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Clinical and Translational Medicine Nov 2022Colon cancer is the second leading cause of death worldwide. Exploring key regulators in colon cancer metastatic progression could lead to better outcomes for patients.
BACKGROUND
Colon cancer is the second leading cause of death worldwide. Exploring key regulators in colon cancer metastatic progression could lead to better outcomes for patients.
METHODS
Initially, the transcriptional profiles of 681 colonrectal cancer (CRC) cases were used to discover signature genes that were significantly correlated with colon cancer metastasis. These signature genes were then validated using another independent 210 CRC cases' transcriptomics and proteomics profiles, and Kaplan-Meier regression analyses were used to screen the key regulators with patients' survival. Immunohistochemical staining was used to confirm the biomarkers, and transit knockdown was used to explore their implications on colon cancer cells migration and invasion abilities. The impact on the key signalling molecules in epithelial-mesenchymal transition (EMT) process that drive tumour metastasis was tested using Western blot. The response to clinical standard therapeutic drugs was compared to clinical prognosis of key regulators using an ROC plotter.
RESULTS
Five genes (BGN, THBS2, SPARC, CDH11 and SPP1) were initially identified as potential biomarkers and therapeutic targets of colon cancer metastasis. The most significant signatures associated with colon cancer metastasis were determined to be BGN and THBS2. Furthermore, highly expression of BGN and THBS2 in tumours was linked to a worse survival rate. BGN and THBS2 knockdown significantly reduced colon cancer cells migration and invasion, as well as down-regulating three EMT-related proteins (Snail, Vimentin and N-cadherin), and increasing the proliferation inhibitory effect of 5-fluorouracil, irinotecan and oxaliplatin treatment.
CONCLUSIONS
CRC metastatic progression, EMT phenotypic transition and poor survival time have been linked to BGN and THBS2. They could be utilized as potential diagnostic and therapeutic targets for colon cancer metastatic patients with a better prognosis.
Topics: Humans; Biglycan; Biomarkers; Cell Movement; Colonic Neoplasms; Epithelial-Mesenchymal Transition; Prognosis
PubMed: 36377223
DOI: 10.1002/ctm2.973 -
Experimental Eye Research Oct 2016The small leucine rich repeat proteoglycans are major components of the cornea. Lumican, keratocan, decorin, biglycan and osteoglycin are present throughout the adult... (Review)
Review
The small leucine rich repeat proteoglycans are major components of the cornea. Lumican, keratocan, decorin, biglycan and osteoglycin are present throughout the adult corneal stroma, and fibromodulin in the peripheral limbal area. In the cornea literature these proteoglycan have been reviewed as structural, collagen fibril-regulating proteins of the cornea. However, these proteoglycans are members of the leucine-rich-repeat superfamily, and share structural similarities with pathogen recognition toll-like receptors. Emerging studies are showing that these have a range of interactions with cell surface receptors, chemokines, growth factors and pathogen associated molecular patterns and are able to regulate host immune response, inflammation and wound healing. This review discusses what is known about their innate immune-related role directly in the cornea, and studies outside the field that find interesting links with innate immune and wound healing responses that are likely to be relevant to the ocular surface. In addition, the review discusses phenotypes of mice with targeted deletion of proteoglycan genes and genetic variants associated with human pathologies.
Topics: Animals; Cornea; Corneal Injuries; Humans; Keratitis; Small Leucine-Rich Proteoglycans; Wound Healing
PubMed: 27569372
DOI: 10.1016/j.exer.2016.08.015 -
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 -
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 -
The International Journal of... Sep 2014Chronic renal inflammation is often associated with a progressive accumulation of various extracellular matrix constituents, including several members of the small... (Review)
Review
Chronic renal inflammation is often associated with a progressive accumulation of various extracellular matrix constituents, including several members of the small leucine-rich proteoglycan (SLRP) gene family. It is becoming increasingly evident that the matrix-unbound SLRPs strongly regulate the progression of inflammation and fibrosis. Soluble SLRPs are generated either via partial proteolytic processing of collagenous matrices or by de novo synthesis evoked by stress or injury. Liberated SLRPs can then bind to and activate Toll-like receptors, thus modulating downstream inflammatory signaling. Preclinical animal models and human studies have recently identified soluble biglycan as a key initiator and regulator of various inflammatory renal diseases. Biglycan, generated by activated macrophages, can enter the circulation and its elevated levels in plasma and renal parenchyma correlate with unfavorable renal function and outcome. In this review, we will focus on the critical role of soluble biglycan in inflammatory signaling in various renal disorders. Moreover, we will provide new data implicating proinflammatory effects of soluble decorin in unilateral ureteral obstruction. Finally, we will critically evaluate the potential application of soluble biglycan vis-à-vis other SLRPs (decorin, lumican and fibromodulin) as a promising target and novel biomarker of inflammatory renal diseases.
Topics: Animals; Biglycan; Biomarkers; Humans; Inflammation; Kidney Diseases
PubMed: 25091702
DOI: 10.1016/j.biocel.2014.07.020 -
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 -
The FEBS Journal Jan 2017This thematic minireview series highlights new concepts in matrix pathobiology. The reviews in this series cover the roles of the two matrix proteoglycans, decorin and...
This thematic minireview series highlights new concepts in matrix pathobiology. The reviews in this series cover the roles of the two matrix proteoglycans, decorin and biglycan, in inflammation and autophagy, the various functions of syndecans in cancer development and prognosis and the recently discovered mechanisms underlying the multiple roles of heparanase in cancer progression, inflammation, and autophagy.
Topics: Biglycan; Decorin; Extracellular Matrix; Glucuronidase; Humans; Neoplasms; Syndecans
PubMed: 28075546
DOI: 10.1111/febs.13945