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Studies have shown that decorin is a potent pan-cancer tumor suppressor that is under-expressed in most cancers. Decorin interacts with receptor tyrosine kinases and functions as a pan-receptor tyrosine kinase inhibitor, thereby suppressing oncogenic signals. Decorin deficiency promotes epithelial-to-mesenchymal transition and enhances cancer dissemination and metastasis. According to recent GLOBOCAN estimates, the most common cancers worldwide are breast, lung, prostate, colorectal, skin (non-melanoma), and stomach. Considering the burden of rising cancer incidence and the importance of discovering novel molecular markers and potential therapeutic agents for cancer management, we have outlined the possible expressional and clinicopathological significance of decorin in major cancers based on available pre-clinical and clinical studies. Measuring plasma decorin is a minimally invasive technique, and human studies have shown that it is useful in predicting clinical outcomes in cancer though it needs further validation. Oncolytic virus-mediated decorin gene transfer has shown significant anti-tumorigenic effects in pre-clinical studies, though its implication in human subjects is yet to be understood. Exogenous decorin delivery in experimental studies has been shown to mitigate cancer growth, but its therapeutic efficacy and safety are poorly understood. Future research is required to translate the tumor-suppressive action of decorin observed in preclinical experiments to therapeutic interventions in human subjects.

Recurrent pregnancy loss (RPL) is a distressing disorder that seriously affects the physical and psychological health of women. RPL is also a sentinel risk marker for future obstetric complications and warrants in-depth investigation. Abnormal polarization and functions of decidual macrophages are associated with RPL; however, the underlying mechanisms remain poorly understood. Decorin expression, localization, and content in the decidua of women with normal pregnancy (NP) and those with RPL were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, immunofluorescence, and enzyme-linked immunosorbent assay. The profiles of decidual macrophage subsets were determined using flow cytometry and immunofluorescence in both groups. The correlation between decorin content and the proportion of decidual macrophage subsets in the decidua of early NP women was determined using Pearson analysis. The effects of decorin on the polarization and functions of macrophages were assessed in an model of Raw264.7 cells via flow cytometry, western blotting, and RT-qPCR. Moreover, the mitochondrial metabolism in Raw264.7 cells under decorin administration was measured via flow cytometry, western blotting, and immunofluorescence. Thirty-three pregnant mice were included in the model and underwent different treatments. The embryo abortion rate, macrophage phenotype in the spleen and uteri, and placental development were evaluated using flow cytometry and hematoxylin-eosin staining. Decorin, derived from decidual stromal cells, was highly expressed in the decidua of women with RPL. A positive correlation between decorin content and the proportion of M1-like macrophages was also observed in the decidua of early NP women. studies showed that decorin treatment inhibited macrophage polarization to M2-like subsets and boosted the inflammatory response, which was related to enhanced anaerobic glycolysis, increased mitochondrial membrane potential and intracellular reactive oxygen species levels, reduced mitochondrial mass, and activation of the myeloid differentiation primary response 88-nuclear factor-κB signaling pathway. Adoptive transfer of decorin-treated bone marrow-derived macrophages in pregnant C57BL/6 mice increased the embryo absorption, accompanied by impaired fetal vascularization. Decidual stromal cell-derived decorin can polarize decidual macrophages toward the M1 phenotype by regulating mitochondrial metabolism, resulting in the occurrence of RPL.

In an effort to develop a new therapy for prostate cancer (PCa) bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wnt/β-catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels and inhibited tumor cell migration. To examine the antitumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle to establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum tartrate-resistant acid phosphatase 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia and an increase in the animal survival. Based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for PCa bone metastasis.

Background Primary sarcopenia is an age‐associated disorder with progressive and generalised loss of skeletal muscle strength and mass. Skeletal muscle fibrosis is one of the significant pathological manifestations of age‐associated sarcopenia. Decorin, a small dermatan–sulfate proteoglycan, participates in extracellular matrix assembly. In numerous studies, the involvement of decorin is not restricted to matrix structural proteins, and it also affects a diverse variety of biological functions like cell growth, adhesion, migration, proliferation and differentiation. Additionally, it modulates the process of inflammation and fibrillogenesis. Based on these preclinical evidences, we hypothesised that decorin may potentially play an important role in skeletal muscles during ageing. Methods Natural ageing mice (Dcn+/+), D‐galactose (D‐gal)–induced Dcn+/+, Dcn−/− mice and NOR‐10 cell models were established. Grip strength and exercise capacity were evaluated, after the mice were sacrificed to collect their gastrocnemius muscles for assessment of atrophy and fibrosis by haematoxylin and eosin staining, qRT‐PCR and Western blotting. Co‐immunoprecipitation was used to identify the interaction between decorin and integrin β1 (ITGB1). Results The expression levels of decorin were reduced at both mRNA and protein levels in muscle during natural ageing in mice (−75.3% of mRNA level; −29.5% of protein level) and NOR‐10 cells (−78% of protein level). si‐Dcn promoted the expression of α‐SMA (+37.2%) and fibronectin (+53.1%), which are related to muscle fibrosis in D‐gal–induced NOR‐10 cells. In addition, in Dcn−/−–D‐gal mice, which exhibited more aggravated muscle atrophy including smaller grip strength (−21.7%, p < 0.001), downregulation of the ratio of gastrocnemius weight (−7.3%), fibre size (Gast: −15.3%) and increased levels of α‐SMA (+70.2%), MuRF‐1 (+30.2%), NLRP3(+19.4%) and p21(+27.2%) proteins compared with Dcn+/+–D‐gal mice. In terms of the underlying mechanisms, the Akt/mTOR signalling pathway was downregulated in Dcn−/−–D‐gal mice compared with aged Dcn+/+–D‐gal mice (p‐S473‐Akt/Akt: −38.1%; p‐Ser2448‐mTOR/mTOR: −28.8%; p‐p70S6K/p70: −40.3%; p‐4E‐BP1: −42.3%, p < 0.05). Decorin activation enhanced ITGB1 expression (+46.7% vs. NC, p < 0.01). si‐ITGB1 suppressed the expression of p‐S473‐Akt and p‐Ser2448‐mTOR in NOR‐10 cells with Dcn overexpression. The interaction between decorin and ITGB1 was found in skeletal muscle, suggesting that the regulation of decorin on Akt/mTOR might depend on ITGB1. Notably, decorin deficiency increased the accumulation of p62 (+47.2%, p < 0.05) and LC3b (+50.9%, p < 0.01). Conclusions The comprehensive results show that decorin plays a sarcoprotective role by activating the ITGB1/Akt/mTOR pathway and may serve as a potential therapeutic reagent in age‐associated sarcopenia.

A link exists between decorin (DCN) and endometriosis, nevertheless, the role of DCN in this condition remains unclear. This study aims to bioinformatically characterize DCN expression, diagnostic value, and related signaling in endometriosis using single-cell and bulk transcriptomic data, with experimental validation of expression level. Single-cell RNA sequencing (scRNA-seq) was analyzed using Scissor and ROGUE algorithms to identify key cell types associated with endometriosis. CIBERSORTx was used to construct a signature matrix for deconvolution of bulk RNA-seq data and estimation of immune and stromal subpopulation proportions. DCN expression was explored across datasets and validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in endometrial and endometriotic stromal cells. Its diagnostic value was assessed by receiver operating characteristic (ROC) curve analysis, and associated pathways were predicted by gene set enrichment analysis (GSEA). Potential DCN-targeted drugs were predicted via bioinformatic databases. Stromal cells were identified as the key cell type with high heterogeneity and dominant DCN expression. Ten stromal subtypes were delineated, with Activated/Myofibroblast-like Stromal Cells (AMSC), Fibrosis-Effector Stromal Cells (FESC), Stemness-Remodeling Stromal Cells (SRSC), and dStromal showing significantly altered proportions in endometriosis. DCN was significantly upregulated in endometriosis at both transcriptomic and cellular levels, with area under the curve (AUC) > 0.8 in two independent datasets, supporting its diagnostic potential. GSEA indicated DCN correlates with complement/coagulation cascades, TGF-β signaling, and other pathways linked to tissue remodeling and inflammation. Seven candidate drugs targeting DCN were predicted as hypothesis-generating leads. This study provides bioinformatic and correlative evidence that DCN is abnormally upregulated in endometriotic stromal cells and exhibits favorable diagnostic value. DCN is associated with pathways relevant to endometriosis pathogenesis and represents a promising biomarker and therapeutic candidate pending future functional and mechanistic validation.

Background Proteoglycans are important tumor microenvironment extracellular matrix components. The regulation of key proteoglycans, such as decorin (DCN), by miRNAs has drawn attention since they have surfaced as novel therapeutic targets in cancer. Accordingly, this study aimed at identifying the impact of miR-181a in liver cancer and its regulatory role on the extracellular matrix proteoglycan, DCN, and hence on downstream oncogenes and tumor suppressor genes. Results DCN was under-expressed in 22 cirrhotic and HCC liver tissues compared to that in 11 healthy tissues of liver transplantation donors. Conversely, miR-181a was over-expressed in HCC liver tissues compared to that in healthy liver tissues. In silico analysis predicted that DCN 3’UTR harbors two high-score oncomiR-181a binding regions. This was validated by pmiRGLO luciferase reporter assay. Ectopic miR-181a expression into HuH-7 cells repressed the transcript and protein levels of DCN as assessed fluorometrically and by western blotting. DCN siRNAs showed similar results to miR-181a, where they both enhanced the cellular viability, proliferation, and clonogenicity. They also increased Myc and E2F and decreased p53 and Rb signaling as assessed using reporter vectors harboring p53, Rb, Myc, and E2F response elements. Our findings demonstrated that miR-181a directly downregulated the expression of its direct downstream target DCN, which in turn affected downstream targets related to cellular proliferation and apoptosis. Conclusion To our knowledge, this is the first study to unveil the direct targeting of DCN by oncomiR-181a. We also highlighted that miR-181a affects targets related to cellular proliferation in HCC which may be partly mediated through inhibition of DCN transcription. Thus, miR-181a could be a promising biomarker for the early detection and monitoring of liver cancer progression. This would pave the way for the future targeting of the oncomiR-181a as a therapeutic approach in liver cancer, where miR-181a-based therapy approach could be potentially combined with chemotherapy and immunotherapy for the management of liver cancer.

The objective of the study was to determine the specific roles of decorin and biglycan in the early and late phases of tendon healing in aged mice. Aged (300 day-old) female wildtype (WT), Dcn flox/flox (I- Dcn -/- ), Bgn flox/flox (I- Bgn -/- ), and compound Dcn flox/flox /Bgn flox/flox (I- Dcn -/- /Bgn -/- ) mice with a tamoxifen (TM) inducible Cre underwent a bilateral patellar tendon injury (PT). Cre excision of the conditional alleles was induced at 5 days (samples collected at 3 and 6 weeks) or 21 days post-injury (samples collected at 6 weeks). Scar tissue area, collagen architecture, gene expression and mechanical properties were assessed during re-establishment of tendon architecture after injury. Fibril diameter distribution was impacted by both decorin and biglycan knockdown at 3 and 6 weeks compared to WT. Although early healing appeared to be delayed in the I- Bgn -/- tendons (larger scar tissue area at 3 weeks), no differences in failure properties were detected. By 6 weeks, in the I- Dcn -/- tendons, we observed a better recovery of viscoelastic properties compared to the WT tendons (reduced stress relaxation and increased dynamic modulus) when the knockdown was induced early. This could be explained by the increased expression of other matrix proteins, such as elastin whose gene expression was increased at 3 weeks in the I- Dcn -/- tendons. Despite an impact on collagen fibrillogenesis, decorin and/or biglycan knockdown did not produce a detectable effect on quasi-static properties after patellar tendon injury. However, early decorin knockdown resulted in better recovery of viscoelastic properties. Mechanisms underlying this result remained to be clarified in further studies.

Multiple sclerosis (MS) is unsurpassed for its clinical and pathological hetherogeneity, but the biological determinants of this variability are unknown. HLA‐DRB1*15, the main genetic risk factor for MS, influences the severity and distribution of MS pathology. This study set out to unravel the molecular determinants of the heterogeneity of MS pathology in relation to HLA‐DRB1*15 status. Shotgun proteomics from a discovery cohort of MS spinal cord samples segregated by HLA‐DRB*15 status revealed overexpression of the extracellular matrix (ECM) proteins, biglycan, decorin, and prolargin in HLA‐DRB*15‐positive cases, adding to established literature on a role of ECM proteins in MS pathology that has heretofore lacked systematic pathological validation. These findings informed a neuropathological characterisation of these proteins in a large autopsy cohort of 41 MS cases (18 HLA‐DRB1*15‐positive and 23 HLA‐DRB1*15‐negative), and seven non‐neurological controls on motor cortical, cervical and lumbar spinal cord tissue. Biglycan and decorin demonstrate a striking perivascular expression pattern in controls that is reduced in MS (−36.5%, p = 0.036 and − 24.7%, p = 0.039; respectively) in lesional and non‐lesional areas. A concomitant increase in diffuse parenchymal accumulation of biglycan and decorin is seen in MS (p = 0.015 and p = 0.001, respectively), particularly in HLA‐DRB1*15‐positive cases (p = 0.007 and p = 0.046, respectively). Prolargin shows a faint parenchymal pattern in controls that is markedly increased in MS cases where a perivascular deposition pattern is observed (motor cortex +97.5%, p = 0.001; cervical cord +49.1%, p = 0.016). Our findings point to ECM proteins and the vascular interface playing a central role in MS pathology within and outside the plaque area. As ECM proteins are known potent pro‐inflammatory molecules, their parenchymal accumulation may contribute to disease severity. This study brings to light novel factors that may contribute to the heterogeneity of the topographical variation of MS pathology. Shotgun proteomic and confirmatory immunohistochemical characterisation of post‐mortem tissue showed region‐specific and HLA‐DRB*15 influenced alteration in extracellular matrix proteins expression between MS and controls. In particular, we shows that non‐neurological controls have a perivascular‐predominant expression pattern of these proteins that is disrupted in MS where instead a marked parenchymal deposition pattern is seen. Our study provides unequivocal evidence for a role of extracellular matrix proteins and the vasculature being key contributors to MS pathology within and outside the plaque area.

Mitochondrial dysfunction with oxidative stress contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) progression. We aimed to evaluate the fibrosis predictive efficacy of a novel non-invasive diagnostic panel using metabolic stress biomarkers. From a population-based general cohort, 144 subjects with MASLD were recruited in the development group and underwent magnetic resonance imaging-based liver examinations, anthropometric and laboratory tests. As an external validation group, 41 patients enrolled in a biopsy-evaluated MASLD cohort participated in this study. Liver fat content and stiffness were measured by magnetic resonance (MR) imaging-proton density fat fraction and MR elastography (MRE), respectively. Serologic stress biomarkers were quantitated by ELISA. Multivariate regression showed that waist-to-height ratio, growth differentiation factor-15 (GDF15), γ-glutamyltransferase, decorin, and alkaline-phosphatase were independent predictors of hepatic fibrosis (rank-ordered by Wald). The area under receiver-operator characteristics curve [AUROC (95% CI)) of the metabolic stress index for fibrosis (MSI-F) was 0.912 (0.85‒0.98) and 0.977 (0.92‒1.00) in development and validation groups, respectively. MSI-F also had better diagnostic accuracy (82.6‒92.4%) than other fibrosis indices in the both study cohorts. MSI-F consistently differentiated fibrosis severities across cohorts of MRE-evaluated general population and biopsy-proven patients with MASLD, while other indices showed no or less discrimination. MSI-F, as a novel non-invasive index based on a stress-stimulated protective hormone GDF15 and decorin, effectively predicted hepatic fibrosis. Furthermore, MSI-F may serve as pre-screening tool to increase the population that could be excluded from further evaluation, reducing unnecessary invasive investigations more effectively than other indices.

Corneal dystrophies are phenotypically and genetically heterogeneous, often resulting in visual impairment caused by corneal opacification. We investigated the genetic cause of an autosomal dominant corneal stromal dystrophy in a pedigree with eight affected individuals in three generations. Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue removed during surgery revealed mild stromal textural alterations with alcianophilic deposits. Whole genome sequence data were generated for four affected individuals. No rare variants (MAF < 0.001) were identified in established corneal dystrophy genes. However, a novel heterozygous missense variant in exon 4 of SPARCL1 , NM_004684: c.334G > A; p.(Glu112Lys), which is predicted to be damaging, segregated with disease. SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. Interestingly, SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN , encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Therefore, we performed immunohistochemistry to compare SPARCL1 and decorin localisation in corneal tissue from an affected family member and an unaffected control. Strikingly, the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium. In summary, we describe a novel autosomal dominant corneal stromal dystrophy associated with a missense variant in SPARCL1 , extending the phenotypic and genetic heterogeneity of inherited corneal disease.