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Fukushima Journal of Medical Science Jan 2024Extracellular matrix (ECM) is a non-cellular constituent found in all tissues and organs. Although ECM was previously recognized as a mere "molecular glue" that supports... (Review)
Review
Extracellular matrix (ECM) is a non-cellular constituent found in all tissues and organs. Although ECM was previously recognized as a mere "molecular glue" that supports the tissue structure of organs such as the lungs, it has recently been reported that ECM has important biological activities for tissue morphogenesis, inflammation, wound healing, and tumor progression. Proteoglycans are the main constituent of ECM, with growing evidence that proteoglycans and their associated glycosaminoglycans play important roles in the pathogenesis of several diseases. However, their roles in the lungs are incompletely understood. Leukocyte migration into the lung is one of the main aspects involved in the pathogenesis of several lung diseases. Glycosaminoglycans bind to chemokines and their interaction fine-tunes leukocyte migration into the affected organs. This review focuses on the role chemokine and glycosaminoglycan interactions in neutrophil migration into the lung. Furthermore, this review presents the role of proteoglycans such as syndecan, versican, and hyaluronan in inflammatory and fibrotic lung diseases.
Topics: Humans; Lung; Extracellular Matrix; Glycosaminoglycans; Versicans; Lung Diseases
PubMed: 38267030
DOI: 10.5387/fms.2023-07 -
American Journal of Physiology. Cell... Sep 2022Proteoglycans are composite molecules comprising a protein backbone, i.e., the core protein, with covalently attached glycosaminoglycan chains of distinct chemical... (Review)
Review
Proteoglycans are composite molecules comprising a protein backbone, i.e., the core protein, with covalently attached glycosaminoglycan chains of distinct chemical types. Most proteoglycans are secreted or attached to the cell membrane. Their specialized structures, binding properties, and biophysical attributes underlie diverse biological roles, which include modulation of tissue mechanics, cell adhesion, and the sequestration and regulated release of morphogens, growth factors, and cytokines. As an irreversible post-translational modification, proteolysis has a profound impact on proteoglycan function, abundance, and localization. Proteolysis is required for molecular maturation of some proteoglycans, clearance of extracellular matrix proteoglycans during tissue remodeling, generation of bioactive fragments from proteoglycans, and ectodomain shedding of cell-surface proteoglycans. Genetic evidence shows that proteoglycan core protein proteolysis is essential for diverse morphogenetic events during embryonic development. In contrast, dysregulated proteoglycan proteolysis contributes to osteoarthritis, cardiovascular disorders, cancer, and inflammation. Proteolytic fragments of perlecan, versican, aggrecan, brevican, collagen XVIII, and other proteoglycans are associated with independent biological activities as so-called matrikines. Yet, proteoglycan proteolysis has been investigated to only a limited extent to date. Here, we review the actions of proteases on proteoglycans and illustrate their functional impact with several examples. We discuss the applications and limitations of strategies used to define cleavage sites in proteoglycans and explain how proteoglycanome-wide proteolytic mapping, which is desirable to fully understand the impact of proteolysis on proteoglycans, can be facilitated by integrating classical proteoglycan isolation methods with mass spectrometry-based proteomics.
Topics: Aggrecans; Extracellular Matrix; Protein Processing, Post-Translational; Proteolysis; Versicans
PubMed: 35785985
DOI: 10.1152/ajpcell.00215.2022 -
Analytical and Bioanalytical Chemistry Apr 2022Extracellular matrix (ECM) proteins, collectively known as the matrisome, include collagens, glycoproteins, and proteoglycans. Alterations in the matrisome have been...
Extracellular matrix (ECM) proteins, collectively known as the matrisome, include collagens, glycoproteins, and proteoglycans. Alterations in the matrisome have been implicated in the neurodegenerative pathologies including Parkinson's disease (PD). In this work, we utilized our previously published PD and control proteomics data from human prefrontal cortex and focused our analysis on the matrisome. Among matrisome proteins, we observed a significant enrichment in the expression of type I collagen in PD vs. control samples. We then performed histological analysis on the same samples used for proteomics study, and examined collagen expression using picrosirius red staining. Interestingly, we observed similar trends in collagen abundance in PD vs. control as in our matrisome analysis; thus, this and other histological analyses will be useful as a complementary technique in the future to study the matrisome in PD with a larger cohort, and it may aid in choosing regions of interest for proteomic analysis. Additionally, collagen hydroxyprolination was less variable in PD compared to controls. Glycoproteomic changes in matrisome molecules were also observed in PD relative to aged individuals, especially related to type VI collagen and versican. We further examined the list of differentially expressed matrisome molecules using network topology-based analysis and found that angiogenesis indicated by alterations in decorin and several members of the collagen family was affected in PD. These findings collectively identified matrisome changes associated with PD; further studies with a larger cohort are required to validate the current results.
Topics: Aged; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Parkinson Disease; Proteoglycans; Proteomics
PubMed: 35112150
DOI: 10.1007/s00216-022-03929-4 -
Frontiers in Oncology 2021A growing body of literature links events associated with the progression and severity of immunity and inflammatory disease with the composition of the tissue... (Review)
Review
A growing body of literature links events associated with the progression and severity of immunity and inflammatory disease with the composition of the tissue extracellular matrix as defined by the matrisome. One protein in the matrisome that is common to many inflammatory diseases is the large proteoglycan versican, whose varied function is achieved through multiple isoforms and post-translational modifications of glycosaminoglycan structures. In cancer, increased levels of versican are associated with immune cell phenotype, disease prognosis and failure to respond to treatment. Whether these associations between versican expression and tumour immunity are the result of a direct role in the pathogenesis of tumours is not clear. In this review, we have focused on the role of versican in the immune response as it relates to tumour progression, with the aim of determining whether our current understanding of the immunobiology of versican warrants further study as a cancer immunotherapy target.
PubMed: 34527586
DOI: 10.3389/fonc.2021.712807 -
Cancers Mar 2023-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer,...
-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human -mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that -mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene /IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.
PubMed: 36980752
DOI: 10.3390/cancers15061866 -
Frontiers in Immunology 2020The extracellular matrix (ECM) proteoglycan, versican increases along with other ECM versican binding molecules such as hyaluronan, tumor necrosis factor stimulated... (Review)
Review
The extracellular matrix (ECM) proteoglycan, versican increases along with other ECM versican binding molecules such as hyaluronan, tumor necrosis factor stimulated gene-6 (TSG-6), and inter alpha trypsin inhibitor (IαI) during inflammation in a number of different diseases such as cardiovascular and lung disease, autoimmune diseases, and several different cancers. These interactions form stable scaffolds which can act as "landing strips" for inflammatory cells as they invade tissue from the circulation. The increase in versican is often coincident with the invasion of leukocytes early in the inflammatory process. Versican interacts with inflammatory cells either indirectly via hyaluronan or directly via receptors such as CD44, P-selectin glycoprotein ligand-1 (PSGL-1), and toll-like receptors (TLRs) present on the surface of immune and non-immune cells. These interactions activate signaling pathways that promote the synthesis and secretion of inflammatory cytokines such as TNFα, IL-6, and NFκB. Versican also influences inflammation by interacting with a variety of growth factors and cytokines involved in regulating inflammation thereby influencing their bioavailability and bioactivity. Versican is produced by multiple cell types involved in the inflammatory process. Conditional total knockout of versican in a mouse model of lung inflammation demonstrated significant reduction in leukocyte invasion into the lung and reduced inflammatory cytokine expression. While versican produced by stromal cells tends to be pro-inflammatory, versican expressed by myeloid cells can create anti-inflammatory and immunosuppressive microenvironments. Inflammation in the tumor microenvironment often contains elevated levels of versican. Perturbing the accumulation of versican in tumors can inhibit inflammation and tumor progression in some cancers. Thus versican, as a component of the ECM impacts immunity and inflammation through regulating immune cell trafficking and activation. Versican is emerging as a potential target in the control of inflammation in a number of different diseases.
Topics: Animals; Extracellular Matrix; Humans; Hyaluronic Acid; Inflammation; Leukocytes; Lipopolysaccharides; Lymphocyte Subsets; Mice; Models, Animal; Myeloid Cells; Rabbits; Rats; Receptors, Cell Surface; Stromal Cells; Toll-Like Receptors; Versicans
PubMed: 32265939
DOI: 10.3389/fimmu.2020.00512 -
Investigative Ophthalmology & Visual... Oct 2023Limbal epithelial stem cells (LESCs) reside within a LSC niche (LSCN). We recently identified that hyaluronan (HA) is a major constituent of the LSCN, and that HA is...
PURPOSE
Limbal epithelial stem cells (LESCs) reside within a LSC niche (LSCN). We recently identified that hyaluronan (HA) is a major constituent of the LSCN, and that HA is necessary for maintaining LESCs in the "stem cell" state, both in vitro and in vivo. Herein, we characterized the LSCN to identify key components of the HA-specific LSCN.
METHODS
The cornea and limbal rim were dissected from mouse corneas, subjected to mRNA extraction, and sequenced using a NextSeq 500 (Illumina) and data processed using CLC Genomics Workbench 20 (Qiagen) and the STRING database to identify key components of the LSCN. Their expression was confirmed by real-time PCR, Western blotting, and immunohistochemistry. Furthermore, the differential expression of key compounds in different corneal cell types were determined with single-cell RNA sequencing.
RESULTS
We identified that the hyaladherins inter-alpha-inhibitor (IαI), TSG-6 and versican are highly expressed in the limbus. Specifically, HA/HC complexes are present in the LSCN, in the stroma underlying the limbal epithelium, and surrounding the limbal vasculature. For IαI, heavy chains 5 and 2 (HC5 and HC2) were found to be the most highly expressed HCs in the mouse and human limbus and were associate with HA-forming HA/HC-specific matrices.
CONCLUSIONS
The LSCN contains HA/HC complexes, which have been previously correlated with stem cell niches. The identification of HA/HC complexes in the LSCN could serve as a new therapeutic avenue for treating corneal pathology. Additionally, HA/HC complexes could be used as a substrate for culturing LESCs before LESC transplantation.
Topics: Humans; Animals; Mice; Stem Cell Niche; Blotting, Western; Cornea; Databases, Factual; Epithelium; Hyaluronic Acid
PubMed: 37906057
DOI: 10.1167/iovs.64.13.48 -
Frontiers in Immunology 2022Increasing evidence has revealed an important role of versican (VCAN) on various aspects of cancer progression. Here, we assessed the impact of VCAN expression on...
BACKGROUND
Increasing evidence has revealed an important role of versican (VCAN) on various aspects of cancer progression. Here, we assessed the impact of VCAN expression on prognosis and the response to adjuvant therapy and immunotherapy in patients with gastric cancer (GC).
METHODS
Four independent cohorts containing 1353 patients with GC, were utilized to investigate the effect of VCAN expression on prognosis and response to adjuvant therapy in GC. Two cohorts treated with immune checkpoint blockades were included to assess the predict value of VCAN expression on response to immunotherapy. Moreover, the bulk RNA-seq and single-cell RNA-seq data were analyzed to illustrate the role of VCAN in tumor microenvironment. Clinical outcomes of patient subgroups were compared by Kaplan-Meier curves with the log-rank test.
RESULT
High VCAN expression was associated with poor prognosis for patients with GC. Compared with patients with high VCAN expression, patients with low VCAN expression benefited more from adjuvant chemotherapy and adjuvant chemoradiotherapy. Moreover, patients with high VCAN expression tended to be resistant to immunotherapy, and VCAN could serve as a promising indicator for predicting the response to immunotherapy. VCAN tumors showed a specific microenvironment with more cancer associated fibroblasts infiltration and significant enrichment of stromal relevant signaling pathways.
CONCLUSION
VCAN could predict the response to adjuvant chemotherapy, adjuvant chemoradiotherapy and immunotherapy in GC, and designing new medicine target to VCAN might be an effective way to improve the efficacy of several treatment options for GC.
Topics: Humans; Immunotherapy; Prognosis; Stomach Neoplasms; Tumor Microenvironment; Versicans
PubMed: 36203562
DOI: 10.3389/fimmu.2022.960570 -
Journal of Vascular Research 2022Extracellular matrix proteins are regulated by metzincin proteases, like the disintegrin metalloproteinases with thrombospondin motifs (ADAMTS) family members. This... (Review)
Review
Extracellular matrix proteins are regulated by metzincin proteases, like the disintegrin metalloproteinases with thrombospondin motifs (ADAMTS) family members. This review focuses on the emerging role which ADAMTS-4 might play in vascular pathology, which has implications for atherosclerosis and vessel wall abnormalities, as well as for the resulting diseases, such as cardiovascular and cerebrovascular disease, aortic aneurysms, and dissections. Major substrates of ADAMTS-4 are proteoglycans expressed physiologically in smooth muscle cells of blood vessels. Good examples are versican and aggrecan, principal vessel wall proteoglycans that are targeted by ADAMTS-4, driving blood vessel atrophy, which is why this metzincin protease was implicated in the pathophysiology of vascular diseases with an atherosclerotic background. Despite emerging evidence, it is important not to exaggerate the role of ADAMTS-4 as it is likely only a small piece of the complex atherosclerosis puzzle and one that could be functionally redundant due to its high structural similarity to other ADAMTS family members. The therapeutic potential of inhibiting ADAMTS-4 to halt the progression of vascular disease after initialization of treatment is unlikely. However, it is not excluded that it might find a purpose as a biomarker of vascular disease, possibly as an indicator in a larger cytokine panel.
Topics: ADAMTS4 Protein; Atherosclerosis; Cardiovascular System; Cytokines; Humans; Myocytes, Smooth Muscle; Proteoglycans
PubMed: 35051931
DOI: 10.1159/000521498