SRGN promotes macrophage recruitment through CCL3 in osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a degenerative disease that affects synovial joints and leads to significant pain and disability, particularly in older adults. Infiltration of macrophages plays a key role in the progression of OA. However, the mechanisms underlying macrophage recruitment in OA are not fully understood. METHODS: The Serglycin (SRGN) expression pattern was analyzed, along with its association with macrophage infiltration in OA, using bioinformatic methods. SRGN expression in chondrocytes was altered by small interfering RNA (siRNA) and plasmids. Conditioned media (CM) was obtained from transfected chondrocytes to establish a co-culture model of chondrocytes and THP-1 derived macrophages. The impact of SRGN on macrophage recruitment was evaluated using a transwell assay. Furthermore, the regulatory effect of SRGN on CCL3 was validated through qPCR, WB, and ELISA experiments. RESULTS: In OA patients, the upregulation of SRGN positively correlated with K-L grade and macrophage infiltration. It was found that SRGN expression and secretion were up-regulated in OA and that it can promote macrophage migration in vitro. Further investigation showed that SRGN affects macrophage migration by regulating the expression of CCL3. CONCLUSION: SRGN in chondrocytes plays a role in promoting the recruitment of THP-1 derived macrophages in vitro by regulating production of CCL3.

The Expression of Serglycin Is Required for Active Transforming Growth Factor ß Receptor I Tumorigenic Signaling in Glioblastoma Cells and Paracrine Activation of Stromal Fibroblasts via CXCR-2.

Serglycin (SRGN) is a pro-tumorigenic proteoglycan expressed and secreted by various aggressive tumors including glioblastoma (GBM). In our study, we investigated the interplay and biological outcomes of SRGN with TGFßRI, CXCR-2 and inflammatory mediators in GBM cells and fibroblasts. SRGN overexpression is associated with poor survival in GBM patients. High SRGN levels also exhibit a positive correlation with increased levels of various inflammatory mediators including members of TGFß signaling pathway, cytokines and receptors including CXCR-2 and proteolytic enzymes in GBM patients. SRGN-suppressed GBM cells show decreased expressions of TGFßRI associated with lower responsiveness to the manipulation of TGFß/TGFßRI pathway and the regulation of pro-tumorigenic properties. Active TGFßRI signaling in control GBM cells promotes their proliferation, invasion, proteolytic and inflammatory potential. Fibroblasts cultured with culture media derived by control SRGN-expressing GBM cells exhibit increased proliferation, migration and overexpression of cytokines and proteolytic enzymes including CXCL-1, IL-8, IL-6, IL-1ß, CCL-20, CCL-2, and MMP-9. Culture media derived by SRGN-suppressed GBM cells fail to induce the above properties to fibroblasts. Importantly, the activation of fibroblasts by GBM cells not only relies on the expression of SRGN in GBM cells but also on active CXCR-2 signaling both in GBM cells and fibroblasts.

SRGN amplifies microglia-mediated neuroinflammation and exacerbates ischemic brain injury.

BACKGROUND: Microglia is the major contributor of post-stroke neuroinflammation cascade and the crucial cellular target for the treatment of ischemic stroke. Currently, the endogenous mechanism underlying microglial activation following ischemic stroke remains elusive. Serglycin (SRGN) is a proteoglycan expressed in immune cells. Up to now, the role of SRGN on microglial activation and ischemic stroke is largely unexplored. METHODS: Srgn knockout (KO), Cd44-KO and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO) to mimic ischemic stroke. Exogenous SRGN supplementation was achieved by stereotactic injection of recombinant mouse SRGN (rSRGN). Cerebral infarction was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Neurological functions were evaluated by the modified neurological severity score (mNSS) and grip strength. Microglial activation was detected by Iba1 immunostaining, morphological analysis and cytokines' production. Neuronal death was examined by MAP2 immunostaining and FJB staining. RESULTS: The expression of SRGN and its receptor CD44 was significantly elevated in the ischemic mouse brains, especially in microglia. In addition, lipopolysaccharide (LPS) induced SRGN upregulation in microglia in vitro. rSRGN worsened ischemic brain injury in mice and amplified post-stroke neuroinflammation, while gene knockout of Srgn exerted reverse impacts. rSRGN promoted microglial proinflammatory activation both in vivo and in vitro, whereas Srgn-deficiency alleviated microglia-mediated inflammatory response. Moreover, the genetic deletion of Cd44 partially rescued rSRGN-induced excessed neuroinflammation and ischemic brain injury in mice. Mechanistically, SRGN boosted the activation of NF-κB signal, and increased glycolysis in microglia. CONCLUSION: SRGN acts as a novel therapeutic target in microglia-boosted proinflammatory response following ischemic stroke.

Investigation of serum endocan and serglycin levels in obstructive sleep apnea.

BACKGROUND: Apnea-related hypoxia, hypercapnia, and blood pressure fluctuations cause production of various proinflammatory cytokines and trigger a vicious cycle that results in vascular endothelial damage and systemic inflammation in obstructive sleep apnea (OSA). Endothelial function is frequently impaired in OSA even in the absence of significant cardiac or vascular disorders. AIMS: This study aimed to investigate the serum endocan and serglycin levels in OSA patients. METHODS: This prospective study included 78 consecutive patients who admitted to the sleep laboratory of a tertiary referral center with the complaints of daytime sleepiness, witnessed sleep apnea, and/or snoring and who underwent all-night polysomnography (PSG). After PSG, the patients were divided into four groups in relation with their apnea-hypopnea indexes. The groups were compared for endocan and serglycin levels and their correlations with OSA severity. The correlations with demographic data and PSG findings were also investigated. RESULTS: The OSA and the control groups had significantly different endocan and serglycin levels ([Formula: see text], for both). On univariate logistic regression analysis, it was found that serglycin and endocan levels and BMI were predictors of OSA. Multiple logistic regression analysis showed that endocan and serglycin levels were independent predictors for OSA ([Formula: see text] and [Formula: see text], respectively). CONCLUSIONS: We have demonstrated that elevated endocan and serglycin levels are predictors for OSA. Furthermore, we have showed for the first time in literature that serglycin is correlated with OSA and is an independent predictor for OSA.

M6PR- and EphB4-Rich Exosomes Secreted by Serglycin-Overexpressing Esophageal Cancer Cells Promote Cancer Progression.

Accumulating evidence shows that exosomes participate in cancer progression. However, the functions of cancer cell exosome-transmitted proteins are rarely studied. Previously, we reported that serglycin (SRGN) overexpression promotes invasion and metastasis of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the paracrine effects of exosomes from SRGN-overexpressing ESCC cells (SRGN Exo) on ESCC cell invasion and tumor angiogenesis, and used mass spectrometry to identify exosomal proteins involved. Cation-dependent mannose-6-phosphate receptor (M6PR) and ephrin type-B receptor 4 (EphB4) were pronouncedly upregulated in SRGN Exo. Upregulated exosomal M6PR mediated the pro-angiogenic effects of SRGN Exo both in vitro and in vivo, while augmented exosomal EphB4 mediated the pro-invasive effect of SRGN Exo on ESCC cells in vitro. In addition, in vitro studies showed that manipulation of M6PR expression affected the viability and migration of ESCC cells. Both M6PR and EphB4 expression levels were positively correlated with that of SRGN in the serum of patients with ESCC. High level of serum M6PR was associated with poor overall survival rates. Taken together, this study presents the first proof that exosomal M6PR and EphB4 play essential roles in tumor angiogenesis and malignancy, and that serum M6PR is a novel prognostic marker for ESCC patients.

Proteoglycans Determine the Dynamic Landscape of EMT and Cancer Cell Stemness.

Proteoglycans (PGs) are pivotal components of extracellular matrices, involved in a variety of processes such as migration, invasion, morphogenesis, differentiation, drug resistance, and epithelial-to-mesenchymal transition (EMT). Cellular plasticity is a crucial intermediate phenotypic state acquired by cancer cells, which can modulate EMT and the generation of cancer stem cells (CSCs). PGs affect cell plasticity, stemness, and EMT, altering the cellular shape and functions. PGs control these functions, either by direct activation of signaling cascades, acting as co-receptors, or through regulation of the availability of biological compounds such as growth factors and cytokines. Differential expression of microRNAs is also associated with the expression of PGs and their interplay is implicated in the fine tuning of cancer cell phenotype and potential. This review summarizes the involvement of PGs in the regulation of EMT and stemness of cancer cells and highlights the molecular mechanisms.

Serglycin Is Involved in TGF-ß Induced Epithelial-Mesenchymal Transition and Is Highly Expressed by Immune Cells in Breast Cancer Tissue.

Serglycin is a proteoglycan highly expressed by immune cells, in which its functions are linked to storage, secretion, transport, and protection of chemokines, proteases, histamine, growth factors, and other bioactive molecules. In recent years, it has been demonstrated that serglycin is also expressed by several other cell types, such as endothelial cells, muscle cells, and multiple types of cancer cells. Here, we show that serglycin expression is upregulated in transforming growth factor beta (TGF-ß) induced epithelial-mesenchymal transition (EMT). Functional studies provide evidence that serglycin plays an important role in the regulation of the transition between the epithelial and mesenchymal phenotypes, and it is a significant EMT marker gene. We further find that serglycin is more expressed by breast cancer cell lines with a mesenchymal phenotype as well as the basal-like subtype of breast cancers. By examining immune staining and single cell sequencing data of breast cancer tissue, we show that serglycin is highly expressed by infiltrating immune cells in breast tumor tissue.

Serglycin-Deficiency Causes Reduced Weight Gain and Changed Intestinal Cytokine Responses in Mice Infected With Giardia intestinalis.

The proteoglycan serglycin (SG) is expressed by different innate and adaptive immune cells, e.g. mast cells, macrophages, neutrophils, and cytotoxic T lymphocytes, where SG contributes to correct granule storage and extracellular activity of inflammatory mediators. Here the serglycin-deficient (SG-/-) mouse strain was used to investigate the impact of SG on intestinal immune responses during infection with the non-invasive protozoan parasite Giardia intestinalis. Young (≈11 weeks old) oral gavage-infected congenic SG-/- mice showed reduced weight gain as compared with the infected SG+/+ littermate mice and the PBS-challenged SG-/- and SG+/+ littermate mice. The infection caused no major morphological changes in the small intestine. However, a SG-independent increased goblet cell and granulocyte cell count was observed, which did not correlate with an increased myeloperoxidase or neutrophil elastase activity. Furthermore, infected mice showed increased serum IL-6 levels, with significantly reduced serum IL-6 levels in infected SG-deficient mice and decreased intestinal expression levels of IL-6 in the infected SG-deficient mice. In infected mice the qPCR analysis of alarmins, chemokines, cytokines, and nitric oxide synthases (NOS), showed that the SG-deficiency caused reduced intestinal expression levels of TNF-α and CXCL2, and increased IFN-γ, CXCL1, and NOS1 levels as compared with SG-competent mice. This study shows that SG plays a regulatory role in intestinal immune responses, reflected by changes in chemokine and cytokine expression levels and a delayed weight gain in young SG-/- mice infected with G. intestinalis.

Proteoglycans and their functions in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly malignant disease that has a poor prognosis. Its high lethality is mainly due to the lack of symptoms at early stages, which culminates in diagnosis at a late stage when the tumor has already metastasized. Unfortunately, the common cancer biomarkers have low sensitivity and specificity in esophageal cancer. Therefore, a better understanding of the molecular mechanisms underlying ESCC progression is needed to identify novel diagnostic markers and therapeutic targets for intervention. The invasion of cancer cells into the surrounding tissue is a crucial step for metastasis. During metastasis, tumor cells can interact with extracellular components and secrete proteolytic enzymes to remodel the surrounding tumor microenvironment. Proteoglycans are one of the major components of extracellular matrix. They are involved in multiple processes of cancer cell invasion and metastasis by interacting with soluble bioactive molecules, surrounding matrix, cell surface receptors, and enzymes. Apart from having diverse functions in tumor cells and their surrounding microenvironment, proteoglycans also have diagnostic and prognostic significance in cancer patients. However, the functional significance and underlying mechanisms of proteoglycans in ESCC are not well understood. This review summarizes the proteoglycans that have been studied in ESCC in order to provide a comprehensive view of the role of proteoglycans in the progression of this cancer type. A long term goal would be to exploit these molecules to provide new strategies for therapeutic intervention.

Associação entre os Níveis Séricos se Serglicina e o Infarto do Miocárdio com Supradesnivelamento do Segmento ST / Association between Serum Serglycin Levels and St-Segment Elevation Myocardial Infarction

Resumo Fundamento: Sugere-se que a serglicina tenha funções importantes na estabilização da fibrina e inflamação, mas há informações limitadas sobre seu valor clínico para a doença cardíaca aterosclerótica. Objetivo: O objetivo do presente estudo é descobrir os níveis séricos de serglicina em pacientes com infarto agudo do miocárdio e nos indivíduos do grupo controle; e investigar a associação entre os níveis de serglicina com marcadores de inflamação e marcadores de tamanho do infarto. Métodos: A população do estudo consistiu em 75 pacientes com infarto do miocárdio com supradesnivelamento do segmento ST (IAMCSST) e 57 pacientes com artérias coronárias normais (NCA) (grupo controle). As características dos pacientes, os níveis séricos de serglicina, os níveis de proteína C-reativa ultrassensível (PCR-us), os níveis máximos de troponina T e outros parâmetros bioquímicos foram registrados. O valor de p<0,05 foi considerado estatisticamente significativo. Resultados: O grupo controle consistiu em indivíduos mais jovens e que fumam menos do que os do grupo IAMCSST. O número de mulheres no grupo controle foi maior do que no grupo IAMCSST. Os níveis séricos de serglicina foram significativamente maiores no grupo IAMCSST do que no grupo controle (102,81±39,42 vs. 57,13±32,25, p<0,001). As análises de correlação revelaram uma correlação positiva significativa entre a serglicina e a troponina (correlação de postos de Spearman: 0,419; p<0,001) e entre a serglicina e a proteína C-reativa ultrassensível (correlação de postos de Spearman: 0,336; p<0,001). A análise de regressão logística multivariada demonstrou que os níveis séricos de serglicina apresentaram-se independentemente associados com IAMCSST. Usando um nível de corte de 80,47 μg/L, o nível de serglicina foi preditor da presença de IAMCSST com uma sensibilidade de 75,7% e especificidade de 68,4%. Conclusão: Os níveis séricos de serglicina apresentaram-se significativamente maiores no grupo IAMCSST do que no grupo controle. Os níveis de serglicina sérica mostraram-se positivamente correlacionados com os níveis de proteína C-reativa ultrassensível e troponina.

Abstract Background: It is suggested that serglycin has important functions in fibrin stabilization and inflammation but there is limited information on its clinical value for atherosclerotic heart disease. Objective: The purpose of this study is to find out serum serglycin levels in acute myocardial infarction patients and in the control group individuals; and to investigate the association between serglycin levels with inflammation markers and infarct size markers. Methods: The study population consisted of 75 patients with ST-segment elevation myocardial infarction (STEMI) and 57 patients with normal coronary arteries (NCA) (control group). Patient characteristics, serum serglycin levels, high-sensitivity C-reactive protein (hs-CRP) levels, peak troponin T levels and other biochemical parameters were recorded. A p value <0.05 was considered statistically significant. Results: The control group consisted of individuals who are younger and smoke less than those of the STEMI group. The number of females in the control group was higher than in the STEMI group. Serum serglycin levels were significantly higher in the STEMI group than in control group (102.81±39.42 vs. 57.13±32.25, p<0.001). Correlation analyses revealed a significant positive correlation between serglycin and troponin (Spearman's Rho: 0.419; p<0.001) and between serglycin and hs CRP (Spearman's Rho: 0.336; p<0.001). Multivariate logistic regression analysis demonstrated that serum serglycin levels were independently associated with STEMI. Using a cutoff level of 80,47 μg/L, the serglycin level predicted the presence of STEMI with a sensitivity of 75.7% and specificity of 68.4%. Conclusion: Serum serglycin levels were significantly higher in the STEMI group than in the control group. Serum serglycin levels were positively correlated with both hs CRP levels and troponin levels.

Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer.

Rationale: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC). Methods: Reverse phase protein array analysis was used to identify activated signaling pathways in SRGN-overexpressing cells. Chemokine array was used to identify differentially secreted factors from SRGN-overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival. Results: In vitro and in vivo experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. SRGN-knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival. Conclusions: This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.

Prognostic Significance of Hematopoietic-cell Serglycin for the Survival of Hepatocellular Carcinoma: A Single-center Retrospective Study.

AIM AND OBJECTIVE: Inflammation-related changes in peripheral blood cells and blood proteins are prognostic factors for survival in hepatocellular carcinoma (HCC), but their usefulness is limited by an active bacterial infection. This study investigated whether infection interfered with the predictive value of serglycin, a proteoglycan found in hematopoietic cells, on survival in HCC. MATERIALS AND METHODS: Patients with hepatitis B virus (HBV)-induced HCC, 100 without and 30 with a bacterial infection, and 30 healthy adult controls were enrolled retrospectively. Baseline clinical data collected before treatment with transarterial chemoembolization (TACE) was evaluated, and serglycin expression was assayed by flow cytometry. Receiver operating characteristic (ROC) curve analysis identified serglycin cutoff values for patient stratification. Cox regression and Kaplan-Meier analyses were performed to identify predictors of overall survival (OS). RESULTS: Serglycin levels in peripheral blood cells were higher in both groups of HCC patients than in the control group. Cholinesterase, lung metastasis, average neutrophil serglycin fluorescence intensity, and aspartate aminotransferase levels were associated with survival risk. Barcelona Clinic Liver Cancer stage A was associated with a good prognosis of OS. CONCLUSION: The intensity of serglycin fluorescence in peripheral neutrophils was independently predictive of survival in HCC, and its value was not limited by a bacterial infection. The method presented here is a simple and feasible way to predict prognosis in HCC patients with TACE.

Molecular Interactions Stabilizing the Promatrix Metalloprotease-9·Serglycin Heteromer.

Previous studies have shown that THP-1 cells produced an SDS-stable and reduction-sensitive complex between proMMP-9 and a chondroitin sulfate proteoglycan (CSPG) core protein. The complex could be reconstituted in vitro using purified serglycin (SG) and proMMP-9 and contained no inter-disulfide bridges. It was suggested that the complex involved both the FnII module and HPX domain of proMMP-9. The aims of the present study were to resolve the interacting regions of the molecules that form the complex and the types of interactions involved. In order to study this, we expressed and purified full-length and deletion variants of proMMP-9, purified CSPG and SG, and performed in vitro reconstitution assays, peptide arrays, protein modelling, docking, and molecular dynamics (MD) simulations. ProMMP-9 variants lacking both the FnII module and the HPX domain did not form the proMMP-9∙CSPG/SG complex. Deletion variants containing at least the FnII module or the HPX domain formed the proMMP-9∙CSPG/SG complex, as did the SG core protein without CS chains. The interacting parts covered large surface areas of both molecules and implicated dynamic and complementary ionic, hydrophobic, and hydrogen bond interactions. Hence, no short single interacting linear motifs in the two macromolecules could explain the strong SDS-stable and reduction-sensitive binding.

Proteoglycan serglycin promotes non-small cell lung cancer cell migration through the interaction of its glycosaminoglycans with CD44.

BACKGROUND: Serglycin (SRGN), previously recognized as an intracellular proteoglycan involved in the storage processes of secretory granules, has recently been shown to be upregulated in several solid tumors. We have previously shown that SRGN in non-small cell lung cancer (NSCLC) promotes malignant phenotypes in a CD44-dependent manner and increased expression of SRGN predicts poor prognosis of primary lung adenocarcinomas. However, the underlying mechanism remains to be defined. METHODS: Overexpression, knockdown and knockout approaches were performed to assess the role of SRGN in cell motility using wound healing and Boyden chamber migration assays. SRGN devoid of glycosaminoglycan (GAG) modification was produced by site-directed mutagenesis or chondroitinase treatment. Liquid chromatography/tandem mass spectrometry was applied for quantitative analysis of the disaccharide compositions and sulfation extent of SRGN GAGs. Western blot and co-immunoprecipitation analyses were performed to determine the expression and interaction of proteins of interest. Actin cytoskeleton organization was monitored by immunofluorescence staining. RESULTS: SRGN expressed by NSCLC cells is readily secreted to the extracellular matrix in a heavily glycosylated form attached with mainly chondroitin sulfate (CS)-GAG chains, and to a lesser extent with heparin sulfate (HS). The CS-GAG moiety serves as the structural motif for SRGN binding to tumor cell surface CD44 and promotes cell migration. SRGN devoid of CS-GAG modification fails to interact with CD44 and has lost the ability to promote cell migration. SRGN/CD44 interaction promotes focal adhesion turnover via Src-mediated paxillin phosphorylation and disassembly of paxillin/FAK adhesion complex, facilitating cell migration. In support, depletion of Src activity or removal of CS-GAGs efficiently blocks SRGN-mediated Src activation and cell migration. SRGN also promotes cell migration via inducing cytoskeleton reorganization mediated through RAC1 and CDC42 activation accompanied with increased lamellipodia and filopodia formation. CONCLUSIONS: Proteoglycan SRGN promotes NSCLC cell migration via the binding of its GAG motif to CD44. SRGN/CD44 interaction induces Rho-family GTPase-mediated cytoskeleton reorganization and facilitates Src-mediated focal adhesion turnover, leading to increased cell migration. These findings suggest that targeting specific glycans in tumor microenvironment that serve as ligands for oncogenic pathways may be a potential strategy for cancer therapy.

Tumorigenic functions of serglycin: Regulatory roles in epithelial to mesenchymal transition and oncogenic signaling.

Numerous studies point out serglycin as an important regulator of tumorigenesis in a variety of malignancies. Serglycin expression correlates with the aggressive phenotype of tumor cells and serves as a poor prognostic indicator for disease progression. Although serglycin is considered as an intracellular proteoglycan, it is also secreted in the extracellular matrix by tumor cells affecting cell properties, oncogenic signaling and exosomes cargo. Serglycin directly interacts with CD44 and possibly other cell surface receptors including integrins, evoking cell adhesion and signaling. Serglycin also creates a pro-inflammatory and pro-angiogenic tumor microenvironment by regulating the secretion of proteolytic enzymes, IL-8, TGFß2, CCL2, VEGF and HGF. Hence, serglycin activates multiple signaling cascades that drive angiogenesis, tumor cell growth, epithelial to mesenchymal transition, cancer cell stemness and metastasis. The interference with the tumorigenic functions of serglycin emerges as an attractive prospect to target malignancies.

Serglycin activates pro-tumorigenic signaling and controls glioblastoma cell stemness, differentiation and invasive potential.

Despite the functional role of serglycin as an intracellular proteoglycan, a variety of malignant cells depends on its expression and constitutive secretion to advance their aggressive behavior. Serglycin arose to be a biomarker for glioblastoma, which is the deadliest and most treatment-resistant form of brain tumor, but its role in this disease is not fully elucidated. In our study we suppressed the endogenous levels of serglycin in LN-18 glioblastoma cells to decipher its involvement in their malignant phenotype. Serglycin suppressed LN-18 (LN-18shSRGN) glioblastoma cells underwent astrocytic differentiation characterized by induced expression of GFAP, SPARCL-1 and SNAIL, with simultaneous loss of their stemness capacity. In particular, LN-18shSRGN cells presented decreased expression of glioma stem cell-related genes and ALDH1 activity, accompanied by reduced colony formation ability. Moreover, the suppression of serglycin in LN-18shSRGN cells retarded the proliferative and migratory rate, the invasive potential in vitro and the tumor burden in vivo. The lack of serglycin in LN-18shSRGN cells was followed by G2 arrest, with subsequent reduction of the expression of cell-cycle regulators. LN-18shSRGN cells also exhibited impaired expression and activity of proteolytic enzymes such as MMPs, TIMPs and uPA, both in vitro and in vivo. Moreover, suppression of serglycin in LN-18shSRGN cells eliminated the activation of pro-tumorigenic signal transduction. Of note, LN-18shSRGN cells displayed lower expression and secretion levels of IL-6, IL-8 and CXCR-2. Concomitant, serglycin suppressed LN-18shSRGN cells demonstrated repressed phosphorylation of ERK1/2, p38, SRC and STAT-3, which together with PI3K/AKT and IL-8/CXCR-2 signaling control LN-18 glioblastoma cell aggressiveness. Collectively, the absence of serglycin favors an astrocytic fate switch and a less aggressive phenotype, characterized by loss of pluripotency, block of the cell cycle, reduced ability for ECM proteolysis and pro-tumorigenic signaling attenuation.

Increased levels of serum serglycin and agrin is associated with adverse perinatal outcome in early onset preeclampsia.

Goal: Our aim was to determine whether alterations in serum serglycin and agrin levels in early-onset preeclampsia (EOPE) are useful in predicting adverse perinatal outcomes such as fetal growth restriction (FGR), intrauterine fetal demise (IUFD), preterm delivery and/or neonatal unit admission. Materials and Methods: A prospective case-controlled study enrolled 88 pregnant patients (44 EOPE and 44 controls). Maternal serum serglycin and agrin levels were determined before the 34th gestational week by enzyme-linked immunosorbent assay. Results: Compared with controls, women with EOPE had significantly higher serglycin and agrin levels (p = .018; p = .048). Multivariable logistic regression analysis revealed serglycin was independently associated with FGR in EOPE (OR 0.866; 95% CI 0.779-0.953). Agrin was independently associated with IUFD in EOPE (OR 0.757, 95% CI 0.636-0.879). Conclusions: The current study suggests that increased maternal serum serglycin is associated with FGR, and increased maternal serum agrin is associated with IUFD in EOPE.

The role of increased synovial fluid A disintegrin and metalloproteinase with thrombospondin motifs4 and serglycin levels in osteoarthritis.

BACKGROUND: The first research to determine synovial fluid ADAMTS4 and serglycin levels in osteoarthritis and OA progression. AIM: We aimed to determine ADAMTS4 and serglycin levels, interactions, and changes in the synovial fluid of knee OA, and also to determine effective in OA progression. METHODS: A case-control study was carried out including a total of 88 participants (29 patients late OA [LOA], 28 early OA [EOA], and 30 controls). Synovial fluid serglycin and ADAMTS4 levels were measured by commercially available ELISA kits, and knee functions of the patients were evaluated with The Western Ontario and McMaster Universities Osteoarthritis score (WOMAC). Logistic regression analysis was applied for the associated with progression of OA. RESULTS: Synovial fluid ADAMTS4 and serglycin levels were significantly higher in LOA than EOA and control groups (p < .001 and p < .001; p = .038 and p = .007, respectively). All parameters were evaluated after adjustment for age. LOA patients had significantly higher levels of WOMAC score than EOA and controls (p < .001 and p < .001). According to the logistic regression analysis, synovial fluid ADAMTS4, serglycin levels, and WOMAC score were found to be significantly associated with progression of OA.

Proteoglycans remodeling in cancer: Underlying molecular mechanisms.

Extracellular matrix is a highly dynamic macromolecular network. Proteoglycans are major components of extracellular matrix playing key roles in its structural organization and cell signaling contributing to the control of numerous normal and pathological processes. As multifunctional molecules, proteoglycans participate in various cell functions during morphogenesis, wound healing, inflammation and tumorigenesis. Their interactions with matrix effectors, cell surface receptors and enzymes enable them with unique properties. In malignancy, extensive remodeling of tumor stroma is associated with marked alterations in proteoglycans' expression and structural variability. Proteoglycans exert diverse functions in tumor stroma in a cell-specific and context-specific manner and they mainly contribute to the formation of a permissive provisional matrix for tumor growth affecting tissue organization, cell-cell and cell-matrix interactions and tumor cell signaling. Proteoglycans also modulate cancer cell phenotype and properties, the development of drug resistance and tumor stroma angiogenesis. This review summarizes the proteoglycans remodeling and their novel biological roles in malignancies with particular emphasis to the underlying molecular mechanisms.

Proteoglycans Are Attractive Biomarkers and Therapeutic Targets in Hepatocellular Carcinoma.

Proteoglycans, which consist of a protein core and glycosaminoglycan chains, are major components of the extracellular matrix and play physiological roles in maintaining tissue homeostasis. In the carcinogenic tissue microenvironment, proteoglycan expression changes dramatically. Altered proteoglycan expression on tumor and stromal cells affects cancer cell signaling pathways, which alters growth, migration, and angiogenesis and could facilitate tumorigenesis. This dysregulation of proteoglycans has been implicated in the pathogenesis of diseases such as hepatocellular carcinoma (HCC) and the underlying mechanism has been studied extensively. This review summarizes the current knowledge of the roles of proteoglycans in the genesis and progression of HCC. It focuses on well-investigated proteoglycans such as serglycin, syndecan-1, glypican 3, agrin, collagen XVIII/endostatin, versican, and decorin, with particular emphasis on the potential of these factors as biomarkers and therapeutic targets in HCC regarding the future perspective of precision medicine toward the "cure of HCC".