Cancer associated fibroblasts-derived SULF1 promotes gastric cancer metastasis and CDDP resistance through the TGFBR3-mediated TGF-β signaling pathway

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 4, 2024

Abstract SULF1 has been implicated in a number of malignancies. The function gastric cancer is disputed. objective this study was to examine the role and underlying molecular mechanisms context cancer. We found that expression increased cancer, especially cancer-associated fibroblasts. overexpression be significantly correlated with unfavorable prognosis among individuals diagnosed Functionally, fibroblasts-derived served as oncogenic molecule which facilitated cells metastasis CDDP resistance. Mechanistically, regulated communication between fibroblasts tumor microenvironment signaling molecule. Cancer-associated fibroblasts-secreted interfered interaction TGF-β1 TGFBR3 by combining on cell membrane, subsequently activated TGF-β pathway. In conclusion, our findings have presented novel approaches for potential treatment prediction through targeting CAFs-SULF1-TGFBR3-TGF-β1 axis.

Language: Английский

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HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1148 - 1148

Published: Jan. 6, 2023

Heparan sulfate is a ubiquitous, variably sulfated interactive glycosaminoglycan that consists of repeating disaccharides glucuronic acid and glucosamine are subject to number modifications (acetylation, de-acetylation, epimerization, sulfation). Variable heparan chain lengths sequences within the chains provide structural diversity generating oligosaccharide binding motifs with diverse range extracellular ligands cellular receptors providing instructional cues over behaviour tissue homeostasis through regulation essential physiological processes in development, health, disease. sulfate-PGs integral components specialized glycocalyx surrounding cells. most heterogeneous glycosaminoglycan, terms its sequence biosynthetic making it difficult molecule fully characterize, multiple also make an elucidation functional properties complicated. Spatio-temporal presentation groups important determinant development control wound healing remodelling pathological tissues. The regulatory mediated via interactions chemokines, chemokine receptors, growth factors morphogens cell proliferation, differentiation, remodelling, healing, immune regulation, inflammation, tumour development. A greater understanding these HS will improve therapeutic procedures prognoses. Advances synthesis sequencing, computational analytical carbohydrate algorithms advanced software for evaluation molecular docking partners now available. These analytic techniques artificial intelligence offer predictive capability conformational effects on sulfate-ligand significantly aiding therapeutics

Language: Английский

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Global impact of proteoglycan science on human diseases

iScience, Journal Year: 2023, Volume and Issue: 26(11), P. 108095 - 108095

Published: Oct. 4, 2023

Language: Английский

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The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 14101 - 14101

Published: Sept. 14, 2023

This review examines the roles of HS-proteoglycans (HS-PGs) in general, and, particular, perlecan and syndecan as representative examples their interactive ligands, which regulate physiological processes cellular behavior health disease. HS-PGs are essential for functional properties tissues both development extracellular matrix (ECM) remodeling that occurs response to trauma or interact with a biodiverse range chemokines, chemokine receptors, protease inhibitors, growth factors immune regulation, inflammation, ECM stabilization, tissue protection. Some cell regulatory proteoglycan receptors dually modified hybrid HS/CS proteoglycans (betaglycan, CD47). Neurexins provide synaptic plasticity, specificity interaction, promoting neurotransduction, neurogenesis, differentiation. Ternary complexes glypican-1 Robbo-Slit neuroregulatory proteins direct axonogenesis neural network formation. Specific neurexin-neuroligin stabilize interactions activity. Disruption these leads neurological deficits disorders cognitive decline. Interactions also promote inhibit tumor development. Thus, have complex diverse normal pathological tissues. Specialized HS-PGs, such neurexins, pikachurin, Eyes-shut, stabilization transduction axenome primary cilium phototoreceptors ribbon synapse bipolar neurons retinal networks, ocular vision. Pikachurin Eyes-Shut an α-dystroglycan photoreceptor synapse. Novel controlling function expected continue be uncovered this fascinating class proteoglycan.

Language: Английский

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Glycosaminoglycans’ Ability to Promote Wound Healing: From Native Living Macromolecules to Artificial Biomaterials

Advanced Science, Journal Year: 2023, Volume and Issue: 11(9)

Published: Dec. 10, 2023

Abstract Glycosaminoglycans (GAGs) are important for the occurrence of signaling molecules and maintenance microenvironment within extracellular matrix (ECM) in living tissues. GAGs GAG‐based biomaterial approaches have been widely explored to promote situ tissue regeneration repair by regulating wound microenvironment, accelerating re‐epithelialization, controlling ECM remodeling. However, most remain unacceptable clinical applications. To improve insights into material design translational applications, this review highlights innate roles bioactive mechanisms native during healing presents common biomaterials adaptability application scenarios facilitating healing. Furthermore, challenges before widespread commercialization shared, ensure that future designed constructed artificial more likely recapitulate unique tissue‐specific profile GAG expression human This provides a explicit clear selection guide researchers designing biomimetic materials, which will resemble or exceed their natural counterparts certain functions, thereby suiting specific environments therapeutic goals.

Language: Английский

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Proteoglycans of basement membranes: Crucial controllers of angiogenesis, neurogenesis, and autophagy

Proteoglycan Research, Journal Year: 2024, Volume and Issue: 2(3)

Published: June 29, 2024

Anti-angiogenic therapy is an established method for the treatment of several cancers and vascular-related diseases. Most agents employed target vascular endothelial growth factor A, major cytokine stimulating angiogenesis. However, efficacy these treatments limited by onset drug resistance. Therefore, it fundamental importance to better understand mechanisms that regulate angiogenesis microenvironmental cues play significant role influence patient outcome. In this context, here we review three basement membrane heparan sulfate proteoglycans (HSPGs), namely perlecan, agrin collagen XVIII. These HSPGs are abundantly expressed in vasculature and, due their complex molecular architecture, they interact with multiple cell receptors, deeply affecting function. Under normal conditions, exert pro-angiogenic functions. pathological conditions such as cancer inflammation, extracellular matrix remodeling leads degradation large precursor molecules liberation bioactive processed fragments displaying potent angiostatic activity. unexpected functions have been demonstrated C-terminal perlecan XVIII, endorepellin endostatin. can also induce autophagy cells which contributes angiostasis. Overall, affect counterbalancing signals during tumor progression, represent possible means develop new prognostic biomarkers novel therapeutic approaches solid tumors.

Language: Английский

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Conformations, interactions and functions of intrinsically disordered syndecans

Biochemical Society Transactions, Journal Year: 2023, Volume and Issue: 51(3), P. 1083 - 1096

Published: June 19, 2023

Syndecans are transmembrane heparan sulfate proteoglycans present on most mammalian cell surfaces. They have a long evolutionary history, single syndecan gene being expressed in bilaterian invertebrates. attracted interest because of their potential roles development and disease, including vascular diseases, inflammation various cancers. Recent structural data is providing important insights into functions, which complex, involving both intrinsic signaling through cytoplasmic binding partners co-operative mechanisms where syndecans form nexus with other receptors such as integrins tyrosine kinase growth factor receptors. While the domain syndecan-4 has well-defined dimeric structure, ectodomains intrinsically disordered, linked to capacity interact multiple partners. However, it remains fully establish impact glycanation partner proteins core protein conformations. Genetic models indicate that conserved property links cytoskeleton calcium channels transient receptor class, compatible mechanosensors. In turn, influence actin organization motility, adhesion extracellular matrix environment. Syndecan clustering surface microdomains relevance tissue differentiation development, for example stem cells, but also disease expression can be markedly up-regulated. Since diagnostic prognostic markers well possible targets some forms cancer, unravel structure/function relationships four syndecans.

Language: Английский

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Trastuzumab Decreases the Expression of G1/S Regulators and Syndecan-4 Proteoglycan in Human Rhabdomyosarcoma

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2137 - 2137

Published: Feb. 27, 2025

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, arises from skeletal muscle cells that fail to differentiate terminally. Two subgroups of RMS, fusion-positive and fusion-negative RMS (FPRMS FNRMS, respectively), are characterized by presence or absence PAX3/7-FOXO1 fusion gene. RMSs frequently exhibit increased expression human epidermal growth factor receptor-2 (HER2). Trastuzumab is a humanized monoclonal antibody targeting HER2, its potential role treatment remains be elucidated. Syndecan-4 (SDC4) heparan sulfate proteoglycan (HSPG) affecting myogenesis via Rac1-mediated actin remodeling. Previously, we demonstrated SDC4 gene amplified 28% FNRMS samples, associated with high mRNA expression, suggesting tumor driver role. In this study, after analyzing copy numbers expressions other HSPGs found addition SDC4, syndecan-1, syndecan-2, glypican-1 were also highly expressed FNRMS. RD (human FNRMS) cells, elevated was accompanied low levels phospho-Ser179 leading Rac1-GTP activity. Notably, decreased following trastuzumab treatment. G1/S checkpoint regulators cyclin E D1 reduced cell number; however, it downregulated cyclin-dependent kinase inhibitor p21. The level MyoD, transcription essential for survival, administration. Our findings contribute understanding Since HER2 about half RMSs, trastuzumab-mediated changes observed here may have therapeutic implications.

Language: Английский

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Efficacy of dispirotripiperazine PDSTP in a golden Syrian hamster model of SARS-CoV-2 infection

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: March 10, 2025

The increasing incidence of viral pandemics calls for new small-molecule therapeutics beyond traditional approaches and targets. Dispirotripiperazine, composed two positively charged nitrogen atoms, represents an unusual scaffold in drug discovery campaigns, molecules based on it are known to prevent virus infection by disrupting early host–pathogen interactions. In this study, the adhesion-blocking dispirotripiperazine core compound PDSTP was evaluated against SARS-CoV-2 vitro vivo . We demonstrated that molecule acceptably active clinical isolates affecting stages cycle. a hamster model pneumonia, treatment resulted reduced loads lungs turbinates milder lung tissue lesions. Overall, these data support as preclinical candidate COVID-19.

Language: Английский

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Glypicans, 35 years later

Proteoglycan Research, Journal Year: 2023, Volume and Issue: 1(2)

Published: April 1, 2023

Abstract Glypicans are a family of proteoglycans that bound to the cell surface by glycosylphosphatidylinositol anchor. These highly conserved during evolution, and mammalian genome contains six members family. carry two four heparan sulfate chains inserted near carboxy terminus. The crystal structure reveals densely packed cylindrical shape is parallel surface. functions glypicans mediated and/or core protein. One main these regulation signaling pathways triggered hedgehogs, Wnts, fibroblast growth factors, bone morphogenetic proteins. can either stimulate or inhibit interaction factors with their receptors. Studies in Drosophila have also shown regulate hedgehog, Wnt, factor gradient formation. In addition, play important roles establishment synapses neuron guidance migration. Glypican mutations cause several developmental syndromes, overexpression proteins contribute progression various cancer types. particular, glypican‐3 currently being used as marker for diagnosis hepatocellular carcinomas, it targeted immunotherapeutic approaches treatment this malignancy.

Language: Английский

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