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Blood Jan 2022
Topics: Syndecan-2
PubMed: 35024813
DOI: 10.1182/blood.2021014116 -
American Journal of Physiology. Cell... Aug 2022Syndecan-1 (SDC-1) is a heparan sulfate (HS)/chondroitin sulfate proteoglycan (PG) of the cell surface and the extracellular matrix (ECM), which regulates a broad... (Review)
Review
Syndecan-1 (SDC-1) is a heparan sulfate (HS)/chondroitin sulfate proteoglycan (PG) of the cell surface and the extracellular matrix (ECM), which regulates a broad spectrum of physiological and pathological processes such as cell proliferation, migration, inflammation, matrix remodeling, wound healing, and tumorigenesis. Syndecan-1 represents the major PG of the liver, expressed by hepatocytes and cholangiocytes, and its elevated expression is a characteristic feature of liver diseases. The highest syndecan-1 expression is found in liver cirrhosis and in hepatocellular carcinoma (HCC) developed in cirrhotic livers. In addition, as being a hepatitis C receptor, hepatitis C virus (HCV)-infected livers produce extremely large amounts of syndecan-1. The serum levels of the cleaved (shedded) extracellular domain have clinical significance, as their increased concentration reflects on poor prognosis in cirrhosis as well as in cancer. In vivo experiments confirmed that syndecan-1 protects against early stages of fibrogenesis mainly by enhanced clearance of transforming growth factor β1 (TGFβ1) and thrombospondin-1 (THBS1) via circulation, and against hepatocarcinogenesis by interfering with several signaling pathways and enhancing cell cycle blockade. In addition, syndecan-1 is capable to hinder lipid metabolism and ribosomal biogenesis in induced cancer models. These observations together with its participation in the uptake of viruses (e.g., HCV and SARS-CoV-2) indicate that syndecan-1 is a central player in liver pathologies.
Topics: Carcinoma, Hepatocellular; Hepatitis C; Humans; Liver; Liver Neoplasms; Proteoglycans; Syndecan-1
PubMed: 35704700
DOI: 10.1152/ajpcell.00039.2022 -
Frontiers in Immunology 2019Syndecans are a four member multifunctional family of cell surface molecules with diverse biological roles. Syndecan-3 (SDC3) is the largest of these, but in comparison... (Review)
Review
Syndecans are a four member multifunctional family of cell surface molecules with diverse biological roles. Syndecan-3 (SDC3) is the largest of these, but in comparison to the other family members relatively little is known about this molecule. SDC3 null mice grow and develop normally, all be it with subtle anatomical phenotypes in the brain. Roles for this molecule in both neuronal and brain tissue have been identified, and is associated with altered satiety responses. Recent studies suggest that SDC3 expression is not restricted to neuronal tissues and has important roles in inflammatory disorders such as rheumatoid arthritis, disease associated processes such as angiogenesis and in the facilitation of infection of dendritic cells by HIV. The purpose of this review article is to explore these new biological insights into SDC3 functions in inflammatory disease.
Topics: Animals; Humans; Inflammation; Neovascularization, Pathologic; Syndecan-3
PubMed: 31998313
DOI: 10.3389/fimmu.2019.03031 -
Cell Reports Mar 2020Muscle regeneration relies on the regulation of muscle stem cells (MuSCs) through paracrine signaling interactions. We analyzed muscle regeneration in mice using...
Muscle regeneration relies on the regulation of muscle stem cells (MuSCs) through paracrine signaling interactions. We analyzed muscle regeneration in mice using single-cell RNA sequencing (scRNA-seq) and generated over 34,000 single-cell transcriptomes spanning four time-points. We identified 15 distinct cell types including heterogenous populations of muscle stem and progenitor cells. We resolved a hierarchical map of these myogenic cells by trajectory inference and observed stage-specific regulatory programs within this continuum. Through ligand-receptor interaction analysis, we identified over 100 candidate regeneration-associated paracrine communication pairs between MuSCs and non-myogenic cells. We show that myogenic stem/progenitor cells exhibit heterogeneous expression of multiple Syndecan proteins in cycling myogenic cells, suggesting that Syndecans may coordinate myogenic fate regulation. We performed ligand stimulation in vitro and confirmed that three paracrine factors (FGF2, TGFβ1, and RSPO3) regulate myogenic cell proliferation in a Syndecan-dependent manner. Our study provides a scRNA-seq reference resource to investigate cell communication interactions in muscle regeneration.
Topics: Adipogenesis; Animals; Cell Communication; Cell Proliferation; Gene Expression Regulation; Ligands; Mice, Inbred C57BL; Models, Biological; Muscle Development; Muscle, Skeletal; Paracrine Communication; RNA-Seq; Receptors, Cell Surface; Regeneration; Signal Transduction; Single-Cell Analysis; Stem Cells; Syndecans
PubMed: 32160558
DOI: 10.1016/j.celrep.2020.02.067 -
The FEBS Journal Aug 2019The four syndecans identified in mammals are membrane proteoglycans that play major roles in regulating cell behavior, cell signaling, and cell-matrix interactions. The... (Review)
Review
The four syndecans identified in mammals are membrane proteoglycans that play major roles in regulating cell behavior, cell signaling, and cell-matrix interactions. The membrane forms of these syndecans function as receptors and co-receptors. Their ectodomains, which are proteolytically released in the extracellular matrix by shedding, also regulate various biological processes. Apart from the cytoplasmic domain of syndecan-4, the 3D structures of syndecans are poorly characterized, which hinders our understanding of the molecular mechanisms underlying syndecan functions that are mediated by numerous interactions. This mini-review summarizes the structural data that are available for syndecans and provides a comprehensive syndecan interactome, which comprises three hundred and fifty-one partners, including those identified by the high-throughput method affinity purification-mass spectrometry. It also gives a perspective on future studies of syndecan structures and interactions, which are required to further elucidate the molecular recognition processes that mediate the biological roles of the membrane and shed forms of syndecans.
Topics: Animals; Binding Sites; Humans; Protein Interaction Maps; Syndecans
PubMed: 30932318
DOI: 10.1111/febs.14828 -
International Journal of Molecular... Apr 2021Cell surface proteoglycans are known to be important regulators of many aspects of cell behavior. The principal family of transmembrane proteoglycans is the syndecans,... (Review)
Review
Cell surface proteoglycans are known to be important regulators of many aspects of cell behavior. The principal family of transmembrane proteoglycans is the syndecans, of which there are four in mammals. Syndecan-1 is mostly restricted to epithelia, and bears heparan sulfate chains that are capable of interacting with a large array of polypeptides, including extracellular matrix components and potent mediators of proliferation, adhesion and migration. For this reason, it has been studied extensively with respect to carcinomas and tumor progression. Frequently, but not always, syndecan-1 levels decrease as tumor grade, stage and invasiveness and dedifferentiation increase. This parallels experiments that show depletion of syndecan-1 can be accompanied by loss of cadherin-mediated adhesion. However, in some tumors, levels of syndecan-1 increase, but the characterization of its distribution is relevant. There can be loss of membrane staining, but acquisition of cytoplasmic and/or nuclear staining that is abnormal. Moreover, the appearance of syndecan-1 in the tumor stroma, either associated with its cellular component or the collagenous matrix, is nearly always a sign of poor prognosis. Given its relevance to myeloma progression, syndecan-1-directed antibody-toxin conjugates are being tested in clinical and preclinical trials, and may have future relevance to some carcinomas.
Topics: Animals; Carcinoma; Epithelial-Mesenchymal Transition; Glycosaminoglycans; Heparitin Sulfate; Humans; Proteoglycans; Syndecan-1
PubMed: 33921767
DOI: 10.3390/ijms22084227 -
Biomolecules Feb 2021Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection... (Review)
Review
Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.
Topics: Animals; Carcinoma, Pancreatic Ductal; Extracellular Matrix; Humans; Proteoglycans; Signal Transduction; Syndecans
PubMed: 33669066
DOI: 10.3390/biom11030349 -
Biomolecules Mar 2021Cancer is an important cause of morbidity and mortality worldwide. Advances in research on the biology of cancer revealed alterations in several key pathways underlying... (Review)
Review
Cancer is an important cause of morbidity and mortality worldwide. Advances in research on the biology of cancer revealed alterations in several key pathways underlying tumorigenesis and provided molecular targets for developing new and improved existing therapies. Syndecan-4, a transmembrane heparan sulfate proteoglycan, is a central mediator of cell adhesion, migration and proliferation. Although several studies have demonstrated important roles of syndecan-4 in cell behavior and its interactions with growth factors, extracellular matrix (ECM) molecules and cytoskeletal signaling proteins, less is known about its role and expression in multiple cancer. The data summarized in this review demonstrate that high expression of syndecan-4 is an unfavorable biomarker for estrogen receptor-negative breast cancer, glioma, liver cancer, melanoma, osteosarcoma, papillary thyroid carcinoma and testicular, kidney and bladder cancer. In contrast, in neuroblastoma and colorectal cancer, syndecan-4 is downregulated. Interestingly, syndecan-4 expression is modulated by anticancer drugs. It is upregulated upon treatment with zoledronate and this effect reduces invasion of breast cancer cells. In our recent work, we demonstrated that the syndecan-4 level was reduced after trastuzumab treatment. Similarly, syndecan-4 levels are also reduced after panitumumab treatment. Together, the data found suggest that syndecan-4 level is crucial for understanding the changes involving in malignant transformation, and also demonstrate that syndecan-4 emerges as an important target for cancer therapy and diagnosis.
Topics: Antineoplastic Agents, Immunological; Apoptosis; Cell Adhesion; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; RNA Interference; Signal Transduction; Syndecan-4
PubMed: 33810567
DOI: 10.3390/biom11040503 -
International Journal of Molecular... Jun 2022Syndecans act as independent co-receptors to exert biological activities and their altered function is associated with many pathophysiological conditions. Here,...
Syndecans act as independent co-receptors to exert biological activities and their altered function is associated with many pathophysiological conditions. Here, syndecan-1 and -4 were examined in lesional skin of patients with psoriasis. Immunohistochemical staining confirmed altered syndecan-1 distribution and revealed absence of syndecan-4 expression in the epidermis. Fibronectin (FN)-known to influence inflammation and keratinocyte hyperproliferation via α5β1 integrin in psoriasis-was also decreased. Syndecan-1 and -4 expression was analyzed in freshly isolated lesional psoriatic human keratinocytes (PHK) characterized based on their proliferation and differentiation properties. mRNA levels of syndecan-1 were similar between healthy and PHK, while syndecan-4 was significantly decreased. Cell growth and release of the pro-inflammatory Tumor Necrosis Factor-alpha (TNFα) were selectively and significantly induced in PHKs plated on FN. Results from co-culture of healthy keratinocytes and psoriatic fibroblasts led to the speculation that at least one factor released by fibroblasts down-regulate syndecan-1 expression in PHK plated on FN. To assay if biological treatments for psoriasis target keratinocyte proliferation, gelatin-based patches enriched with inteleukin (IL)-17α or TNFα blockers were prepared and tested using a full-thickness healthy epidermal model (Phenion). Immunohistochemistry analysis showed that both blockers impacted the localisation of syndecan-1 within the refined epidermis. These results provide evidence that syndecans expression are modified in psoriasis, suggesting that they may represent markers of interest in this pathology.
Topics: Epidermis; Humans; Keratinocytes; Psoriasis; Syndecan-1; Syndecan-4; Tumor Necrosis Factor-alpha
PubMed: 35742957
DOI: 10.3390/ijms23126511 -
American Journal of Physiology. Cell... Nov 2022Expression of the cell surface heparan sulfate proteoglycan syndecan-4 is dysregulated in breast cancer, the most frequent malignancy in women. High expression of... (Review)
Review
Expression of the cell surface heparan sulfate proteoglycan syndecan-4 is dysregulated in breast cancer, the most frequent malignancy in women. High expression of syndecan-4 correlates with a worse survival in the subgroup of estrogen receptor negative and estrogen/progesterone-receptor negative patients. Aberrant expression of syndecan-4 in breast cancer involves both transcriptional and posttranscriptional mechanisms, including estrogen- and growth factor-dependent regulation, mutations in , , , and , as well as targeting by microRNAs. At the functional level, syndecan-4 plays an important role in various stages of breast cancer progression by interacting with ligands as diverse as plasma proteins, extracellular matrix proteins, growth factors, and surface receptors, as well as members of the integrin family. Mechanisms including integrin recycling, ectodomain shedding, and crosstalk with other syndecans expand the repertoire of syndecan-4 function. Through these interactions, syndecan-4 regulates cellular processes such as adhesion, migration, and invasion. Additional possible functions of syndecan-4 in cells of the microenvironment contribute to the complexity of its pathophysiology. Notably, syndecan-4 expression is modulated by drugs used in breast cancer treatment, such as trastuzumab and zoledronate. Overall, these findings mark syndecan-4 as a novel pathogenesis factor and promising target for therapeutic interventions in breast cancer.
Topics: Humans; Female; Syndecan-4; Heparan Sulfate Proteoglycans; Breast Neoplasms; Zoledronic Acid; Progesterone; Ligands; Receptors, Estrogen; Extracellular Matrix Proteins; MicroRNAs; Intercellular Signaling Peptides and Proteins; Trastuzumab; Integrins; Estrogens; Syndecan-1; Tumor Microenvironment
PubMed: 36094435
DOI: 10.1152/ajpcell.00152.2022