-
Frontiers in Oncology 2023Exit of quiescent disseminated cancer cells from dormancy is thought to be responsible for metastatic relapse and a better understanding of dormancy could pave the way...
Exit of quiescent disseminated cancer cells from dormancy is thought to be responsible for metastatic relapse and a better understanding of dormancy could pave the way for novel therapeutic approaches. We used an model of triple negative breast cancer brain metastasis to identify differences in transcriptional profiles between dormant and proliferating cancer cells in the brain. gene, encoding a small proteoglycan biglycan, was strongly upregulated in dormant cancer cells . expression was significantly downregulated in patient brain metastases as compared to the matched primary breast tumors and overexpression in cancer cells inhibited their growth and . Dormant cancer cells were further characterized by a reduced expression of glycolysis genes , and inhibition of glycolysis resulted in a reversible growth arrest reminiscent of dormancy. Our study identified mechanisms that could be targeted to induce/maintain cancer dormancy and thereby prevent metastatic relapse.
PubMed: 37456245
DOI: 10.3389/fonc.2023.1191980 -
Neurobiology of Disease Oct 2023Stroke is the second leading cause of death worldwide and has two major subtypes: ischemic stroke and hemorrhagic stroke. Neuroinflammation is a pathological hallmark of... (Review)
Review
Stroke is the second leading cause of death worldwide and has two major subtypes: ischemic stroke and hemorrhagic stroke. Neuroinflammation is a pathological hallmark of ischemic stroke and intracerebral hemorrhage (ICH), contributing to the extent of brain injury but also in its repair. Neuroinflammation is intricately linked to the extracellular matrix (ECM), which is profoundly altered after brain injury and in aging. In the early stages after ischemic stroke and ICH, immune cells are involved in the deposition and remodeling of the ECM thereby affecting processes such as blood-brain barrier and cellular integrity. ECM components regulate leukocyte infiltration into the central nervous system, activate a variety of immune cells, and induce the elevation of matrix metalloproteinases (MMPs) after stroke. In turn, excessive MMPs may degrade ECM into components that are pro-inflammatory and injurious. Conversely, in the later stages after stroke, several ECM molecules may contribute to tissue recovery. For example, thrombospondin-1 and biglycan may promote activity of regulatory T cells, inhibit the synthesis of proinflammatory cytokines, and aid regenerative processes. We highlight these roles of the ECM in ischemic stroke and ICH and discuss their potential cellular and molecular mechanisms. Finally, we discuss therapeutics that could be considered to normalize the ECM in stroke. Our goal is to spur research on the ECM in order to improve the prognosis of ischemic stroke and ICH.
Topics: Humans; Ischemic Stroke; Neuroinflammatory Diseases; Cerebral Hemorrhage; Stroke; Brain Injuries; Extracellular Matrix
PubMed: 37683956
DOI: 10.1016/j.nbd.2023.106282 -
International Journal of General... 2021Previous studies have confirmed the biglycan (BGN) as a core gene in stomach adenocarcinoma (STAD). Present study aimed at conducting further investigations to reveal...
OBJECTIVE
Previous studies have confirmed the biglycan (BGN) as a core gene in stomach adenocarcinoma (STAD). Present study aimed at conducting further investigations to reveal the potential function of BGN in STAD.
METHODS
The mRNA and protein expressions of BGN in STAD were firstly evaluated, followed by immune infiltration analyses. The influence of BGN expression on the overall survival of STAD patients was subsequently analyzed, and a restrict survival analysis was performed as well. The protein-protein interaction (PPI) network analysis on the co-expressed genes with BGN was finally adopted to obtain the most important module in the whole network, and significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway associated with hub genes within the main module was further predicted.
RESULTS
(1) We verified the mRNA high expression of BGN in STAD (all <0.05), and higher expression was observed in patients with stage 4 (<0.001) and grade 3 (<0.001). The BGN protein was mainly localized to the golgi apparatus, and protein expression displayed an individual difference. (2) Immune infiltration analysis showed the strongest correlation between BGN expression and abundance of natural killer cell (<0.001), Transforming Growth Factor beta 1 (TGFB1) (<0.001), TNF Receptor Superfamily Member 4 (TNFRSF4) (<0.001) and C-X-C Motif Chemokine Ligand 12 (CXCL12) (<0.001) in STAD. BGN expression was also correlated to immune subtypes (=0.0347) and molecular subtypes (=0.0263) in STAD. (3) High expression of BGN shortened the overall survival time of STAD patients (all <0.01). The influence of BGN expression on the prognosis was statistically affected by several clinical phenotypes and cohorts of patients. Cox regression showed that BGN can be considered as a prognostic predictor of STAD (<0.05). (4) Pathway analysis indicated that BGN possibly participated in ECM-receptor interaction, focal adhesion, human papillomavirus infection and PI3K-Akt signaling pathway (all <0.001).
CONCLUSION
BGN was highly expressed in STAD, implying a poor prognosis of patients. Relevant signal pathways associated with BGN were distinguished as well. BGN could be used as a potential therapeutic biomarker for STAD.
PubMed: 34295178
DOI: 10.2147/IJGM.S321641 -
The Journal of Infectious Diseases Jun 2019Borrelia burgdorferi sensu lato spirochetes (Borrelia) causing Lyme borreliosis are able to disseminate from the initial entry site to distant organs in the host....
BACKGROUND
Borrelia burgdorferi sensu lato spirochetes (Borrelia) causing Lyme borreliosis are able to disseminate from the initial entry site to distant organs in the host. Outer-surface adhesins are crucial in the bacterial dissemination and adhesion to various tissues. Two well-characterized Borrelia adhesins, decorin-binding proteins A and B, have been shown to bind to 2 host receptors, decorin and biglycan. However, the role of biglycan in Borrelia infection has not been characterized in vivo.
METHODS
We infected biglycan knockout (KO) and wild-type (WT) C3H mice with strains representing 3 Borrelia genospecies, Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii. The infection was monitored by measuring joint swelling, Borrelia culture, polymerase chain reaction analysis, and serologic analysis. The host immune responses were analyzed by histological scoring of the inflammation in tissues and by cytokine profiling.
RESULTS
B. burgdorferi sensu stricto and B. garinii established long-term infection in mice of both genotypes, while B. afzelii failed to disseminate in KO mice. Further, the B. burgdorferi sensu stricto-infected KO mice had persistent inflammation in the joints.
CONCLUSIONS
The dissemination and tissue colonization of Borrelia and the inflammatory response of the host differ in a mouse biglycan expression- and Borrelia genospecies-dependent manner.
Topics: Adhesins, Bacterial; Animals; Biglycan; Borrelia burgdorferi; Decorin; Female; Lyme Disease; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Polymerase Chain Reaction
PubMed: 30698707
DOI: 10.1093/infdis/jiz050 -
Biomolecules Jul 2023The progressive degeneration of the skeletal musculature in Duchenne muscular dystrophy is accompanied by reactive myofibrosis, fat substitution, and chronic... (Review)
Review
The progressive degeneration of the skeletal musculature in Duchenne muscular dystrophy is accompanied by reactive myofibrosis, fat substitution, and chronic inflammation. Fibrotic changes and reduced tissue elasticity correlate with the loss in motor function in this X-chromosomal disorder. Thus, although dystrophinopathies are due to primary abnormalities in the gene causing the almost-complete absence of the cytoskeletal Dp427-M isoform of dystrophin in voluntary muscles, the excessive accumulation of extracellular matrix proteins presents a key histopathological hallmark of muscular dystrophy. Animal model research has been instrumental in the characterization of dystrophic muscles and has contributed to a better understanding of the complex pathogenesis of dystrophinopathies, the discovery of new disease biomarkers, and the testing of novel therapeutic strategies. In this article, we review how mass-spectrometry-based proteomics can be used to study changes in key components of the endomysium, perimysium, and epimysium, such as collagens, proteoglycans, matricellular proteins, and adhesion receptors. The mouse diaphragm displays severe myofibrosis, making it an ideal model system for large-scale surveys of systematic alterations in the matrisome of dystrophic fibers. Novel biomarkers of myofibrosis can now be tested for their appropriateness in the preclinical and clinical setting as diagnostic, pharmacodynamic, prognostic, and/or therapeutic monitoring indicators.
Topics: Animals; Mice; Mice, Inbred mdx; Diaphragm; Proteomics; Muscular Dystrophy, Duchenne; Muscle, Skeletal; Extracellular Matrix; Extracellular Matrix Proteins; Biomarkers
PubMed: 37509144
DOI: 10.3390/biom13071108 -
International Journal of Molecular... Nov 2021Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to...
BACKGROUND
Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Different ECM proteins are known to initiate platelet adhesion and activation. In atherosclerotic mice, the small, leucine-rich proteoglycan biglycan is important for the regulation of thrombin activity via heparin cofactor II. However, nothing is known about the role of biglycan for hemostasis and thrombosis under nonatherosclerotic conditions.
METHODS
The role of biglycan for platelet adhesion and thrombus formation was investigated using a recombinant protein and biglycan knockout mice.
RESULTS
The present study identified biglycan as important ECM protein for the adhesion and activation of platelets, and the formation of three-dimensional thrombi under flow conditions. Platelet adhesion to immobilized biglycan induces the reorganization of the platelet cytoskeleton. Mechanistically, biglycan binds and activates the major collagen receptor glycoprotein (GP)VI, because reduced platelet adhesion to recombinant biglycan was observed when GPVI was blocked and enhanced tyrosine phosphorylation in a GPVI-dependent manner was observed when platelets were stimulated with biglycan. In vivo, the deficiency of biglycan resulted in reduced platelet adhesion to the injured carotid artery and prolonged bleeding times.
CONCLUSIONS
Loss of biglycan in the vessel wall of mice but not in platelets led to reduced platelet adhesion at the injured carotid artery and prolonged bleeding times, suggesting a crucial role for biglycan as ECM protein that binds and activates platelets via GPVI upon vessel injury.
Topics: Animals; Biglycan; Blood Platelets; Carotid Arteries; Carotid Artery Injuries; Collagen; Cytoskeleton; Extracellular Matrix Proteins; Healthy Volunteers; Hemorrhage; Humans; Integrins; Male; Mice, Inbred C57BL; Platelet Activation; Platelet Adhesiveness; Platelet Membrane Glycoproteins; Thrombosis; Mice
PubMed: 34830059
DOI: 10.3390/ijms222212168 -
Matrix Biology : Journal of the... Jan 2022The cervix undergoes rapid and dramatic shifts in collagen and elastic fiber structure to achieve its disparate physiological roles of competence during pregnancy and...
The cervix undergoes rapid and dramatic shifts in collagen and elastic fiber structure to achieve its disparate physiological roles of competence during pregnancy and compliance during birth. An understanding of the structure-function relationships of collagen and elastic fibers to maintain extracellular matrix (ECM) homeostasis requires an understanding of the mechanisms executed by non-structural ECM molecules. Small-leucine rich proteoglycans (SLRPs) play key functions in biology by affecting collagen fibrillogenesis and regulating enzyme and growth factor bioactivities. In the current study, we evaluated collagen and elastic fiber structure-function relationships in mouse cervices using mice with genetic ablation of decorin and/or biglycan genes as representative of Class I SLRPs, and lumican gene representative of Class II SLRP. We identified structural defects in collagen fibril and elastic fiber organization in nonpregnant mice lacking decorin, or biglycan or lumican with variable resolution of defects noted during pregnancy. The severity of collagen and elastic fiber defects was greater in nonpregnant mice lacking both decorin and biglycan and defects were maintained throughout pregnancy. Loss of biglycan alone reduced tissue extensibility in nonpregnant mice while loss of both decorin and biglycan manifested in decreased rupture stretch in late pregnancy. Collagen cross-link density was similar in the Class I SLRP null mice as compared to wild-type nonpregnant and pregnant controls. A broader range in collagen fibril diameter along with an increase in mean fibril spacing was observed in the mutant mice compared to wild-type controls. Collectively, these findings uncover functional redundancy and hierarchical roles of Class I and Class II SLRPs as key regulators of cervical ECM remodeling in pregnancy. These results expand our understating of the critical role SLRPs play to maintain ECM homeostasis in the cervix.
Topics: Animals; Biglycan; Cervix Uteri; Chondroitin Sulfate Proteoglycans; Decorin; Extracellular Matrix Proteins; Female; Fibromodulin; Humans; Lumican; Mice; Pregnancy; Small Leucine-Rich Proteoglycans; Uterine Cervical Neoplasms
PubMed: 34863915
DOI: 10.1016/j.matbio.2021.11.004 -
Data in Brief Apr 2023This dataset is composed of photomicrographs of the immunohistochemical expression of Biglycan (BGN) in breast tissue, with and without cancer, using only the staining...
This dataset is composed of photomicrographs of the immunohistochemical expression of Biglycan (BGN) in breast tissue, with and without cancer, using only the staining of 3-3' diaminobenzidine (DAB), after processing images with color deconvolution plugin, from Image J. The immunohistochemical DAB expression of BGN was obtained using the monoclonal antibody (M01) (clone 4E1-1G7 - Abnova Corporation, mouse anti-human). Photomicrographs were obtained, under standard conditions, using an optical microscope, with UPlanFI 100x objective (resolution: 2.75 mm), yielding an image size of 4800 × 3600 pixels. After color deconvolution, the dataset with 336 images was divided into 2 two categories: (I) with cancer and (II) without cancer. This dataset allows the training and validation of machine learning models to diagnose, recognize and classify the presence of breast cancer, using the intensity of the colors of the BGN.
PubMed: 36879615
DOI: 10.1016/j.dib.2023.108978 -
The FEBS Journal Aug 2019It is well established that biglycan, a small leucine-rich proteoglycan, acts as an extracellular matrix-derived danger signal in its soluble form. By binding to innate... (Review)
Review
It is well established that biglycan, a small leucine-rich proteoglycan, acts as an extracellular matrix-derived danger signal in its soluble form. By binding to innate immunity Toll-like receptors (TLR) 2 and 4, biglycan initiates and perpetuates the inflammatory response. Previous work has conveyed that biglycan's role in inflammation extends far beyond its function as a canonical danger signal. It has been shown that biglycan acts in an anti-inflammatory capacity, wherein it tightly regulates the inflammatory response. In this review, we will discuss a paradigm shift to our understanding of biglycan signaling in inflammation. Mounting evidence suggests that the selective interactions between biglycan, TLRs, and their adapter proteins critically regulate downstream signaling and disease outcome. Biglycan can act as a high-affinity ligand for TLR coreceptors CD14 and CD44, further providing an additional layer of complexity. We propose a novel concept, that biglycan steers signaling toward inflammation by interacting with CD14, whereas it can trigger autophagy by binding to CD44. Thus, biglycan, and perhaps others soluble proteoglycans, could function as molecular switches which could either propagate the signaling of chronic inflammation or promote the resolution of inflammatory processes. Obviously, these new functions have broad implications in the regulation of various inflammatory diseases and could provide the basis for developing novel therapeutic regimens that would selectively target the interactions between biglycan, TLRs, coreceptors, and adapter molecules.
Topics: Animals; Aortic Valve; Aortic Valve Stenosis; Autoimmune Diseases; Autophagy; Biglycan; Calcinosis; Diabetic Nephropathies; Humans; Toll-Like Receptors
PubMed: 30776184
DOI: 10.1111/febs.14791 -
Computational and Mathematical Methods... 2022Biglycan (BGN) is a family member of small leucine-rich repeat proteoglycans. High expression of BGN might enhance the invasion and metastasis in some types of tumors....
BACKGROUND
Biglycan (BGN) is a family member of small leucine-rich repeat proteoglycans. High expression of BGN might enhance the invasion and metastasis in some types of tumors. Here, the prognostic significance of BGN was evaluated in gastric cancer. . Two independent Gene Expression Omnibus (GEO) gastric cancer microarray datasets ( = 64 and = 432) were collected for this study. Kaplan-Meier analysis was applied to evaluate if BGN impacts the outcomes of gastric cancer. Protein-protein interaction (PPI) analysis was performed on gastric cancer-related genes and BGN targets, and those interactions with confidence interval (CI) ≥ 0.7 were chosen to construct a PPI network. The gene set enrichment analysis (GSEA) was used to explore BGN and cancer-related gene signatures. Gene Transcription Regulation Database (GTRD) and ALGGEN-PROMO predicted the transcription factor binding sites (TFBSs) of the BGN promoter. BGN protein level in gastric cancer tissue was determined by immunohistochemistry (IHC). Bioinformatic analysis predicted the putative TFs of BGN.
RESULTS
For gastric cancer, the mRNA expression level of BGN in tumor tissue was significantly higher than that in normal tissue. Kaplan-Meier analysis showed that higher expression of BGN mRNA was significantly associated with more reduced recurrence-free survival (RFS). GSEA results suggested that BGN was significantly enriched in gene signatures related to metastasis and poor prognosis, revealing that BGN might be associated with cell proliferation, poor differentiation, and high invasiveness of gastric cancer. Meanwhile, the putative TFs, including AR, E2F1, and TCF4, were predicted by bioinformatic analysis and also significantly correlated with expression of BGN in mRNA levels.
CONCLUSION
High expression of BGN mRNA was significantly related to poor prognosis, which suggested that BGN was a potential prognostic biomarker and therapeutic target of gastric cancer.
Topics: Biglycan; Biomarkers; Humans; Prognosis; RNA, Messenger; Stomach Neoplasms; Transcription Factors
PubMed: 36110576
DOI: 10.1155/2022/2656480