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Matrix Biology : Journal of the... Jul 2017Hyaluronan and versican are extracellular matrix (ECM) components that are enriched in the provisional matrices that form during the early stages of development and... (Review)
Review
Hyaluronan and versican are extracellular matrix (ECM) components that are enriched in the provisional matrices that form during the early stages of development and disease. These two molecules interact to create pericellular "coats" and "open space" that facilitate cell sorting, proliferation, migration, and survival. Such complexes also impact the recruitment of leukocytes during development and in the early stages of disease. Once thought to be inert components of the ECM that help hold cells together, it is now quite clear that they play important roles in controlling cell phenotype, shaping tissue response to injury and maintaining tissue homeostasis. Conversion of hyaluronan-/versican-enriched provisional matrix to collagen-rich matrix is a "hallmark" of tissue fibrosis. Targeting the hyaluronan and versican content of provisional matrices in a variety of diseases including, cardiovascular disease and cancer, is becoming an attractive strategy for intervention.
Topics: Animals; Cell Proliferation; Cells, Cultured; Collagen; Disease Models, Animal; Extracellular Matrix; Female; Fibrosis; Gene Expression Regulation; Humans; Hyaluronic Acid; Leiomyosarcoma; Mice; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; RNA, Small Interfering; Transforming Growth Factor beta; Uterine Neoplasms; Versicans
PubMed: 27932299
DOI: 10.1016/j.matbio.2016.12.001 -
Respiratory Research May 2023This study aimed to investigate the expression of plasma versican and plasma exosomal versican in non-small cell lung cancer (NSCLC) and its correlation with...
BACKGROUND AND AIMS
This study aimed to investigate the expression of plasma versican and plasma exosomal versican in non-small cell lung cancer (NSCLC) and its correlation with clinicopathological features, and to evaluate its diagnostic performance in NSCLC and its predictive function for NSCLC incidence and metastasis risk.
MATERIALS AND METHODS
There were 110 instances of NSCLC, 42 cases of benign lung disease, and 55 healthy controls from September 2018 to October 2020 at Tongji Hospital Affiliated to Tongji University. Blood was collected and plasma was separated before surgery, and plasma exosomes were extracted by ExoQuick kit. Morphological and molecular phenotype identification of exosomes was performed by transmission electron microscopy, Nanosight particle tracking analysis, and western blotting. Plasma versican and plasma exosomal versican were detected in all subjects to assess their expression levels and diagnostic value in NSCLC. Clinicopathological data were collected to explore correlations between abnormal plasma versican and plasma exosomal versican expression and clinicopathological parameters. Receiver operating characteristic (ROC) curve was used to judge its diagnostic performance in NSCLC, and binary logistic regression analysis was used to predict the risk of NSCLC incidence and metastasis.
RESULTS
Plasma versican and plasma exosomal versican expression in NSCLC patients was significantly upregulated and was significantly higher in T3 + T4 patients compared with T1 + T2 patients (P < 0.05); the levels of plasma versican and plasma exosomal versican were positively correlated with lymph node metastasis, distant metastases (e.g., brain, bone), and mutation(e.g., EGFR,ALK)in NSCLC patients (all P < 0.05). Furthermore, ROC curve analysis showed that plasma versican and plasma exosomal versican had higher AUC values than NSE, CYFRA21-1, and SCC, and better diagnostic performance in NSCLC patients. However, the AUC and diagnostic performances of plasma versican and plasma exosomal versican in advanced-stage NSCLC patients were not shown to be significantly better than CEA. The results of binary logistic regression analysis showed that high levels of plasma exosomal versican had higher predictive value for lung cancer incidence, while high levels of plasma versican had higher predictive value for lung cancer metastasis.
CONCLUSION
Our findings showed that plasma versican and plasma exosomal versican might be potential diagnostic markers for NSCLC. High plasma exosomal versican expression can be used as a predictor of NSCLC risk and high plasma versican expression can be used as a predictor of NSCLC metastasis risk.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Versicans; Biomarkers, Tumor
PubMed: 37259101
DOI: 10.1186/s12931-023-02423-4 -
International Journal of Molecular... Mar 2021The hyalectan family is composed of the proteoglycans aggrecan, versican, brevican and neurocan. Hyalectans, also known as lecticans, are components of the extracellular... (Review)
Review
The hyalectan family is composed of the proteoglycans aggrecan, versican, brevican and neurocan. Hyalectans, also known as lecticans, are components of the extracellular matrix of different tissues and play essential roles in key biological processes including skeletal development, and they are related to the correct maintenance of the vascular and central nervous system. For instance, hyalectans participate in the organization of structures such as perineural nets and in the regulation of neurite outgrowth or brain recovery following a traumatic injury. The ADAMTS (A Disintegrin and Metalloprotease domains, with thrombospondin motifs) family consists of 19 secreted metalloproteases. These enzymes also perform important roles in the structural organization and function of the extracellular matrix through interactions with other matrix components or as a consequence of their catalytic activity. In this regard, some of their preferred substrates are the hyalectans. In fact, ADAMTSs cleave hyalectans not only as a mechanism for clearance or turnover of proteoglycans but also to generate bioactive fragments which display specific functions. In this article we review some of the physiological and pathological effects derived from cleavages of hyalectans mediated by ADAMTSs.
Topics: ADAMTS Proteins; Brain; Brain Injuries, Traumatic; Extracellular Matrix; Humans; Hyalectins; Neuronal Outgrowth; Thrombospondins; Versicans
PubMed: 33804223
DOI: 10.3390/ijms22062988 -
Journal of Proteomics Oct 2021The chondroitin sulfate proteoglycan versican is important for embryonic development and several human disorders. The versican V1 splice isoform is widely expressed and...
The chondroitin sulfate proteoglycan versican is important for embryonic development and several human disorders. The versican V1 splice isoform is widely expressed and cleaved by ADAMTS proteases at a well-characterized site, Glu-Ala. Since ADAMTS proteases cleave the homologous proteoglycan aggrecan at multiple sites, we hypothesized that additional cleavage sites existed within versican. We report a quantitative label-free approach that ranks abundance of liquid chromatography-tandem mass spectrometry (LC-MS/MS)-identified semi-tryptic peptides after versican digestion by ADAMTS1, ADAMTS4 and ADAMTS5 to identify site-specific cleavages. Recombinant purified versican V1 constructs were digested with the recombinant full-length proteases, using catalytically inactive mutant proteases in control digests. Semi-tryptic peptide abundance ratios determined by LC-MS/MS in ADAMTS:control digests were compared to the mean of all identified peptides to obtain a z-score by which outlier peptides were ranked, using semi-tryptic peptides identifying Glu -Ala cleavage as the benchmark. Tryptic peptides with higher abundance in control digests supported cleavage site identification. We identified several novel cleavage sites supporting the ADAMTS1/4/5 cleavage site preference for a P1-Glu residue in proteoglycan substrates. Digestion of proteins in vitro and application of this z-score approach is potentially widely applicable for mapping protease cleavage sites using label-free proteomics. SIGNIFICANCE: Versican abundance and turnover are relevant to the pathogenesis of several human disorders. Versican is cleaved by A Disintegrin-like And Metalloprotease with Thrombospondin type 1 motifs (ADAMTS) family members at Glu-Ala, generating a bioactive proteoform called versikine, but additional cleavage sites and the site-specificity of individual ADAMTS proteases is unexplored. Here, we used a label-free proteomics strategy to identify versican cleavage sites for 3 ADAMTS proteases, applying a novel z-score-based statistical approach to compare the protease digests of versican to controls (digests with inactive protease) using the known protease cleavage site as a benchmark. We identified 21 novel cleavage sites that had a comparable z-score to the benchmark. Given the functional significance of versikine, they represent potentially significant cleavages and helped to refine a substrate site preference for each protease.The z-score approach is potentially widely applicable for discovery of site-specific cleavages within an purified protein or small ensemble of proteins using any protease.
Topics: ADAM Proteins; ADAMTS1 Protein; ADAMTS4 Protein; ADAMTS5 Protein; Chromatography, Liquid; Humans; Proteomics; Tandem Mass Spectrometry; Versicans
PubMed: 34450332
DOI: 10.1016/j.jprot.2021.104358 -
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 -
The Journal of Histochemistry and... Nov 2020Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan belonging to the aggrecan/lectican family. In adults, this proteoglycan serves as a structural... (Review)
Review
Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan belonging to the aggrecan/lectican family. In adults, this proteoglycan serves as a structural macromolecule of the extracellular matrix in the brain and large blood vessels. In contrast, versican is transiently expressed at high levels during development and under pathological conditions when the extracellular matrix dramatically changes, including in the inflammation and repair process. There are many reports showing the upregulation of versican in cancer, which correlates with cancer aggressiveness. Versican has four classical splice variants, and all the variants contain G1 and G3 domains at N- and C-termini, respectively. There are two glycosaminoglycan attachment domains CSα and CSβ. The largest V0 variant contains both CSα and CSβ, V1 contains CSβ, V2 contains CSα, and the shortest G3 variant has neither of them. Versican degradation is initiated by cleavage at a site in the CSβ domain by ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases. The N-terminal fragment containing the G1 domain has been reported to exert various biological functions, although its mechanisms of action have not yet been elucidated. In this review, we describe the role of versican in inflammation and cancer and also address the biological function of versikine.
Topics: Animals; Extracellular Matrix; Humans; Inflammation; Neoplasms; Versicans
PubMed: 33131383
DOI: 10.1369/0022155420953922 -
Matrix Biology : Journal of the... Mar 2022Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan that plays a key role in the formation of the provisional matrix. Here, we generated dextran...
Versican is a large chondroitin sulfate/dermatan sulfate proteoglycan that plays a key role in the formation of the provisional matrix. Here, we generated dextran sulfate sodium-induced colitis in knockin-mice, R/R, expressing ADAMTS-resistant versican, and investigated the impact of accumulating versican and its turnover in the inflammatory colon mucosa. Histologically, R/R colon showed decreased levels of tissue destruction and an increased number of myofibroblasts and macrophages. Characterization of inflammatory cells revealed an increase in F4/80+ macrophages in R/R colon, compared with wildtype, without a clear shift between M1 and M2 populations. Intestinal stroma exhibited a higher number of myofibroblasts in R/R, suggesting increased levels of tissue regeneration. Coculture of macrophages and stromal fibroblasts obtained from inflammatory colon showed that wild-type macrophages inhibited myofibroblastic differentiation of R/R fibroblasts but not wild-type. This inhibitory effect was due to an increased level of versikine, a cleaved fragment of versican by ADAMTS proteinases. Taken together, our results demonstrate versikine as the direct regulator that inhibits repair of inflamed tissue.
Topics: Animals; Colitis; Fibroblasts; Mice; Versicans; Wound Healing
PubMed: 35176450
DOI: 10.1016/j.matbio.2022.02.004 -
Methods in Molecular Biology (Clifton,... 2015Versican is a widely distributed chondroitin sulfate proteoglycan that forms large complexes with the glycosaminoglycan hyaluronan (HA). As a consequence of HA binding...
Versican is a widely distributed chondroitin sulfate proteoglycan that forms large complexes with the glycosaminoglycan hyaluronan (HA). As a consequence of HA binding to its receptor CD44 and interactions of the versican C-terminal globular (G3) domain with a variety of extracellular matrix proteins, versican is a key component of well-defined networks in pericellular matrix and extracellular matrix. It is crucial for several developmental processes in the embryo and there is increasing interest in its roles in cancer and inflammation. Versican proteolysis by ADAMTS proteases is highly regulated, occurs at specific peptide bonds, and is relevant to several physiological and disease mechanisms. In this chapter, methods are described for the isolation and detection of intact and cleaved versican in tissues using morphologic and biochemical techniques. These, together with the methodologies for purification and analysis of recombinant versican and a versican fragment provided here, are likely to facilitate further progress on the biology of versican and its proteolysis.
Topics: Antibodies; Antigens; Cells, Cultured; Chromatography, Affinity; Humans; Hyaluronic Acid; Paraffin Embedding; Protein Isoforms; Protein Structure, Tertiary; Proteolysis; Reference Standards; Staining and Labeling; Versicans
PubMed: 25325983
DOI: 10.1007/978-1-4939-1714-3_46 -
Trends in Cardiovascular Medicine Aug 2006Versican is an abundant proteoglycan in the blood vessel wall that is increased after vascular injury and accumulates in advanced atherosclerotic plaques. Versican is a... (Review)
Review
Versican is an abundant proteoglycan in the blood vessel wall that is increased after vascular injury and accumulates in advanced atherosclerotic plaques. Versican is a large molecule with domains that mediate binding to cytokines, enzymes, lipoproteins, other extracellular matrix molecules, and signaling receptors. There is evidence that versican exists in the normal, as well as the diseased, vessel wall as discrete fragments, which represent these functional domains. We review the literature on versican degradation in vascular tissue and the function of versican domains, all of which suggest that proteolytic modification of versican may have physiologic as well as pathologic implications for the vascular system.
Topics: Animals; Humans; Hyperplasia; Tunica Intima; Vascular Diseases; Versicans
PubMed: 16839865
DOI: 10.1016/j.tcm.2006.03.011 -
Glycobiology Mar 2015Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure comprises four different types of the core... (Review)
Review
Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure comprises four different types of the core protein with attached glycosaminoglycans (GAGs) that can be sulfated to various extents and has the capacity to regulate differentiation of different cell types, migration, cell adhesion, proliferation, tissue stabilization and inflammation. Versican's regulatory properties are of importance during both homeostasis and changes that lead to disease progression. The GAGs that are attached to the core protein are of the chondroitin sulfate/dermatan sulfate type and are known to be important in inflammation through interactions with cytokines and growth factors. For a more complex understanding of versican, it is of importance to study the tissue niche, where the wound healing process in both healthy and diseased conditions take place. In previous studies, our group has identified changes in the amount of the multifaceted versican in chronic lung disorders such as asthma, chronic obstructive pulmonary disease, and bronchiolitis obliterans syndrome, which could be a result of pathologic, transforming growth factor β driven, on-going remodeling processes. Reversely, the context of versican in its niche is of great importance since versican has been reported to have a beneficial role in other contexts, e.g. emphysema. Here we explore the vast mechanisms of versican in healthy lung and in lung disorders.
Topics: Animals; Extracellular Matrix; Humans; Lung Diseases; Versicans
PubMed: 25371494
DOI: 10.1093/glycob/cwu120