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Frontiers in Oncology 2021The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has... (Review)
Review
The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer development. In this review, we summarize growing evidence for the complex roles of decorin and biglycan signaling in tumor biology and address potential novel therapeutic implications.
PubMed: 34917515
DOI: 10.3389/fonc.2021.801801 -
Advanced Drug Delivery Reviews Feb 2016Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple... (Review)
Review
Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple receptor tyrosine kinases within the target-rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell mitophagy, and angiostasis. Decorin is also pro-inflammatory by modulating macrophage function and cytokine secretion. Decorin suppresses tumorigenic growth, angiogenesis, and prevents metastatic lesions in a variety of in vitro and in vivo tumor models. Therefore, decorin would be an ideal therapeutic candidate for combating solid malignancies.
Topics: Animals; Autophagy; Decorin; ErbB Receptors; Genetic Therapy; Humans; Neoplasms; Neovascularization, Pathologic; Proto-Oncogene Proteins c-met
PubMed: 26522384
DOI: 10.1016/j.addr.2015.10.016 -
Matrix Biology : Journal of the... Feb 2021In cartilage tissue engineering, one key challenge is for regenerative tissue to recapitulate the biomechanical functions of native cartilage while maintaining normal...
In cartilage tissue engineering, one key challenge is for regenerative tissue to recapitulate the biomechanical functions of native cartilage while maintaining normal mechanosensitive activities of chondrocytes. Thus, it is imperative to discern the micromechanobiological functions of the pericellular matrix, the ~ 2-4 µm-thick domain that is in immediate contact with chondrocytes. In this study, we discovered that decorin, a small leucine-rich proteoglycan, is a key determinant of cartilage pericellular matrix micromechanics and chondrocyte mechanotransduction in vivo. The pericellular matrix of decorin-null murine cartilage developed reduced content of aggrecan, the major chondroitin sulfate proteoglycan of cartilage and a mild increase in collagen II fibril diameter vis-à-vis wild-type controls. As a result, decorin-null pericellular matrix showed a significant reduction in micromodulus, which became progressively more pronounced with maturation. In alignment with the defects of pericellular matrix, decorin-null chondrocytes exhibited decreased intracellular calcium activities, [Ca], in both physiologic and osmotically evoked fluidic environments in situ, illustrating impaired chondrocyte mechanotransduction. Next, we compared [Ca] activities of wild-type and decorin-null chondrocytes following enzymatic removal of chondroitin sulfate glycosaminoglycans. The results showed that decorin mediates chondrocyte mechanotransduction primarily through regulating the integrity of aggrecan network, and thus, aggrecan-endowed negative charge microenvironment in the pericellular matrix. Collectively, our results provide robust genetic and biomechanical evidence that decorin is an essential constituent of the native cartilage matrix, and suggest that modulating decorin activities could improve cartilage regeneration.
Topics: Aggrecans; Animals; Biomechanical Phenomena; Calcium Signaling; Cartilage, Articular; Decorin; Extracellular Matrix; Female; Loss of Function Mutation; Male; Mechanotransduction, Cellular; Mice; Regeneration
PubMed: 33246102
DOI: 10.1016/j.matbio.2020.11.002 -
Matrix Biology : Journal of the... Apr 2015Angiogenesis, the formation of new blood vessels from preexisting vessels, is a highly complex process. It is regulated in a finely-tuned manner by numerous molecules... (Review)
Review
Angiogenesis, the formation of new blood vessels from preexisting vessels, is a highly complex process. It is regulated in a finely-tuned manner by numerous molecules including not only soluble growth factors such as vascular endothelial growth factor and several other growth factors, but also a diverse set of insoluble molecules, particularly collagenous and non-collagenous matrix constituents. In this review we have focused on the role and potential mechanisms of a multifunctional small leucine-rich proteoglycan decorin in angiogenesis. Depending on the cellular and molecular microenvironment where angiogenesis occurs, decorin can exhibit either a proangiogenic or an antiangiogenic activity. Nevertheless, in tumorigenesis-associated angiogenesis and in various inflammatory processes, particularly foreign body reactions and scarring, decorin exhibits an antiangiogenic activity, thus providing a potential basis for the development of decorin-based therapies in these pathological situations.
Topics: Angiogenesis Inhibitors; Animals; Cellular Microenvironment; Decorin; Extracellular Matrix; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic
PubMed: 25661523
DOI: 10.1016/j.matbio.2015.01.023 -
Journal of the College of Physicians... Nov 2021To evaluate immunohistochemical (IHC) staining of decorin and vascular endothelial growth factor (VEGF) of ovarian and endometrial tissues in patients with and without...
OBJECTIVE
To evaluate immunohistochemical (IHC) staining of decorin and vascular endothelial growth factor (VEGF) of ovarian and endometrial tissues in patients with and without endometriosis. Study Design: Descriptive study.
PLACE AND DURATION OF STUDY
Department of Obstetrics and Gynecology, ZeynepKamil Training and Research Hospital, Istanbul, Turkey, between Istanbul, TurkeyJanuary 2018 and June 2019.
METHODOLOGY
Thirty patients, who underwent total abdominal hysterectomy (TAH) + bilateral salpingo-oophorectomy (BSO)/unilateral salpingo-oophorectomy (USO) and were in the proliferative phase of menstrual cycle,were included. The study population consisted of 20 patients (patient group) with an endometriomaand the control group consisted of 10 patients who were operated for benign gynecological pathologies.The ovarian and endometrial tissue specimens were collected from the archives. IHC staining was performed using decorin and VEGF.
RESULTS
Decorin analysis showed a significantly higher intensity of staining in both endometrial and ovarian tissues in control group than patient group. Patients with endometriosis had a lower intensity of staining of decorin and a higher intensity of staining of VEGF compared to control group. There was a negative, statistically significant concordance between VEGF and decorin staining of endometrial tissues of both groups (concordance rate -0.560, p=0.001). Therewas a negative, statistically significant concordance between VEGF and decorin staining of ovarian tissues of both groups (concordance rate -0.564, p<0.001).
CONCLUSION
Angiogenesis plays a critical role in endometriosisand interaction between decorin and VEGF,which suggests that decorin may be a promising molecule for the treatment of endometriosis. Key Words: Decorin, Endometriosis, Immunohistochemical staining, Vascular endothelial Growth factor.
Topics: Decorin; Endometriosis; Endometrium; Female; Humans; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 34689484
DOI: 10.29271/jcpsp.2021.11.1285 -
Clinical Kidney Journal Aug 2023Endothelial damage and cardiovascular disease complicate chronic kidney disease (CKD). The increased atherogenicity observed in patients with CKD can be linked to...
BACKGROUND
Endothelial damage and cardiovascular disease complicate chronic kidney disease (CKD). The increased atherogenicity observed in patients with CKD can be linked to microinflammation and endothelial damage. Circulating endothelial glycocalyx degradation products, such as perlecan and decorin, tend to be elevated in CKD. We aimed to explore the association between the plasma perlecan and decorin levels and this pro-inflammatory and atherogenic state by studying monocyte subpopulations and intracellular adhesion molecule (ICAM)-1 expression in patients with CKD.
METHODS
We studied 17 healthy controls, 23 patients with advanced CKD, 25 patients on haemodialysis, 23 patients on peritoneal dialysis and 20 patients who underwent kidney transplantation. Perlecan and decorin levels were evaluated using enzyme-linked immunosorbent assays, and the monocyte phenotype was analysed using direct immunofluorescence and flow cytometry.
RESULTS
The plasma perlecan levels were higher in patients with CKD than in the healthy controls. These levels were associated with a higher prevalence of ICAM-1+ monocytes. Conversely, patients with advanced CKD (pre-dialysis) had higher plasma decorin levels, which were associated with a reduced ICAM-1 expression per monocyte.
CONCLUSIONS
Elevated perlecan levels in CKD may be associated with a higher prevalence of ICAM-1+ monocytes and a pro-inflammatory phenotype. Elevated decorin levels may act as a negative regulator of ICAM-1 expression in monocytes. Therefore, perlecan and decorin may be related to inflammation and monocyte activation in CKD and may act as potential markers of endothelial damage.
PubMed: 37529650
DOI: 10.1093/ckj/sfad051 -
Advances in Experimental Medicine and... 2021Proteoglycans consist of protein cores to which at least one glycosaminoglycan chain is attached. They play important roles in the physiology and biomechanical function...
Proteoglycans consist of protein cores to which at least one glycosaminoglycan chain is attached. They play important roles in the physiology and biomechanical function of tendons, ligaments, cardiovascular system, and other systems through their involvement in regulation of assembly and maintenance of extracellular matrix, and through their participation in cell proliferation together with growth factors. They can be divided into two main groups, small and large proteoglycans. The small proteoglycans are also known as small leucine-rich proteoglycans (SLRPs) which are encoded by 18 genes and are further subclassified into Classes I-V. Several members of Class I and II, such as decorin and biglycan from Class I, and Class II fibromodulin and lumican, are known to regulate collagen fibrillogenesis. Decorin limits the diameter of collagen fibrils during fibrillogenesis. The function of biglycan in fibrillogenesis is similar to that of decorin. Though biomechanical function of tendon is compromised in decorin-deficient mice, decorin can substitute for lack of biglycan in biglycan-deficient mice. New data also indicate an important role for biglycan in disorders of the cardiovascular system, including aortic valve stenosis and aortic dissection. Two members of the Class II of SLRPs, fibromodulin and lumican bind to the same site within the collagen molecule and can substitute for each other in fibromodulin- or lumican-deficient mice.Aggrecan and versican are the major representatives of the large proteoglycans. Though they are mainly found in the cartilage where they provide resilience and toughness, they are present also in tensile portions of tendons and, in slightly different biochemical form in fibrocartilage. Degradation by aggrecanase is responsible for the appearance of different forms of aggrecan and versican in different parts of the tendon where these cleaved forms play different roles. In addition, they are important components of the ventricularis of cardiac valves. Mutations in the gene for versican or in the gene for elastin (which binds to versican ) lead to severe disruptions of normal developmental of the heart at least in mice.
Topics: Animals; Collagen; Decorin; Extracellular Matrix; Keratan Sulfate; Mice; Versicans
PubMed: 34807417
DOI: 10.1007/978-3-030-80614-9_5 -
International Journal of Molecular... Jan 2021Proteoglycan (PG) is a glycosaminoglycan (GAG)-conjugated protein essential for maintaining tissue strength and elasticity. The most abundant skin PGs, biglycan and...
Proteoglycan (PG) is a glycosaminoglycan (GAG)-conjugated protein essential for maintaining tissue strength and elasticity. The most abundant skin PGs, biglycan and decorin, have been reported to decrease as skin ages. Insulin-like growth factor-1 (IGF-1) is important in various physiological functions such as cell survival, growth, and apoptosis. It is well known that the serum level of IGF-1 decreases with age. Therefore, we investigated whether and how IGF-1 affects biglycan and decorin. When primary cultured normal human dermal fibroblasts (NHDFs) were treated with IGF-1, protein levels of biglycan and decorin increased, despite no difference in mRNA expression. This increase was not inhibited by transcription blockade using actinomycin D, suggesting that it is mediated by IGF-1-induced enhanced translation. Additionally, both mRNA and protein expression of ADAMTS5, a PG-degrading enzyme, were decreased in IGF-1-treated NHDFs. Knockdown of ADAMTS5 via RNA interference increased protein expression of biglycan and decorin. Moreover, mRNA and protein expression of ADAMTS5 increased in aged human skin tissues compared to young tissue. Overall, IGF-1 increases biglycan and decorin, which is achieved by improving protein translation to increase synthesis and preventing ADAMTS5-mediated degradation. This suggests a new role of IGF-1 as a regulator for biglycan and decorin in skin aging process.
Topics: ADAMTS5 Protein; Adolescent; Adult; Aged; Aged, 80 and over; Biglycan; Cells, Cultured; Child; Decorin; Down-Regulation; Female; Fibroblasts; Gene Expression Profiling; Gene Knockdown Techniques; Healthy Volunteers; Humans; Insulin-Like Growth Factor I; Male; Primary Cell Culture; Protein Biosynthesis; Proteolysis; Skin; Skin Aging; Up-Regulation; Young Adult
PubMed: 33573338
DOI: 10.3390/ijms22031403 -
Matrix Biology : Journal of the... Sep 2016Decorin, a prototype small leucine-rich proteoglycan, regulates a vast array of cellular processes including collagen fibrillogenesis, wound repair, angiostasis, tumor... (Review)
Review
Decorin, a prototype small leucine-rich proteoglycan, regulates a vast array of cellular processes including collagen fibrillogenesis, wound repair, angiostasis, tumor growth, and autophagy. This functional versatility arises from a wide array of decorin/protein interactions also including interactions with its single glycosaminoglycan side chain. The decorin-binding partners encompass numerous categories ranging from extracellular matrix molecules to cell surface receptors to growth factors and enzymes. Despite the diversity of the decorin interacting network, two main roles emerge as prominent themes in decorin function: maintenance of cellular structure and outside-in signaling, culminating in anti-tumorigenic effects. Here we present contemporary knowledge regarding the decorin interacting network and discuss in detail the biological relevance of these pleiotropic interactions, some of which could be targeted by therapeutic interventions.
Topics: Animals; Collagen; Decorin; Extracellular Matrix; Glycosaminoglycans; Humans; Protein Interaction Maps; Proteoglycans; Signal Transduction
PubMed: 27693454
DOI: 10.1016/j.matbio.2016.09.009 -
Matrix Biology : Journal of the... Jun 2021In recent years, extensive research has uncovered crucial regulatory roles for the extracellular matrix (ECM) in regulating autophagy. Autophagy is a ubiquitous and...
In recent years, extensive research has uncovered crucial regulatory roles for the extracellular matrix (ECM) in regulating autophagy. Autophagy is a ubiquitous and highly conserved catabolic process that allows the selective removal and recycling of cytosolic components via lysosomal or vacuolar degradation. Due to its pivotal role in cellular homeostasis, the impairment of autophagy is involved in the pathophysiology of numerous diseases, comprising infectious diseases, immune and neurodegenerative disorders, renal and hepatic diseases, intervertebral and cartilage disorders, as well as fibrosis and cancer. Several ECM-derived proteoglycans and proteins, including decorin, biglycan, endorepellin, endostatin, collagen VI, and plasminogen kringle 5, have been identified as strong inducers of autophagy. In contrast, laminin α2, perlecan, and lumican exert opposite function by suppressing autophagy. Importantly, by direct interaction with various receptors, which interplay with their co-receptors and adhesion molecules, the ECM is able to direct autophagy in a molecular and cell context-specific manner. Thus, vast pharmacological potential resides in translating this knowledge into the development of ECM-derived therapeutics selectively regulating autophagy.
Topics: Autophagy; Biglycan; Collagen; Decorin; Extracellular Matrix; Extracellular Matrix Proteins
PubMed: 34217800
DOI: 10.1016/j.matbio.2021.06.002