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The FEBS Journal Jan 2017Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and... (Review)
Review
Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and decorin, play pivotal roles in the regulation of these vital cellular pathways and, as such, are intrinsically involved in cancer initiation and progression. In this minireview, we will address novel functions of biglycan and decorin in inflammation and autophagy, and analyze new emerging signaling events triggered by these proteoglycans, which directly or indirectly modulate these processes. We will critically discuss the dual role of proteoglycan-driven inflammation and autophagy in tumor biology, and delineate the potential mechanisms through which soluble extracellular matrix constituents affect the microenvironment associated with inflammatory and neoplastic diseases.
Topics: Autophagy; Biglycan; Cytokines; Decorin; Endothelial Cells; ErbB Receptors; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Neoplasms; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Proto-Oncogene Proteins c-met; Signal Transduction; Vascular Endothelial Growth Factor A
PubMed: 27860287
DOI: 10.1111/febs.13963 -
Medicine Jul 2022Migration of bladder cancer (BC) cells poses a substantial threat to human health. It is critical to elucidate the mechanism of BC invasion and progression for surgical...
Migration of bladder cancer (BC) cells poses a substantial threat to human health. It is critical to elucidate the mechanism of BC invasion and progression for surgical treatment and the prognosis of patients. Decorin is of interest as an anticancer treatment that can play a vital role in regulating tumorigenesis. The effect of decorin expression on survival in clinical patients was screened and analyzed using bladder urothelial carcinoma data from the Cancer Genome Atlas (TCGA) database. The differential expression of transforming growth factor-β1 (TGF-β1) in tumors was compared against that of normal samples to analyze the correlation between them. MTT, flow cytometry, and Wound/Transwell assays were used to detect cell proliferation, cycle arrest, apoptosis, migration, and invasion. Analysis of TCGA data showed that decorin expression was significantly lower in bladder urothelial carcinoma samples than in normal tissues, while TGF-β1 expression did not change significantly. We found that decorin was correlated with TGF-β1 expression in bladder urothelial cancer. In addition, decorin blocked the G1/S phase by upregulating p21 protein and inhibiting the expression of TGF-β1 and MMP2, promoting the occurrence of apoptosis and inhibiting the proliferation of human BC T24 cells. Moreover, decorin increased the adhesion of tumor cells in vitro, and effectively inhibited cell metastasis. Decorin regulated the expression of TGF-β1 and MMP2 through p21 protein, promoted apoptosis and adhesion, and inhibited the proliferation and metastasis of BC cells.
Topics: Carcinoma, Transitional Cell; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Decorin; Humans; Matrix Metalloproteinase 2; Transforming Growth Factor beta1; Urinary Bladder Neoplasms
PubMed: 35777025
DOI: 10.1097/MD.0000000000029760 -
PloS One 2021Effective patient prognosis necessitates identification of novel tumor promoting drivers of gastric cancer (GC) which contribute to worsened conditions by analysing...
Effective patient prognosis necessitates identification of novel tumor promoting drivers of gastric cancer (GC) which contribute to worsened conditions by analysing TCGA-gastric adenocarcinoma dataset. Small leucine-rich proteoglycans, asporin (ASPN) and decorin (DCN), play overlapping roles in development and diseases; however, the mechanisms underlying their interplay remain elusive. Here, we investigated the complex interplay of asporin, decorin and their interaction with TGFβ in GC tumor and corresponding normal tissues. The mRNA levels, protein expressions and cellular localizations of ASPN and DCN were analyzed using real-time PCR, western blot and immunohistochemistry, respectively. The protein-protein interaction was predicted by in-silico interaction analysis and validated by co-immunoprecipitation assay. The correlations between ASPN and EMT proteins, VEGF and collagen were achieved using western blot analysis. A significant increase in expression of ASPN in tumor tissue vs. normal tissue was observed in both TCGA and our patient cohort. DCN, an effective inhibitor of the TGFβ pathway, was negatively correlated with stages of GC. Co-immunoprecipitation demonstrated that DCN binds with TGFβ, in normal gastric epithelium, whereas in GC, ASPN preferentially binds TGFβ. Possible activation of the canonical TGFβ pathway by phosphorylation of SMAD2 in tumor tissues suggests its role as an intracellular tumor promoter. Furthermore, tissues expressing ASPN showed unregulated EMT signalling. Our study uncovers ASPN as a GC-promoting gene and DCN as tumor suppressor, suggesting that ASPN can act as a prognostic marker in GC. For the first time, we describe the physical interaction of TGFβ with ASPN in GC and DCN with TGFβ in GC and normal gastric epithelium respectively. This study suggests that prevention of ASPN-TGFβ interaction or overexpression of DCN could serve as promising therapeutic strategies for GC patients.
Topics: Decorin; Extracellular Matrix Proteins; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Staging; Phosphorylation; Prognosis; Protein Binding; RNA, Messenger; Smad2 Protein; Stomach Neoplasms; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A
PubMed: 34379688
DOI: 10.1371/journal.pone.0255915 -
The FEBS Journal May 2013The stromal-specific proteoglycan decorin has emerged in recent years as a critical regulator of tumor initiation and progression. Decorin regulates the biology of... (Review)
Review
The stromal-specific proteoglycan decorin has emerged in recent years as a critical regulator of tumor initiation and progression. Decorin regulates the biology of various types of cancer by modulating the activity of several receptor tyrosine kinases coordinating growth, survival, migration, and angiogenesis. Decorin binds to surface receptors for epidermal growth factor and hepatocyte growth factor with high affinity, and negatively regulates their activity and signaling via robust internalization and eventual degradation. The insulin-like growth factor (IGF)-I system plays a critical role in the regulation of cell growth both in vivo and in vitro. The IGF-I receptor (IGF-IR) is also essential for cellular transformation, owing to its ability to enhance cell proliferation and protect cancer cells from apoptosis. Recent data have pointed to a role of decorin in regulating the IGF-I system in both nontransformed and transformed cells. Significantly, there is a surprising dichotomy in the mechanism of decorin action on IGF-IR signaling, which differs considerably between physiological and pathological cellular models. In this review, we summarize the current knowledge on decorin regulation of the IGF-I system in normal and transformed cells, and discuss possible decorin-based therapeutic approaches to target IGF-IR-driven tumors.
Topics: Animals; Cell Proliferation; Cell Transformation, Neoplastic; Decorin; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor I; Ligands; Mice; Phosphorylation; Protein Binding; Receptor, IGF Type 1; Receptor, IGF Type 2; Signal Transduction; Urinary Bladder Neoplasms
PubMed: 23351020
DOI: 10.1111/febs.12149 -
The American Journal of Pathology Aug 2012Decorin, an archetypal member of the small leucine-rich proteoglycan gene family, has a broad binding repertoire that encompasses matrix structural components, such as... (Review)
Review
Decorin, an archetypal member of the small leucine-rich proteoglycan gene family, has a broad binding repertoire that encompasses matrix structural components, such as collagens, and growth factors, particularly those that belong to the transforming growth factor-β ligand superfamily. Within the tumor microenvironment, stromal decorin has an inherent proclivity to directly bind and down-regulate several receptor tyrosine kinases, which are often overexpressed in cancer cells. The decorin interactome commands a powerful antitumorigenic signal by potently repressing and attenuating tumor cell proliferation, survival, migration, and angiogenesis. This collection of interacting molecules also regulates key downstream signaling processes indirectly via the sequestration of growth factors or directly via the antagonism of receptor tyrosine kinases. We propose that decorin can be considered a "guardian from the matrix" because of its innate ability to oppose pro-tumorigenic cues.
Topics: Animals; Cell Transformation, Neoplastic; Decorin; Extracellular Matrix; Humans; Neoplasms; Neovascularization, Pathologic; Stromal Cells
PubMed: 22735579
DOI: 10.1016/j.ajpath.2012.04.029 -
Journal of Biomechanical Engineering Jun 2022Cervical remodeling is critical for a healthy pregnancy. The proper regulation of extracellular matrix (ECM) turnover leads to remodeling throughout gestation,...
Cervical remodeling is critical for a healthy pregnancy. The proper regulation of extracellular matrix (ECM) turnover leads to remodeling throughout gestation, transforming the tissue from a stiff material to a compliant, extensible, viscoelastic tissue prepared for delivery. Small leucine-rich proteoglycans (SLRPs) regulate structural fiber assembly in the cervical ECM and overall tissue material properties. To quantify the SLRPs' mechanical role in the cervix, whole cervix specimens from nonpregnant and late pregnant knockout mice of SLRPs, decorin and biglycan, were subjected to cyclic load-unload, ramp-hold, and load-to-failure mechanical tests. Further, a fiber composite material model, accounting for collagen fiber bundle waviness, was developed to describe the cervix's three-dimensional large deformation equilibrium behavior. In nonpregnant tissue, SLRP knockout cervices have the same equilibrium material properties as wild-type tissue. In contrast, the load-to-failure and ramp-hold tests reveal SLRPs impact rupture and time-dependent relaxation behavior. Loss of decorin in nonpregnant (NP) cervices results in inferior rupture properties. After extensive remodeling, cervical strength is similar between all genotypes, but the SLRP-deficient tissue has a diminished ability to dissipate stress during a ramp-hold. In mice with a combined loss of decorin and biglycan, the pregnant cervix loses its extensibility, compliance, and viscoelasticity. These results suggest that decorin and biglycan are necessary for crucial extensibility and viscoelastic material properties of a healthy, remodeled pregnant cervix.
Topics: Animals; Biglycan; Cervix Uteri; Decorin; Extracellular Matrix; Extracellular Matrix Proteins; Female; Mice; Mice, Knockout; Pregnancy
PubMed: 35348624
DOI: 10.1115/1.4054199 -
Matrix Biology : Journal of the... Jan 2019Autophagy, a fundamental and evolutionarily-conserved eukaryotic pathway, coordinates a complex balancing act for achieving both nutrient and energetic requirements for... (Review)
Review
Autophagy, a fundamental and evolutionarily-conserved eukaryotic pathway, coordinates a complex balancing act for achieving both nutrient and energetic requirements for proper cellular function and homeostasis. We have discovered that soluble proteoglycans evoke autophagy in endothelial cells and mitophagy in breast carcinoma cells by directly interacting with receptor tyrosine kinases, including VEGF receptor 2 and Met. Under these circumstances, autophagic regulation is considered "non-canonical" and is epitomized by the bioactivity of the small leucine-rich proteoglycan, decorin. Soluble matrix-derived cues being transduced downstream of receptor engagement converge upon a newly-discovered nexus of autophagic machinery consisting of Peg3 for endothelial cell autophagy and mitostatin for tumor cell mitophagy. In this thematic mini-review, we will provide an overview of decorin-mediated autophagy and mitophagy and propose that regulating intracellular catabolism is the underlying molecular basis for the versatility of decorin as a potent oncosuppressive agent.
Topics: Autophagy; Carrier Proteins; Decorin; Humans; Kruppel-Like Transcription Factors; Metabolism; Mitophagy; Proto-Oncogene Proteins c-met; Signal Transduction; Tumor Suppressor Proteins; Vascular Endothelial Growth Factor Receptor-2
PubMed: 29080840
DOI: 10.1016/j.matbio.2017.10.005 -
Aging May 2021Desmoplasia in the extracellular matrix (ECM) is one of the hallmarks of pancreatic cancer (PC), a virtually incurable disease. Decorin, a classical small leucine-rich...
Desmoplasia in the extracellular matrix (ECM) is one of the hallmarks of pancreatic cancer (PC), a virtually incurable disease. Decorin, a classical small leucine-rich proteoglycan found in the ECM, was upregulated in PC tissue samples according to the data of TCGA. However, decorin plays a protective role in the ECM. So it is necessary to study the roles of decorin in the progression of PC. A significantly upregulated expression of decorin was observed in the PC tissue samples compared with the normal tissues. However, there was no considerable difference in the level of expression of decorin during different pathological stages, which was supported by the immunoblot analysis. Western blot showed a higher expression of decorin A in the para-carcinoma tissue than in the cancerous tissue but the expression of decorin B, C, and D was elevated in the cancerous tissue. The results of the MTT and scratch wound healing assays revealed an elevated proliferation ability and migration rate in decorin B-overexpressing cells but were inhibited in the decorin A-overexpressing cells. Overexpression of decorin A significantly elevated the expression of the apoptosis-related genes and Decorin B-overexpression elevated proliferation-related genes. All the results showed that decorin B played important roles in the promoting of PC.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Decorin; Disease Progression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Models, Biological; Pancreatic Neoplasms
PubMed: 34021540
DOI: 10.18632/aging.203060 -
The Journal of Histochemistry and... Apr 2012Hepatic fibrosis and cirrhosis are worldwide health care problems, especially in regions with a high rate of hepatitis infection. As these diseases affect a major part... (Review)
Review
Hepatic fibrosis and cirrhosis are worldwide health care problems, especially in regions with a high rate of hepatitis infection. As these diseases affect a major part of the human population, the search for antifibrotic therapies has a high priority in medical research. Transforming growth factor β1 (TGF-β1) is one of the most powerful profibrotic cytokines. Thus, blocking TGF-β1 activity by natural inhibitors represents a valid and logical strategy to combat hepatic fibrosis. One of the natural inhibitors of TGF-β1 is decorin, a small leucine-rich proteoglycan that binds with high affinity to this cytokine and prevents its interaction with pro-fibrotic receptors. Recent evidence has shown that decorin has a protective role in liver fibrogenesis insofar as its genetic ablation in mice leads to enhanced matrix deposition, impaired matrix degradation, and "activation" of hepatic stellate cells, the main producers of fibrotic tissue. Moreover, TGF-β1 exerts a stronger effect when functional decorin is absent. These data provide robust genetic evidence for a direct role of endogenous decorin in preventing and retarding hepatic fibrosis. Thus, boosting the endogenous production of decorin or systemic delivery of recombinant decorin could represent an additional therapeutic modality against hepatic fibrosis.
Topics: Animals; Decorin; Humans; Liver Cirrhosis; Transforming Growth Factor beta
PubMed: 22260996
DOI: 10.1369/0022155412438104 -
The Journal of Histochemistry and... Apr 2018It is now well-established that members of the small leucine-rich proteoglycan (SLRP) family act in their soluble form, released proteolytically from the extracellular... (Review)
Review
It is now well-established that members of the small leucine-rich proteoglycan (SLRP) family act in their soluble form, released proteolytically from the extracellular matrix (ECM), as danger-associated molecular patterns (DAMPs). By interacting with Toll-like receptors (TLRs) and the inflammasome, the two SLRPs, biglycan and decorin, autonomously trigger sterile inflammation. Recent data indicate that these SLRPs, besides their conventional role as pro-inflammatory DAMPs, additionally trigger anti-inflammatory signaling pathways to tightly control inflammation. This is brought about by selective employment of TLRs, their co-receptors, various adaptor molecules, and through crosstalk between SLRP-, reactive oxygen species (ROS)-, and sphingolipid-signaling. In this review, the complexity of SLRP signaling in immune and kidney resident cells and its relevance for renal inflammation is discussed. We propose that the dichotomy in SLRP signaling (pro- and anti-inflammatory) allows for fine-tuning the inflammatory response, which is decisive for the outcome of inflammatory kidney diseases.
Topics: Animals; Autophagy; Biglycan; Decorin; Fibrosis; Humans; Immunity, Innate; Inflammasomes; Inflammation; Kidney; Kidney Diseases; Signal Transduction; Small Leucine-Rich Proteoglycans; Transforming Growth Factor beta
PubMed: 29290137
DOI: 10.1369/0022155417738752