited HCC cell adhesion and migration to fibronectin in a concentration-dependent manner. It also inhibited HCC cell migration and invasion through an integrin-binding arginine-glycine-aspartic acid (RGD) motif by downregulating MMP-7.
CONCLUSION: These results suggest that lower FBLN-5 expression is an important indicator of poor survival and that FBLN-5 inhibits HCC motility via an integrin-dependent mechanism. RGD-dependent suppression of MMP-7 by FBLN-5 might contribute to the development of new therapeutic strategies for HCC.
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Noda K, Nakamura T, Komatsu Y. Fibulin-5 deficiency causes developmental defect of premaxillary bone in mice. Biochem Biophys Res Commun 2015; 466:585-91. [PMID: 26399686 DOI: 10.1016/j.bbrc.2015.09.089] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 09/16/2015] [Indexed: 12/26/2022]
Abstract
Craniofacial sutures govern the shape of the craniofacial skeleton during postnatal development. The differentiation of suture mesenchymal cells to osteoblasts is precisely regulated in part by signaling through cell surface receptors that interact with extracellular proteins. Here we report that fibulin-5, a key extracellular matrix protein, is important for craniofacial skeletal development in mice. Fibulin-5 is deposited as a fibrous matrix in cranial neural crest-derived mesenchymal tissues, including craniofacial sutures. Fibulin-5-null mice show decreased premaxillary bone outgrowth during postnatal stages. While premaxillo-maxillary suture mesenchymal cells in fibulin-5-null mice were capable of differentiating into osteoblasts, suture cells in mutant mice were less proliferative. Our study provides the first evidence that fibulin-5 is indispensable for the regulation of facial suture mesenchymal cell proliferation required for craniofacial skeletal morphogenesis.
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Affiliation(s)
- Kazuo Noda
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
| | - Tomoyuki Nakamura
- Department of Pharmacology, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Yoshihiro Komatsu
- Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
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Heo JH, Song JY, Jeong JY, Kim G, Kim TH, Kang H, Kwon AY, An HJ. Fibulin-5 is a tumour suppressor inhibiting cell migration and invasion in ovarian cancer. J Clin Pathol 2015; 69:109-16. [PMID: 26251522 DOI: 10.1136/jclinpath-2015-203129] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 07/16/2015] [Indexed: 11/04/2022]
Abstract
AIMS Fibulin-5 is an extracellular matrix (ECM) glycoprotein which has a role in the organisation and stabilisation of ECM structures and regulating cell proliferation and tumourigenesis. Here, the expression of fibulin-5 and its functional effects on the migration and invasion of ovarian cancer cells were assessed. METHODS Expression of fibulin-5 was detected in 44 ovarian tumour tissues by qRT-PCR, Western blotting and immunohistochemistry. We performed cell migration and invasion assays, and cell cycle analysis in fibulin-5 transfected SKOV3 (SKOV3-FBLN5) cells and the parental SKOV3 cells. We further examined the expression of three tissue inhibitors of metalloproteinases (TIMPs) and seven matrix metalloproteinases (MMPs) by RT-PCR. RESULTS mRNA and protein expression of fibulin-5 were down-regulated (0.05-fold and 0.1-fold) in ovarian carcinomas compared with control tissues (p<0.01 and p=0.022). In wound-healing and invasion assays, significantly fewer SKOV3-FBLN5 cells than SKOV3 control cells migrated and invaded (39.1%, p=0.046 and 70%, p=0.03, respectively), which was reversed by siRNA-treatment. Overexpression of fibulin-5 induced G2/M arrest and increased cyclin B1, CDC2 and CDC25C. Expression of TIMP-2 (0.56-fold), MMP-3 (0.43-fold) and MMP-13 (0.18-fold) was lower and MMP-9 expression (2.20-fold) was higher in SKOV3-FBLN5 cells than in control cells. CONCLUSIONS Fibulin-5 is significantly down-regulated in ovarian carcinoma and acts as a tumour suppressor by inhibiting the migration and invasion of ovarian cancer cells.
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Affiliation(s)
- Jin Hyung Heo
- Department of Pathology, CHA Bundang Medical Center, CHA University, Sungnam, Korea
| | - Ji-Ye Song
- Clinical Research Institute, CHA Bundang Medical Center, CHA University, Sungnam, Korea
| | - Ju-Yeong Jeong
- Clinical Research Institute, CHA Bundang Medical Center, CHA University, Sungnam, Korea
| | - Gwangil Kim
- Department of Pathology, CHA Bundang Medical Center, CHA University, Sungnam, Korea Clinical Research Institute, CHA Bundang Medical Center, CHA University, Sungnam, Korea
| | - Tae Heon Kim
- Department of Pathology, CHA Bundang Medical Center, CHA University, Sungnam, Korea Clinical Research Institute, CHA Bundang Medical Center, CHA University, Sungnam, Korea
| | - Haeyoun Kang
- Department of Pathology, CHA Bundang Medical Center, CHA University, Sungnam, Korea
| | - Ah-Young Kwon
- Department of Pathology, CHA Bundang Medical Center, CHA University, Sungnam, Korea
| | - Hee Jung An
- Department of Pathology, CHA Bundang Medical Center, CHA University, Sungnam, Korea Clinical Research Institute, CHA Bundang Medical Center, CHA University, Sungnam, Korea
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Setyawati MI, Tay CY, Docter D, Stauber RH, Leong DT. Understanding and exploiting nanoparticles' intimacy with the blood vessel and blood. Chem Soc Rev 2015; 44:8174-99. [PMID: 26239875 DOI: 10.1039/c5cs00499c] [Citation(s) in RCA: 222] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
While the blood vessel is seldom the target tissue, almost all nanomedicine will interact with blood vessels and blood at some point of time along its life cycle in the human body regardless of their intended destination. Despite its importance, many bionanotechnologists do not feature endothelial cells (ECs), the blood vessel cells, or consider blood effects in their studies. Including blood vessel cells in the study can greatly increase our understanding of the behavior of any given nanomedicine at the tissue of interest or to understand side effects that may occur in vivo. In this review, we will first describe the diversity of EC types found in the human body and their unique behaviors and possibly how these important differences can implicate nanomedicine behavior. Subsequently, we will discuss about the protein corona derived from blood with foci on the physiochemical aspects of nanoparticles (NPs) that dictate the protein corona characteristics. We would also discuss about how NPs characteristics can affect uptake by the endothelium. Subsequently, mechanisms of how NPs could cross the endothelium to access the tissue of interest. Throughout the paper, we will share some novel nanomedicine related ideas and insights that were derived from the understanding of the NPs' interaction with the ECs. This review will inspire more exciting nanotechnologies that had accounted for the complexities of the real human body.
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Affiliation(s)
- Magdiel Inggrid Setyawati
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore.
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Furie N, Shteynberg D, Elkhatib R, Perry L, Ullmann Y, Feferman Y, Preis M, Flugelman MY, Tzchori I. Fibulin-5 regulates keloid-derived fibroblast-like cells through integrin beta-1. Int J Cosmet Sci 2015; 38:35-40. [PMID: 26095157 DOI: 10.1111/ics.12245] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 06/05/2015] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Keloid scar is pathological tissue that appears after skin injury, and that is more aggressive than hypertrophic scars. Keloid scars are characterized by increased proliferation of fibroblast-like cells (FLCs) and the accumulation of extracellular matrix, mainly collagen. Fibulin-5, a glycoprotein secreted by many cell types, is a component of the extracellular matrix. We investigated the effect of fibulin-5 on the adhesion and proliferation of FLCs derived from keloid scars and the role of integrin beta-1 in these activities. METHODS Fibroblast-like cells were isolated from six keloid scars and cultured on plates coated with fibulin-5 or with gelatin. Cells were incubated for 72-96 h to examine proliferation rates and incubated for 240 min, with washings at 20, 40, 60, 90, 120, 180 min, to assess adhesion rates. To examine the role of integrin beta-1, the anti-human integrin beta-1 (CD29) antibody was added to the culture medium. RESULTS Fibroblast-like cells from keloids cultured on a fibulin-5-coated surface showed a significantly reduced proliferation rate and a delayed adhesion rate, compared to cells cultured on gelatin-coated dishes. Adherence of these cells to fibulin-5 pre-coated wells was significantly reduced in the presence of anti-human integrin beta-1 (CD29) antibodies. Our current findings are similar to previously observed reduced proliferation in vascular smooth muscle cells overexpressing fibulin-5. We did not test the effects of fibulin-5 on normal fibroblasts. CONCLUSION This study demonstrates the pivotal role of the extracellular protein, fibulin-5, on the adhesion and proliferation of human keloid-derived cells, through binding to integrin beta-1.
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Affiliation(s)
- N Furie
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, 7 Michal Street, Haifa 34361, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT, P.O.B. 9649, Efron Street, Bat Galim, Haifa 31096, Israel
| | - D Shteynberg
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, 7 Michal Street, Haifa 34361, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT, P.O.B. 9649, Efron Street, Bat Galim, Haifa 31096, Israel
| | - R Elkhatib
- Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT, P.O.B. 9649, Efron Street, Bat Galim, Haifa 31096, Israel.,Department of Plastic Surgery, Ramabam - Health Care Campus, P.O.B 9602, Haifa 3109601, Israel
| | - L Perry
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, 7 Michal Street, Haifa 34361, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT, P.O.B. 9649, Efron Street, Bat Galim, Haifa 31096, Israel
| | - Y Ullmann
- Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT, P.O.B. 9649, Efron Street, Bat Galim, Haifa 31096, Israel.,Department of Plastic Surgery, Ramabam - Health Care Campus, P.O.B 9602, Haifa 3109601, Israel
| | - Y Feferman
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, 7 Michal Street, Haifa 34361, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT, P.O.B. 9649, Efron Street, Bat Galim, Haifa 31096, Israel
| | - M Preis
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, 7 Michal Street, Haifa 34361, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT, P.O.B. 9649, Efron Street, Bat Galim, Haifa 31096, Israel
| | - M Y Flugelman
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, 7 Michal Street, Haifa 34361, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT, P.O.B. 9649, Efron Street, Bat Galim, Haifa 31096, Israel
| | - I Tzchori
- Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, 7 Michal Street, Haifa 34361, Israel.,Ruth and Bruce Rappaport Faculty of Medicine, Technion IIT, P.O.B. 9649, Efron Street, Bat Galim, Haifa 31096, Israel
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45
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Qureshi R, Arora H, Rizvi M. EMT in cervical cancer: Its role in tumour progression and response to therapy. Cancer Lett 2015; 356:321-31. [DOI: 10.1016/j.canlet.2014.09.021] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/07/2014] [Accepted: 09/10/2014] [Indexed: 12/22/2022]
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47
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Tu K, Dou C, Zheng X, Li C, Yang W, Yao Y, Liu Q. Fibulin-5 inhibits hepatocellular carcinoma cell migration and invasion by down-regulating matrix metalloproteinase-7 expression. BMC Cancer 2014; 14:938. [PMID: 25494879 PMCID: PMC4295477 DOI: 10.1186/1471-2407-14-938] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 12/04/2014] [Indexed: 12/20/2022] Open
Abstract
Background Fibulin-5 has been considered as a tumor suppressor through inhibiting tumor growth and invasion. Reduced expression of Fibulin-5 is frequently observed in various human cancers. In this study, we investigate the clinical significance of Fibulin-5 and its role in hepatocellular carcinoma (HCC) cell migration and invasion. Methods The expression of Fibulin-5 was evaluated by qRT-PCR and immunoblotting in HCC and matched noncancerous tissues. Fibulin-5 was over-expressed or knocked down by a retrovirus-mediated expression plasmid or a specific siRNA in HCC cells. Boyden chamber and Transwell assays were used to test HCC cell migration and invasion. Immunostaining was performed to determine matrix metalloproteinase-7 (MMP-7) expression in HCC specimens. MMP-7 retroviruses and siRNA were used to alter MMP-7 expression in HCC cells. Results In our study, the expression levels of Fibulin-5 protein and mRNA were down-regulated in HCC tissues as compared with those in matched noncancerous tissues. Reduced expression of Fibulin-5 was observed in all HCC cell lines (HepG2, SMMC-7721, MHCC97L, Hep3B, MHCC97H and HCC-LM3) as compare with that in a non-transformed hepatic cell line (LO2). Low expression of Fibulin-5 was significantly correlated with poor prognostic features including multiple tumor nodes, venous infiltration, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) tumor stage. Furthermore, we demonstrated that Fibulin-5 was a novel independent prognostic marker for predicting 5-year survival of HCC patients. Our in vitro studies showed that Fibulin-5 overexpression inhibited HCC cell migration and invasion. While Fibulin-5 knockdown increased the number of migrated and invaded HCC cells. Fibulin-5 negatively regulated MMP-7 abundance in HCC cells. Moreover, the inverse correlation between Fibulin-5 and MMP-7 expressions was observed in HCC tissues. Mechanistically, we disclosed that MMP-7 knockdown reduced the number of migrated and invaded HCC cells. Restoring MMP-7 expression abrogated the suppressive effect of Fibulin-5 on HCC cell migration and invasion in vitro, suggesting that Fibulin-5 exerted its anti-metastatic function, at least in part, by down-regulating the expression of MMP-7 in HCC cells. Conclusions These results indicate that Fibulin-5 may serve as a prognostic biomarker and inhibits HCC invasion and metastasis by suppressing MMP-7 expression.
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Affiliation(s)
- Kangsheng Tu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, PR China.
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Cangemi C, Hansen ML, Argraves WS, Rasmussen LM. Fibulins and their role in cardiovascular biology and disease. Adv Clin Chem 2014; 67:245-65. [PMID: 25735864 DOI: 10.1016/bs.acc.2014.09.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Fibulins are a group of extracellular matrix proteins of which many are present in high amounts in the cardiovascular system. They share common biochemical properties and are often found in relation to basement membranes or elastic fibers. Observations in humans with specific mutations in fibulin genes, together with results from genetically engineered mice and data from human cardiovascular tissue suggest that the fibulin family of proteins play important functional roles in the cardiovascular system. Moreover, fibulin-1 circulates in high concentrations in plasma and may function as a cardiovascular disease marker.
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Affiliation(s)
- Claudia Cangemi
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
| | - Maria Lyck Hansen
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
| | - William Scott Argraves
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Lars Melholt Rasmussen
- Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
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Kantaputra PN, Kaewgahya M, Wiwatwongwana A, Wiwatwongwana D, Sittiwangkul R, Iamaroon A, Dejkhamron P. Cutis laxa with pulmonary emphysema, conjunctivochalasis, nasolacrimal duct obstruction, abnormal hair, and a novel FBLN5 mutation. Am J Med Genet A 2014; 164A:2370-7. [PMID: 24962763 DOI: 10.1002/ajmg.a.36630] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Accepted: 05/16/2014] [Indexed: 12/15/2022]
Abstract
We report on a 4-year-old girl with autosomal recessive cutis laxa, type IA, or pulmonary emphysema type (ARCL1A; OMIM #219100), with loose and wrinkled skin, mitral and tricuspid valve prolapse, conjunctivochalasis, obstructed nasolacrimal ducts, hypoplastic maxilla, and early childhood-onset pulmonary emphysema. Mutation analysis of FBLN5 showed a homozygous c.432C>G missense mutation, and heterozygosity in the parents. This is predicted to cause amino acid substitution p.Cys144Trp. Conjunctivochalasis or redundant folds of conjunctiva and obstructed nasolacrimal ducts have not been reported to be associated with FBLN5 mutations. Histopathological study of the conjunctival biopsy showed that most blood vessels had normal elastic fibers. The gingiva appeared normal, but histologically elastic fibers were defective. Scanning electron micrography of scalp hair demonstrated hypoplastic hair follicles. The cuticles appear intact underneath the filamentous meshwork.
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Affiliation(s)
- Piranit Nik Kantaputra
- Center of Excellence in Medical Genetics Research, Chiang Mai University, Chiang Mai, Thailand; Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand; Craniofacial Genetics Laboratory, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand; Dentaland Clinic, Chiang Mai, Thailand
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Three-dimensional multilayers of smooth muscle cells as a new experimental model for vascular elastic fiber formation studies. Atherosclerosis 2014; 233:590-600. [DOI: 10.1016/j.atherosclerosis.2014.01.045] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Revised: 01/20/2014] [Accepted: 01/21/2014] [Indexed: 02/01/2023]
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