Decorin Research Articles

Identification of key genes involved in the development and progression of early-onset colorectal cancer by co-expression network analysis.

A number of studies have revealed that there is an increasing incidence of early-onset colorectal cancer (CRC) in young adults (before the age of 50 years) and a progressive decline in CRC among older patients, after the age of 50 years (late-onset CRC). However, the etiology of early-onset CRC is not fully understood. The aim of the present study was to identify key genes associated with the development of early-onset CRC through weighted gene co-expression network analysis (WGCNA). The GSE39582 dataset was downloaded from the Gene Expression Omnibus database, and the data profiles of tissues from patients diagnosed before the age of 50 years were selected. The top 10,000 genes with the highest variability were used to construct the WGCNA. Hub genes were identified from the modules associated with clinical traits using gene significance >0.2 and module membership >0.8 as the cut-off criteria. Gene Ontology and pathway analyses were subsequently performed on the hub genes and a protein-protein interaction network (PPI) was constructed. The diagnostic value of module hub genes with a degree score >5 in the PPI network was verified in samples from patients with CRC diagnosed before the age of 50 years obtained from The Cancer Genome Atlas. Eight co-expressed gene modules were identified in the WGCNA and two modules (blue and turquoise) were associated with the tumor-node-metastasis stage. A total of 140 module hub genes were identified and found to be enriched in ‘mitochondrial large ribosomal subunit’, ‘structural constituent of ribosome’, ‘poly (A) RNA binding’, ‘collagen binding’, ‘protein ubiquitination’ and ‘ribosome pathway’. Twenty-six module hub genes were found to have a degree score >5 in the PPI network, seven of which [secreted protein acidic and cysteine rich (SPARC), decorin (DCN), fibrillin 1 (FBN1), WW domain containing transcription regulator 1 (WWTR1), transgelin (TAGLN), DEAD-box helicase 28 (DDX28) and cold shock domain containing C2 (CSDC2)], had good prognostic values for patients with early-onset CRC, but not late-onset CRC. Therefore, SPARC, DCN, FBN1, WWTR1, TAGLN, DDX28 and CSDC2 may contribute to the development of early-onset CRC and may serve as potential diagnostic biomarkers.

Identification of potential pathogenic candidates or diagnostic biomarkers in papillary thyroid carcinoma using expression and methylation profiles.

The mechanisms underlying the pathogenesis of papillary thyroid carcinoma (PTC) have not yet been elucidated. The aim of the current study was to identify potential pathogenic biomarkers in PTC by comprehensively analyzing gene expression and methylation profiles, and to increase the understanding of PTC pathogenesis. The gene expression profiles of the GSE97001 and GSE83520 datasets, the miRNA expression profiles of the GSE73182 dataset, and the DNA methylation profiles of the GSE86961 and GSE97466 datasets were downloaded from Gene Expression Omnibus database. The differentially expressed genes (DEGs) and the differentially expressed microRNAs (DEMs) were identified using the limma package in R, and the differentially methylated sites (DMSs) were identified using the β distribution and two-sample t-tests. The Database for Annotation, Visualization and Integrated Discovery, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome were subsequently used to perform functional and pathway enrichment analysis. The miRNA target genes were predicted using the online databases miRWalk. The protein-protein interactions (PPI) were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins. The regulatory network was constructed, and the gene expression and methylation levels of the key nodes were detected using reverse-transcription quantitative-polymerase chain reaction (PCR) and methylation-specific PCR. A total of 155 overlapping DEGs were identified between the GSE97001 and GSE83520 datasets, and 19 DEMs between PTC tissue and normal tissue samples were identified in the GSE73182 set. In the GSE86961 and GSE97466 datasets, 2,910 overlapping DMSs that were associated with 38 downregulated methylated genes were identified. The overlapping DEGs were enriched in 46 Gene Ontology terms and one KEGG pathway. A total of 60 PPI pairs were identified for the overlapping DEGs and 12 negative miRNA-gene pairs were identified for the DEMs. The expression levels of hsa-miR-199a-5p and decorin (DCN) were decreased in patients with PTC. C-X-C motif chemokine ligand 12 (CXCL12) was hypermethylated and had a decreased expression level in PTC tissues. LDL receptor related protein 4 (LRP4) and carbonic anhydrase 12 (CA12) were hypomethylated and had an increased expression level. The present study revealed that hsa-miR-199a-5p, DCN, CXCL12, LRP4 and CA12 may serve important roles in the pathogenesis of PTC.

Placental and serum levels of human Klotho in severe preeclampsia: A potential sensitive biomarker

IntroductionThe Klotho (KL) gene, initially defined as an anti-aging gene in mice, shares 86% of the amino acid sequence withthe human KL protein. The KL gene plays roles in endothelial nitric oxide production, angiogenesis, antioxidant enzyme production and protecting against endothelial dysfunction, all of which may be associated with preeclampsia (PE). Human KL is the precursor of the gene products: α-KL and β-KL. In this study, we evaluated the gene expression, serum and placental levels of human KL in women with severe PE, pregnant women with chronic hypertension and healthy pregnant controls. Also, the gene expression, serum and placental levels of human decorin (DCN) were evaluated. MethodsA total of 36 patients with severe PE, 10 with chronic hypertension, and 28 with healthy controls were enrolled. Placental and serum levels together with of KL and DCN were measured by ELISA and alsogene expression of these were evaluated. ResultsPlacental and serum KL levels were significantly higher in the PE than in the controls and in women with chronic hypertension. Serum DCN levels were significantly higher in the PE women compared to controls and pregnant women with chronic hypertension. Placental DCN was similar in PE and healthy controls. There was no significant difference in the gene expression of KL and DCN in the groups. The best cut-off level for human KL to identify the presence of PE was calculated as 12.48 pg/ml with a sensitivity of 100% and and specificity of 96%, whereas for DCN 62.33 ng/ml to assess the presence of PE with a sensitivity of 86.1% and a specificity of 88%. ConclusionHuman KL may be a valuable marker for PE, with high sensitivity and specificity. It also appears to be more sensitive and specific than human DCN.

Differential expression of extracellular matrix‑related genes DCN, EPHA4, FN1, SPARC, SPON2 and SPP1 in colorectal carcinogenesis.

During colorectal carcinogenesis, a spectrum of lesions is formed with different malignant potentials and occasionally with ambiguous morphologic features. To identify novel biomarkers, we previously performed a bioinformatics study to detect differentially expressed genes between colorectal adenoma (CRA) and colorectal carcinoma (CRC). The present study validated the diagnostic and prognostic significance of 6 components of the extracellular matrix (ECM) that were identified in the previous bioinformatics analysis [decorin (DCN), erythropoietin‑producing hepatoma receptor A4 (EPHA4), fibronectin 1 (FN1), secreted protein acidic and cysteine rich (SPARC), spondin 2 (SPON2) and secreted phosphoprotein 1 (SPP1)], by analyzing their gene and protein expression levels in all samples. A total of 60 formalin‑fixed paraffin‑embedded biopsy samples were included in the present study, from 40 patients with CRA, malignant polyps and CRC with and without lymph node metastases. The expression of the ECM‑related genes was evaluated on the mRNA level using reverse transcription‑quantitative PCR (RT‑qPCR) and on the protein level using immunohistochemistry. RT‑qPCR results revealed differential expression among the groups for all genes, except for EPHA4. Their expression proportionally increased with the level of malignancy. Among them, SPARC, SPON2 and SPP1 were differentially expressed between CRA and malignant polyps. Immunohistochemistry analysis revealed two patterns: Positive staining of SPON2 and SPP1 in epithelial cells of healthy mucosa and dysplastic glands of CRA and CRC, and positive staining of DCN and SPARC in the lamina propria in healthy mucosa and stroma of CRA and CRC. The intensity of staining increased with the severity of lesions. The present results suggested that ECM‑related proteins may have an important role in the development of CRC, with a possible diagnostic use for differentiation among various lesions, such as between CRA and malignant polyps. However, no significant potential was detected for these genes to predict lymph node metastases in CRC.

Functional polymorphisms within the inflammatory pathway regulate expression of extracellular matrix components in a genetic risk dependent model for anterior cruciate ligament injuries

ObjectivesTo investigate the functional effect of genetic polymorphisms of the inflammatory pathway on structural extracellular matrix components (ECM) and the susceptibility to an anterior cruciate ligament (ACL) injury. DesignLaboratory study, case–control study. MethodsEight healthy participants were genotyped for interleukin (IL)1B rs16944 C>T and IL6 rs1800795 G>C and classified into genetic risk profile groups. Differences in type I collagen (COL1A1), type V collagen (COL5A1), biglycan (BGN) and decorin (DCN) gene expression were measured in fibroblasts either unstimulated or following IL-1β, IL-6 or tumor necrosis factor (TNF)-α treatment.Moreover, a genetic association study was conducted in: (i) a Swedish cohort comprised of 116 asymptomatic controls (CON) and 79 ACL ruptures and (ii) a South African cohort of 100 CONs and 98 ACLs. Participants were genotyped for COL5A1 rs12722 C>T, IL1B rs16944 C>T, IL6 rs1800795 G>C and IL6R rs2228145 G>C. ResultsIL1B high-risk fibroblasts had decreased BGN (p=0.020) and COL5A1 (p=0.012) levels after IL-1β stimulation and expressed less COL5A1 (p=0.042) following TNF-α treatment. Similarly, unstimulated IL6 high-risk fibroblasts had lower COL5A1 (p=0.012) levels than IL6 low-risk fibroblasts.In the genetic association study, the COL5A1-IL1B-IL6 T–C–G (p=0.034, Haplo-score 2.1) and the COL5A1-IL1B-IL6R T–C–A (p=0.044, Haplo-score: 2.0) combinations were associated with an increased susceptibility to ACL injury in the Swedish cohort when only male participants were evaluated. ConclusionsThis study shows that polymorphisms within genes of the inflammatory pathway modulate the expression of structural and fibril-associated ECM components in a genetic risk depended manner, contributing to an increased susceptibility to ACL injuries.

Gene expression in stress urinary incontinence: a systematic review.

A contribution of genetic factors to the development of stress urinary incontinence (SUI) is broadly acknowledged. This study aimed to: (1) provide insight into the genetic pathogenesis of SUI by gathering and synthesizing the available data from studies evaluating differential gene expression in SUI patients and (2) identify possible novel therapeutic targets and leads. A systematic literature search was conducted through September 2017 for the concepts of genetics and SUI. Gene networking connections and gene-set functional analyses of the identified genes as differentially expressed in SUI were performed using GeneMANIA software. Of 3019 studies, 4 were included in the final analysis. A total of 13 genes were identified as being differentially expressed in SUI patients. Eleven genes were overexpressed: skin-derived antileukoproteinase (SKALP/elafin), collagen type XVII alpha 1 chain (COL17A1), plakophilin 1 (PKP1), keratin 16 (KRT16), decorin (DCN), biglycan (BGN), protein bicaudal D homolog 2 (BICD2), growth factor receptor-bound protein 2 (GRB2), signal transducer and activator of transcription 3 (STAT3), apolipoprotein E (APOE), and Golgi SNAP receptor complex member 1 (GOSR1), while two genes were underexpressed: fibromodulin (FMOD) and glucocerebrosidase (GBA). GeneMANIA revealed that these genes are involved in intermediate filament cytoskeleton and extracellular matrix organization. Many genes are involved in the pathogenesis of SUI. Furthermore, whole-genome studies are warranted to identify these genetic connections. This study lays the groundwork for future research and the development of novel therapies and SUI biomarkers in clinical practice.

Identification of Key Biomarkers and Potential Molecular Mechanisms in Renal Cell Carcinoma by Bioinformatics Analysis.

Renal cell carcinoma (RCC) is the most common form of kidney cancer, caused by renal epithelial cells. RCC remains to be a challenging public health problem worldwide. Metastases that are resistant to radiotherapy and chemotherapy are the major cause of death from cancer. However, the underlying molecular mechanism regulating the metastasis of RCC is poorly known. Publicly available databases of RCC were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using GEO2R analysis, whereas the Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by Gene Set Enrichment Analysis (GSEA) and Metascape. Protein-protein interaction (PPI) network of DEGs was analyzed by STRING online database, and Cytoscape software was used for visualizing PPI network. Survival analysis of hub genes was conducted using GEPIA online database. The expression levels of hub genes were investigated from The Human Protein Atlas online database and GEPIA online database. Finally, the comparative toxicogenomics database (CTD; http://ctdbase.org) was used to identify hub genes associated with tumor or metastasis. We identified 229 DEGs comprising 135 downregulated genes and 94 upregulated genes. Functional analysis revealed that these DEGs were associates with cell recognition, regulation of immune, negative regulation of adaptive immune response, and other functions. And these DEGs mainly related to P53 signaling pathway, cytokine-cytokine receptor interaction, Natural killer cell mediated cytotoxicity, and other pathways are involved. Ten genes were identified as hub genes through module analyses in the PPI network. Finally, survival analysis of 10 hub genes was conducted, which showed that the MMP2 (matrix metallo peptidase 2), DCN, COL4A1, CASR (calcium sensing receptor), GPR4 (G protein-coupled receptor 4), UTS2 (urotensin 2), and LDLR (low density lipoprotein receptor) genes were significant for survival. In this study, the DEGs between RCC and metastatic RCC were analyzed, which assist us in systematically understanding the pathogeny underlying metastasis of RCC. The MMP2, DCN, COL4A1, CASR, GPR4, UTS2, and LDLR genes might be used as potential targets to improve diagnosis and immunotherapy biomarkers for RCC.

The inhibitory effect of decorin on apoptosis of human lens epithelial cells under high glucose condition and its mechanism

Objective To investigate the effects of decorin (DCN) on apoptosis and oxidative stress in human lens epithelial cells (LECs) under high glucose condition. Methods HLE-B3 cells were cultured in vitro and the effect of DCN with different concentrations on HLE-B3 viability was determined by using cell counting kit-8 (CCK-8). The cultured cells were divided into normal control group, DCN group, high glucose group and DCN + high glucose group.Flow cytometry was used to detect the apoptosis rate and the expression of reactive oxygen species (ROS) in the cells.Microplate spectrophotometer was used to measure total superoxide dismutase (SOD) enzyme activity and the radio of glutathione (GSH)/glutathione disulfide (GSSG). Western blot was used to detect the expressions of bax and bcl-2 proteins. Results HLE-B3 cells were spindle shaped, with centered and clearly visible nuclei and neatly cell arrangment.According to CCK-8 method, survival rates of HLE-B3 in all groups were more than 90%.Different concentrations of DCN showed no significant effect on HLE-B3 survival rate (all at P>0.05). After 48 hours of cell culture, the apoptosis rate of high glucose group was significantly higher than that of normal control group, and the apoptosis rate of DCN+ high glucose group was significantly lower than that of high glucose group (both at P=0.000). The mean fluorescence intensity of intracellular ROS in the high-glucose group was significantly higher than that in the normal control group, and the mean fluorescence intensity of ROS in the DCN group was significantly higher than that in the high glucose group (both at P=0.000). The total SOD activity in the high glucose group was significantly lower than that in the normal control group and DCN group (P=0.007, 0.004). The GSH/GSSG ratio of the high-glucose group was significantly lower than that of the normal control group and DCN group (both at P=0.000). Conclusions DCN can inhibit the apoptosis and oxidative stress of HLE-B3 under high glucose, which provides the basis for the treatment of diabetic cataract. Key words: Decorin; Human lens epithelial cell; High glucose condition; Oxidative stress; Apoptosis; Inhibitory effect; Mechanism

Effects of ultrasound therapy on the synovial fluid proteome in a rabbit surgery-induced model of knee osteoarthritis

BackgroundUltrasound (US) therapy may improve osteoarthritis symptoms. We investigated the effects of US on the synovial fluid (SF) proteome in a rabbit knee osteoarthritis (KOA) model to explore its therapeutic mechanisms.MethodsSixteen healthy 6-month-old New Zealand white rabbits (eight male, eight female), weighing 2.5–3.0 kg, were randomly divided into groups A and B with eight rabbits per group. Both groups were subjected to right anterior cruciate ligament transaction. Six weeks after surgery, we treated the operated knee joint of group A rabbits with US and of group B rabbits with sham US for 2 weeks. The proteomes of knee joint SF from groups A and B rabbits were then analyzed using a label-free mass spectrometry (MS) quantification method.ResultsWe identified 19 protein sequences annotated by 361 Gene Ontology (GO) items. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database of rabbit protein sequences, we then annotated the KO numbers of homologous/similar proteins to 32 relevant KEGG pathways. We extracted 10 significantly differentially expressed proteins among the 32 relevant KEGG messages/metabolism pathways. The proteins whose levels were decreased were apolipoprotein A-I (AopA-1), transferrin (TF), carboxypeptidase B2 (CBP2), arylesterase/paraoxonase (PON), fibrinogen alpha chain, and alpha-2-macroglobulin (A2M). The proteins whose levels were increased were molecular chaperone HtpG/heat shock proteins (htpG, HSP90A), decorin (DCN), pyruvate kinase (PK, pyk), and fatty acid-binding protein 4/adipocyte (FABP4, aP2).ConclusionsUS therapy can alter protein levels in SF, which can decrease AopA-1, TF, CBP2, PON, fibrinogen alpha chain and A2M protein levels, and increase HtpG/HSP90A, DCN, PK/PKY, and FABP4/aP2 protein levels in SF of KOA, suggesting that the therapeutic mechanisms of US therapy on KOA may occur through changes in the SF proteome.

Tumor-dependent Effects of Proteoglycans and Various Glycosaminoglycan Synthesizing Enzymes and Sulfotransferases on Patients' Outcome.

The small leucine-rich proteoglycans (SLRPs) biglycan (BGN) and decorin (DCN) linked with sulfated glycosaminoglycan (GAG) chains exhibit oncogenic or tumor suppressive potentials depending on the cellular context and association with GAGs. We hypothesized that structural alterations and expression levels of BGN, DCN and their associated chondroitin sulfate (CS) polymerizing enzymes, dermatan sulfate (DS) epimerases and various sulfatases might be correlated with the tumor (sub)type and patients' survival. We acquired breast cancer (BC) and glioma patients' datasets from cBioPortal and R2 Genomics. Structural alterations and the expression pattern of CS polymerizing enzymes, DS epimerases and carbohydrate sulfotransferases (CHST) were compared to that of BGN and DCN and correlated to their clinical relevance. In BC, no mutations, but amplifications (0.2 - 2.1 %) and deletions (0.05 - 0.4 %) were found in BGN, DCN and CS/DS enzymes. In contrast, missense and/or truncated mutations (0.1 - 0.5 %), but a reduced amplification rate (0 - 1.5 %) were found in glioma. When compared to BC, the structural abnormalities caused altered mRNA expression levels of BGN, DCN, GAG synthesizing enzymes and CHST. Mutations in SLPRs, CHSY1, CHST4 and CHSY3 were correlated with a poor prognosis in glioma, while lack of mutations and copy number variations in the SLRPs, CHSY3, CHST15 and DSE displayed an increased survival in BC. A distinct association of BGN and DCN with CHST, CS polymerizing enzymes and DS epimerases was found in BC and glioma. Thus, a unique pattern of structural alterations and expression, which has clinical relevance, was found for PGs and GAG synthesizing enzymes and CHST in BC and glioma, which might help to identify high-risk patients and to develop personalized therapeutics.

Decorin-supplemented collagen hydrogels for the co-delivery of bone morphogenetic protein-2 and microvascular fragments to a composite bone-muscle injury model with impaired vascularization

Traumatic musculoskeletal injuries that result in bone defects or fractures often affect both bone and the surrounding soft tissue. Clinically, these types of multi-tissue injuries have increased rates of complications and long-term disability. Vascular integrity is a key clinical indicator of injury severity, and revascularization of the injury site is a critical early step of the bone healing process. Our lab has previously established a pre-clinical model of composite bone-muscle injury that exhibits impaired bone healing; however, the vascularization response in this model had not yet been investigated. Here, the early revascularization of a bone defect following composite injury is shown to be impaired, and subsequently the therapeutic potential of combined vascularization and osteoinduction was investigated to overcome the impaired regeneration in composite injuries. A decorin (DCN)-supplemented collagen hydrogel was developed as a biomaterial delivery vehicle for the co-delivery microvascular fragments (MVF), which are multicellular segments of mature vasculature, and bone morphogenetic protein-2 (BMP-2), a potent osteoinductive growth factor. We hypothesized that collagen + DCN would increase BMP-2 retention over collagen alone due to DCN’s ability to sequester TGF-ß growth factors. We further hypothesized that MVF would increase both early vascularization and subsequent BMP-2-mediated bone regeneration. Contrary to our hypothesis, BMP + MVF decreased the number of blood vessels relative to BMP alone and had no effect on bone healing. However, collagen + DCN was demonstrated to be a BMP-2 delivery vehicle capable of achieving bridging in the challenging composite defect model that is comparable to that achieved with a well-established alginate-based delivery system. Statement of SignificanceWe have previously established a model of musculoskeletal trauma that exhibits impaired bone healing. For the first time, this work shows that the early revascularization response is also significantly, albeit modestly, impaired. A decorin-supplemented collagen hydrogel was used for the first time in vivo as a delivery vehicle for both a cell-based vascular therapeutic, MVF, and an osteoinductive growth factor, BMP-2. While MVF did not improve vascular volume or bone healing, collagen + DCN is a BMP-2 delivery vehicle capable of achieving bridging in the challenging composite defect model. Based on its support of robust angiogenesis in vitro, collagen + DCN may be extended for future use with other vascular therapeutics such as pre-formed vascular networks.

Defining the baseline transcriptional fingerprint of rabbit hamstring autograft

Anterior cruciate ligament (ACL) injuries are common and of high relevance given their significant effects on patient function, quality of life, and posttraumatic arthritis. To date, investigators have reported on the expression of genes classically associated with tendon and ligament reconstruction, including decorin (DCN) and collagen type 1 (COL1A1 and COL1A2). However, the transcriptional fingerprint for hamstring tendons, one of the most common autografts used for ACLR, remains to be determined. The purpose of this study was to characterize the baseline transcriptional state of semitendinosus autografts in a rabbit model for ACLR and to employ such characterization to guide scientifically-driven target gene selection for future analyses.Next generation RNA sequencing was performed on whole semitendinosus autografts from four New Zealand White rabbits (mean age: 193 ± 0 days, mean weight: 2.78 kg ± 0.15 kg) and subsequently analyzed using gene enrichment and protein-protein interaction network analysis. Decorin, Secreted Protein Acidic and Cysteine Rich (SPARC), Collagen type 1, and Proline and Arginine Rich End Leucine Rich Repeat Protein (PRELP) and were determined to be the highest expressed genes with tendon-associated ontology. These results strengthen the association between genes such as DCN, COL1A1, and COL1A2 and tendon tissues as well as provide the novel addition of further high-expression, tendon characteristic genes such as SPARC and PRELP to provide guidance as to which molecules serve as high-signal candidates for future ACL research. In addition, this paper provides open-access to the expression fingerprint of hamstring autograft for ACLR in New Zealand White rabbits, thus providing a readily-accessible collaborative reference, in alignment with ethical animal research principles.

Identification of CAV1 and DCN as potential predictive biomarkers for lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common histological form of lung cancer that is clinically diagnosed. The aim of this study is to explore the novel genes associated with LUAD tumorigenesis. Comprehensive bioinformatics analyses of the data were obtained from several publicly available databases, such as the Gene Expression Omnibus, the Human Protein Atlas project, and the Cancer Cell Line Encyclopedia. The clinical relevance of these novel genes in LUAD was further examined by immunohistochemistry. We identified the overlapping differentially expressed genes (DEGs) in five independent microarray data sets from the Gene Expression Omnibus database ( GSE75037 , GSE85716 , GSE85841 , GSE63459 , and GSE32867 ). Using the criteria of |log (fold change)| ≥ 1 and P value <0.05, 167 genes were preliminarily validated as co-DEGs. Protein-protein interaction network analysis indicated that caveolin 1 (CAV1) and decorin (DCN) levels were significantly reduced and that these genes were the most promising predictive biomarkers for the occurrence and prognosis of LUAD. A cell proliferation assay indicated that overexpressed CAV1 and DCN could significantly inhibit the proliferation rate of A549 and H157 cells. Additionally, these two downregulated candidate genes were further verified by immunohistochemistry conducted on a LUAD tissue array and comprehensive bioinformatics analyses, including those using the Oncomine platform and the Cancer Cell Line Encyclopedia. Our study demonstrates low levels of CAV1 and DCN in LUAD. An understanding of their functional roles in LUAD biology would give us important insights that would be useful in further investigations.

Cooperative and Independent Functions of the miR-23a~27a~24-2 Cluster in Bovine Adipocyte Adipogenesis.

The miR-23a~27a~24-2 cluster is an important regulator in cell metabolism. However, the cooperative and independent functions of this cluster in bovine adipocyte adipogenesis have not been elucidated. In this study, we found that expression of the miR-23a~27a~24-2 cluster was induced during adipogenesis and this cluster acted as a negative regulator of adipogenesis. miR-27a and miR-24-2 were shown to inhibit adipogenesis by directly targeting glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) and diacylglycerol O-acyltransferase 2 (DGAT2), both of which promoted adipogenesis. Meanwhile, miR-23a and miR-24-2 were shown to target decorin (DCN), glucose-6-phosphate dehydrogenase (G6PD), and lipoprotein lipase (LPL), all of which repressed adipogenesis in this study. Thus, the miR-23a~27a~24-2 cluster exhibits a non-canonical regulatory role in bovine adipocyte adipogenesis. To determine how the miR-23a~27a~24-2 cluster inhibits adipogenesis while targeting anti-adipogenic genes, we identified another target gene, fibroblast growth factor 11 (FGF11), a positive regulator of adipogenesis, that was commonly targeted by the entire miR-23a~27a~24-2 cluster. Our findings suggest that the miR-23a~27a~24-2 cluster fine-tunes the regulation of adipogenesis by targeting two types of genes with pro- or anti-adipogenic effects. This balanced regulatory role of miR-23a~27a~24-2 cluster finally repressed adipogenesis.

Short Leucine-Rich Proteoglycans Modulate Complement Activity and Increase Killing of the Respiratory Pathogen Moraxella catarrhalis.

The respiratory pathogen Moraxella catarrhalis is a human-specific commensal that frequently causes acute otitis media in children and stimulates acute exacerbations in chronic obstructive pulmonary disease patients. The exact molecular mechanisms defining host-pathogen interactions promoting pathogenesis are not clearly understood. Limited knowledge hampers vaccine and immunotherapeutic development required to treat this emerging pathogen. In this study, we reveal in detail a novel antibacterial role displayed by short leucine-rich proteoglycans (SLRPs) in concert with complement. We show that fibromodulin (FMOD), osteoadherin (OSAD), and biglycan (BGN) but not decorin (DCN) enhance serum killing of M. catarrhalis. Our results suggest that M. catarrhalis binding to SLRPs is a conserved feature, as the overwhelming majority of clinical and laboratory strains bound all four SLRPs. Furthermore, we resolve the binding mechanism responsible for this interaction and highlight the role of the ubiquitous surface protein (Usp) A2/A2H in mediating binding to host SLRPs. A conserved immune evasive strategy used by M. catarrhalis and other pathogens is the surface acquisition of host complement inhibitors such as C4b-binding protein (C4BP). We observed that FMOD, OSAD, and BGN competitively inhibit binding of C4BP to the surface of M. catarrhalis, resulting in increased C3b/iC3b deposition, membrane attack complex (MAC) formation, and subsequently decreased bacterial survival. Furthermore, both OSAD and BGN promote enhanced neutrophil killing in vitro, both in a complement-dependent and independent fashion. In summary, our results illustrate that SLRPs, FMOD, OSAD, and BGN portray complement-modulating activity enhancing M. catarrhalis killing, defining a new antibacterial role supplied by SLRPs.

Extracellular proteoglycan decorin maintains human hair follicle stem cells.

Hair follicle stem cells (HFSC) are localized in the bulge region of the hair follicle and play a role in producing hair. Recently, it has been shown that the number of HFSC decreases with age, which is thought to be a cause of senile alopecia. Therefore, maintaining HFSC may be key for the prevention of age-related hair loss, but the regulatory mechanisms of HFSC and the effects of aging on them are largely unknown. In general, stem cells are known to require regulatory factors in the pericellular microenvironment, termed the stem cell niche, to maintain their cell function. In this study, we focused on the extracellular matrix proteoglycan decorin (DCN) as a candidate factor for maintaining the human HFSC niche. Gene expression analysis showed that DCN was highly expressed in the bulge region. We observed decreases in DCN expression as well as the number of KRT15-positive HFSC with age. In vitro experiments with human plucked hair-derived HFSC revealed that HFSC lost their undifferentiated state with increasing passages, and prior to this change a decrease in DCN expression was observed. Furthermore, knockdown of DCN promoted HFSC differentiation. In contrast, when HFSC were cultured on DCN-coated plates, they showed an even more undifferentiated state. From these results, as a novel mechanism for maintaining HFSC, it was suggested that DCN functions as a stem cell niche component, and that the deficit of HFSC maintenance caused by a reduction in DCN expression could be a cause of age-related hair loss.

Injured Achilles Tendons Treated with Adipose-Derived Stem Cells Transplantation and GDF-5.

Tendon injuries represent a clinical challenge in regenerative medicine because their natural repair process is complex and inefficient. The high incidence of tendon injuries is frequently associated with sports practice, aging, tendinopathies, hypertension, diabetes mellitus, and the use of corticosteroids. The growing interest of scientists in using adipose-derived mesenchymal stem cells (ADMSC) in repair processes seems to be mostly due to their paracrine and immunomodulatory effects in stimulating specific cellular events. ADMSC activity can be influenced by GDF-5, which has been successfully used to drive tenogenic differentiation of ADMSC in vitro. Thus, we hypothesized that the application of ADMSC in isolation or in association with GDF-5 could improve Achilles tendon repair through the regulation of important remodeling genes expression. Lewis rats had tendons distributed in four groups: Transected (T), transected and treated with ADMSC (ASC) or GDF-5 (GDF5), or with both (ASC+GDF5). In the characterization of cells before application, ADMSC expressed the positive surface markers, CD90 (90%) and CD105 (95%), and the negative marker, CD45 (7%). ADMSC were also differentiated in chondrocytes, osteoblast, and adipocytes. On the 14th day after the tendon injury, GFP-ADMSC were observed in the transected region of tendons in the ASC and ASC+GDF5 groups, and exhibited and/or stimulated a similar genes expression profile when compared to the in vitro assay. ADMSC up-regulated Lox, Dcn, and Tgfb1 genes expression in comparison to T and ASC+GDF5 groups, which contributed to a lower proteoglycans arrangement, and to a higher collagen fiber organization and tendon biomechanics in the ASC group. The application of ADMSC in association with GDF-5 down-regulated Dcn, Gdf5, Lox, Tgfb1, Mmp2, and Timp2 genes expression, which contributed to a lower hydroxyproline concentration, lower collagen fiber organization, and to an improvement of the rats’ gait 24 h after the injury. In conclusion, although the literature describes the benefic effect of GDF-5 for the tendon healing process, our results show that its application, isolated or associated with ADMSC, cannot improve the repair process of partial transected tendons, indicating the higher effectiveness of the application of ADMSC in injured Achilles tendons. Our results show that the application of ADMSC in injured Achilles tendons was more effective in relation to its association with GDF-5.

Anti-tumor responses to hypofractionated radiation in mice grafted with triple negative breast cancer is associated with decorin induction in peritumoral muscles.

Triple negative breast cancer (TNBC) is the most lethal one for all types of breast cancer. Though radiotherapy is an efficient treatment, long-term survival rate of TNBC patients is still suboptimal. Hyprofractionated radiotherapy, an improved radiotherapy, has made an inspiring result in clinic. However, the mechanism underlying TNBC treated with hyprofractionated radiotherapy is not clear. Decorin (DCN) is a small poteoglycan of matrix which has an inhibitory effect on the breast cancer and is secreted by muscle under certain conditions. In this study, we demonstrated that peritumoral muscles secrete more DCN at higher dose irradiation than that at conventional irradiation dose in TNBC tumor-bearing mice. Thus, it indicates that DCN secreted from peritumoral muscle may be one of the reasons why hyprofractionated radiotherapy could inhibit the growth of TNBC more effectively. Moreover, we also indicated that the up-regulated DCN attenuated lung metastasis of TNBC. In conclusion, we demonstrated that hypofractionated radiation promotes the secretion of DCN in peritumoral muscle, thus enhancing the inhibitory effect on TNBC, which might help to optimize the strategy of radiotherapy for TNBC patients in the future.

Decorin, Tenascin C, Total Antioxidant, and Total Oxidant Level Changes in Patients with Pseudoexfoliation Syndrome.

Purpose Pseudoexfoliation syndrome (PEX) is an eye disease that develops under the influence of regional population differences, genetic factors, age, and environmental factors and is characterized by visualization of a gray-white fibrogranular substance in the lens anterior capsule and/or pupil margin during anterior segment examination. The underlying biochemical mechanisms of the disease have not yet been fully elucidated. Therefore, this study was designed to show the changes in aqueous humor and blood serum levels of matrix metalloproteinases (decorin and tenascin C), total antioxidants (TAS), and total oxidants (TOS) in both cataract patients who have unilateral PEX material and cataract patients who do not have unilateral PEX material. Methods Biological samples were simultaneously collected from 22 cataract patients who had unilateral pseudoexfoliation (PEX patients) and 22 cataract patients who did not have unilateral pseudoexfoliation (control patients). From the collected biological samples, decorin (DEC) and tenascin C (TN-C) were measured with the enzyme-linked immunosorbent assay (ELISA) method, and TAS and TOS were measured with an autoanalyzer. Results When decorin, tenascin C, and TOS values of PEX patients were compared with those of control patients, there was a statistically significant increase in all three parameters. Conversely, TAS values showed a statistically significant decrease in PEX patients compared to controls. DEC, TN-C, TAS values, and TOS values were significantly higher in aqueous fluid than in blood in both the PEX patient and control groups. Conclusions We suggest that parameters such as DEC, TN-C, TAS, and TOS play a role in the etiopathology of pseudoexfoliation syndrome. Thus, bringing these increased levels of extracellular proteins and TOS and decreased levels of TAS back to within physiological limits can mediate the reorganization of the blood-aqueous fluid barrier and slow the progression of pseudoexfoliation syndrome.

Effects of transplanted adipose derived stem cells on the expressions of α-SMA and DCN in fibroblasts of hypertrophic scar tissues in rabbit ears.

To study the effects of transplanted adipose derived stem cells (ADSCs) on the expressions of α-smooth muscle actin (α-SMA) and decorin (DCN) in fibroblasts of hypertrophic scar tissues in rabbit ears. Twelve New Zealand white rabbits were selected; the normal subcutaneous adipose tissues in inguinal region were removed, ADSCs were extracted via enzyme digestion, cultured in Dulbecco's modified Eagle's medium (DMEM) and inoculated into the culture dish (3–5×104 cells/ml). After the rabbit ear hypertrophic scar model was established successfully, the fibroblasts of hypertrophic scar tissues in rabbit ears were separated and cultured using the mechanical method combined with enzyme digestion, and the ADSCs and scar fibroblasts were cultured in non-contact Transwell co-culture system for 21 days (experimental group); the corresponding scar fibroblasts were cultured in an ordinary 6-well plate without any treatment for 21 days (control group). The content of collagen I in fibroblasts was detected using the enzyme-linked immunosorbent assay (ELISA) kit, the mRNA expressions of α-SMA and DCN were detected via reverse transcription-polymerase chain reaction (RT-PCR), the protein expressions of α-SMA and DCN were detected via western blot analysis, and the expressions and distribution of α-SMA and DCN were detected via immunofluorescence assay. The results of ELISA showed that the content of collagen I in experimental group was decreased significantly (p<0.01). The results of RT-PCR and western blot analysis revealed that the mRNA and protein expression levels of α-SMA were significantly decreased (P<0.01, but those of DCN were significantly increased (p<0.01). Moreover, the results of immunofluorescence assay showed that the expression of α-SMA in experimental group was significantly decreased, while the expression of DCN was significantly increased. ADSCs can inhibit the mRNA and protein expressions of α-SMA and promote the mRNA and protein expressions of DCN in in vitro culture system, and they are expected to be used in the prevention and treatment of pathological scars.