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Journal of Clinical Medicine Apr 2024The etiopathogenesis of ACL rupture is not clarified. The aim of this study is to identify genomic regions and genetic variants relevant to anterior cruciate ligament... (Review)
Review
BACKGROUND
The etiopathogenesis of ACL rupture is not clarified. The aim of this study is to identify genomic regions and genetic variants relevant to anterior cruciate ligament injury susceptibility that could be involved in non-contact anterior cruciate ligament ruptures.
METHODS
A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with a PRISMA checklist and algorithm. A search of PubMed, MEDLINE, CINAHL, Cochrane, EMBASE, and Google Scholar databases was conducted using combinations of the terms "anterior cruciate ligament", "ACL", "rupture", "genetics", "single nucleotide polymorphisms", and "SNP" since the inception of the databases until 2021.
RESULTS
Twenty-three studies were included. A total of 7724 patients were analyzed. In total, 3477 patients had ACL ruptures and 4247 patients were controls. Genetic variants in genes encoding for collagens, elastin, fibrillin, matrix metalloproteinases, proteoglycans, angiogenesis-associated signaling cascade proteins, growth differentiation factors, tissue inhibitors of metalloproteases, interleukins, and fibrinogen were analyzed.
CONCLUSION
Findings regarding the association between genes encoding for collagen (COL3A1, COL1A1, and COL12A1), aggrecan (ACAN), decorin (DCN), matrix metalloproteinase (MMP3), interleukin 6 (IL-6), vascular endothelial growth factor A (VEGFA), biglycan (BGN), fibrinogen (FGB), and ACL injuries were found to be inconclusive. Additional evidence is required in order to establish substantial conclusions regarding the association between genetic variants and ACL rupture.
PubMed: 38673603
DOI: 10.3390/jcm13082330 -
BMC Cancer Apr 2024Numerous studies have indicated that cancer-associated fibroblasts (CAFs) play a crucial role in the progression of colorectal cancer (CRC). However, there are still...
BACKGROUND
Numerous studies have indicated that cancer-associated fibroblasts (CAFs) play a crucial role in the progression of colorectal cancer (CRC). However, there are still many unknowns regarding the exact role of CAF subtypes in CRC.
METHODS
The data for this study were obtained from bulk, single-cell, and spatial transcriptomic sequencing data. Bioinformatics analysis, in vitro experiments, and machine learning methods were employed to investigate the functional characteristics of CAF subtypes and construct prognostic models.
RESULTS
Our study demonstrates that Biglycan (BGN) positive cancer-associated fibroblasts (BGN + Fib) serve as a driver in colorectal cancer (CRC). The proportion of BGN + Fib increases gradually with the progression of CRC, and high infiltration of BGN + Fib is associated with poor prognosis in terms of overall survival (OS) and recurrence-free survival (RFS) in CRC. Downregulation of BGN expression in cancer-associated fibroblasts (CAFs) significantly reduces migration and proliferation of CRC cells. Among 101 combinations of 10 machine learning algorithms, the StepCox[both] + plsRcox combination was utilized to develop a BGN + Fib derived risk signature (BGNFRS). BGNFRS was identified as an independent adverse prognostic factor for CRC OS and RFS, outperforming 92 previously published risk signatures. A Nomogram model constructed based on BGNFRS and clinical-pathological features proved to be a valuable tool for predicting CRC prognosis.
CONCLUSION
In summary, our study identified BGN + Fib as drivers of CRC, and the derived BGNFRS was effective in predicting the OS and RFS of CRC patients.
Topics: Colorectal Neoplasms; Humans; Machine Learning; Cancer-Associated Fibroblasts; Prognosis; Biglycan; Cell Proliferation; Biomarkers, Tumor; Male; Gene Expression Regulation, Neoplastic; Female; Cell Movement; Tumor Microenvironment
PubMed: 38654221
DOI: 10.1186/s12885-024-12251-4 -
Proceedings of the National Academy of... Apr 2024The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These...
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.
Topics: Decorin; Lymphangiogenesis; Animals; Mice; Humans; Female; Breast Neoplasms; Lymphatic Vessels; Cell Line, Tumor; Disease Progression; Vesicular Transport Proteins; Membrane Glycoproteins; Gene Expression Regulation, Neoplastic
PubMed: 38652741
DOI: 10.1073/pnas.2317760121 -
NPJ Genomic Medicine Mar 2024Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection...
Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5' untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.
PubMed: 38531898
DOI: 10.1038/s41525-024-00413-z -
The Turkish Journal of Pediatrics 2024Campotodactyly-artrhropathy-coxa vara-pericarditis (CACP) syndrome is a very rare autosomal recessive genetic disorder. It is characterized by flexion contracture of the...
BACKGROUND
Campotodactyly-artrhropathy-coxa vara-pericarditis (CACP) syndrome is a very rare autosomal recessive genetic disorder. It is characterized by flexion contracture of the fifth finger (camptodactyly); noninflammatory arthropathy; decreased angle between the shaft and the head of the femur (coxa vara) and pericarditis. Its association with mitral stenosis has not yet been reported. Hereby we report this unique association with CACP syndrome.
CASE
An eleven-year-old girl presented with non-productive cough, dyspnea, and orthopnea. She was diagnosed CACP syndrome at the age of seven and a biallelic frameshift mutation in the PRG4 gene was determined. The physical examination revealed pectus excavatum, camptodactyly, genu valgum, tachypnea and orthopnea. The functional capacity was NYHA III-IV. She had 2/6 soft pansystolic murmur at 4th left intercostal space and a rumbling diastolic murmur at apex. Echocardiography revealed an enlarged left atrium, severe stenotic mitral valve with a mean diastolic transmitral gradient of 22.5 mmHg, mild mitral regurgitation and mild apical pericardial effusion. The patient had mitral comissurotomy and partial pericardiectomy operation. Her post-operative transmitral gradient decreased to 6.9 mmHg and the pulmonary pressure was 30 mmHg. Her functional capacity increased to NYHA I-II.
CONCLUSIONS
The main defect is the proteoglycan 4 protein which acts like a lubricant in articular and visceral surfaces. Therefore, the leading clinical feature is arthropathy. Cardiac involvement other than clinically mild pericarditis is not usually expected. Three types of proteoglycans (decorin, biglycan, and versican) are present in the mitral valve. This could be the reason of mitral valve involvement in rare cases as like ours. It is important that these patients undergo echocardiographic examination regularly.
Topics: Female; Humans; Child; Coxa Vara; Mitral Valve Stenosis; Joint Diseases; Pericarditis; Dyspnea; Arthropathy, Neurogenic; Hand Deformities, Congenital; Synovitis
PubMed: 38523390
DOI: 10.24953/turkjped.2023.647 -
Frontiers in Oncology 2024Hypoxia plays an important role in the heterogeneity, relapse, metastasis, and drug resistance of breast cancer. In this study, we explored the hypoxia-related...
INTRODUCTION
Hypoxia plays an important role in the heterogeneity, relapse, metastasis, and drug resistance of breast cancer. In this study, we explored the hypoxia-related biological signatures in different subtypes of breast cancer and identified the key prognostic factors by bioinformatics methods.
METHODS
Based on The Cancer Genome Atlas (TCGA) Breast Cancer datasets, we divided the samples into immune-activated/suppressed populations by single-sample gene set enrichment analysis (ssGSEA) and then used hierarchical clustering to further identify hypoxic/non-hypoxic populations from the immune-suppressed samples. A hypoxia related risk model of breast cancer was constructed.
RESULTS
Nuclear factor interleukin-3 regulated (NFIL3), serpin family E member 1 (SERPINE1), FOS, biglycan (BGN), epidermal growth factor receptor (EGFR), and sushi-repeat-containing protein, X-linked (SRPX) were identified as key hypoxia-related genes. Margin status, American Joint Committee on Cancer (AJCC) stage, hypoxia status, estrogen receptor/progesterone receptor (ER/PR) status, NFIL3, SERPINE1, EGFR, and risk score were identified as independent prognostic indicators for breast cancer patients. The 3- and 5-year survival curves of the model and immunohistochemical staining on the breast cancer microarray verified the statistical significance and feasibility of our model. Among the different molecular types of breast cancer, ER/PR+ and HER2+ patients might have higher hypoxia-related risk scores. ER/PR-negative samples demonstrated more activated immune-related pathways and better response to most anticancer agents.
DISCUSSION
Our study revealed a novel risk model and potential feasible prognostic factors for breast cancer and might provide new perspectives for individual breast cancer treatment.
PubMed: 38500661
DOI: 10.3389/fonc.2024.1350426 -
Heliyon Feb 2024Predicting the outcome of oral squamous cell carcinoma (OSCC) is challenging due to its diverse nature and intricate causes. This research explores how...
BACKGROUND
Predicting the outcome of oral squamous cell carcinoma (OSCC) is challenging due to its diverse nature and intricate causes. This research explores how lysosome-associated genes (LRGs) might forecast overall survival (OS) and correlate with immune infiltration in OSCC patients.
METHODS
We analyzed OSCC patients' LRGs' mRNA expression data and clinical details from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Through univariate Cox regression, we pinpointed LRGs with prognostic potential. A signature comprising 12 LRGs linked to prognosis was developed via the Least Absolute Shrinkage and Selection Operator (LASSO) in a training dataset. Patients were classified as higher or lower risk based on their risk scores, and the prognostic independence of the risk score was assessed using multivariate analysis. The model's robustness and precision were confirmed through bioinformatics in the GEO test set. Differential gene expression analysis between risk groups highlighted functional disparities, while various immune evaluation methods elucidated immune differences.
RESULTS
The prognostic framework utilized 12 LRGs (SLC46A3, MANBA, NEU1, SDCBP, BRI3, TMEM175, CD164, GPC1, SFTPB, TPP1, Biglycan (BGN) and TMEM192), showing that higher risk was associated with poorer OS. This set of genes independently predicted OS in OSCC, linking LRGs to cellular adhesion and extracellular matrix involvement. Initial assessments using ssGSEA and CIBERSORT suggested that the adverse outcomes in the higher-risk cohort may be tied to immune system deregulation.
CONCLUSION
Twelve-LRGs signature has been identified for OSCC prognosis prediction, offering novel directions for lysosome-targeted therapies against OSCC.
PubMed: 38420448
DOI: 10.1016/j.heliyon.2024.e26100 -
Journal of Biological Engineering Feb 2024The extracellular matrix (ECM) is a three-dimensional network of proteins that encases and supports cells within a tissue and promotes physiological and pathological...
BACKGROUND
The extracellular matrix (ECM) is a three-dimensional network of proteins that encases and supports cells within a tissue and promotes physiological and pathological cellular differentiation and functionality. Understanding the complex composition of the ECM is essential to decrypt physiological processes as well as pathogenesis. In this context, the method of decellularization is a useful technique to eliminate cellular components from tissues while preserving the majority of the structural and functional integrity of the ECM.
RESULTS
In this study, we employed a bottom-up proteomic approach to elucidate the intricate network of proteins in the decellularized extracellular matrices of murine liver and kidney tissues. This approach involved the use of a novel, perfusion-based decellularization protocol to generate acellular whole organ scaffolds. Proteomic analysis of decellularized mice liver and kidney ECM scaffolds revealed tissue-specific differences in matrisome composition, while we found a predominantly stable composition of the core matrisome, consisting of collagens, glycoproteins, and proteoglycans. Liver matrisome analysis revealed unique proteins such as collagen type VI alpha-6, fibrillin-2 or biglycan. In the kidney, specific ECM-regulators such as cathepsin z were detected.
CONCLUSION
The identification of distinct proteomic signatures provides insights into how different matrisome compositions might influence the biological properties of distinct tissues. This experimental workflow will help to further elucidate the proteomic landscape of decellularized extracellular matrix scaffolds of mice in order to decipher complex cell-matrix interactions and their contribution to a tissue-specific microenvironment.
PubMed: 38389090
DOI: 10.1186/s13036-024-00413-8 -
Matrix Biology Plus Feb 2024Cardiovascular disease is the leading cause of death, with atherosclerosis the major underlying cause. While often asymptomatic for decades, atherosclerotic plaque...
Cardiovascular disease is the leading cause of death, with atherosclerosis the major underlying cause. While often asymptomatic for decades, atherosclerotic plaque destabilization and rupture can arise suddenly and cause acute arterial occlusion or peripheral embolization resulting in myocardial infarction, stroke and lower limb ischaemia. As extracellular matrix (ECM) remodelling is associated with plaque instability, we hypothesized that the ECM composition would differ between plaques. We analyzed atherosclerotic plaques obtained from 21 patients who underwent carotid surgery following recent symptomatic carotid artery stenosis. Plaques were solubilized using a new efficient, single-step approach. Solubilized proteins were digested to peptides, and analyzed by liquid chromatography-mass spectrometry using data-independent acquisition. Identification and quantification of 4498 plaque proteins was achieved, including 354 ECM proteins, with unprecedented coverage and high reproducibility. Multidimensional scaling analysis and hierarchical clustering indicate two distinct clusters, which correlate with macroscopic plaque morphology (soft/unstable versus hard/stable), ultrasound classification (echolucent versus echogenic) and the presence of hemorrhage/ulceration. We identified 714 proteins with differential abundances between these groups. Soft/unstable plaques were enriched in proteins involved in inflammation, ECM remodelling, and protein degradation (e.g. matrix metalloproteinases, cathepsins). In contrast, hard/stable plaques contained higher levels of ECM structural proteins (e.g. collagens, versican, nidogens, biglycan, lumican, proteoglycan 4, mineralization proteins). These data indicate that a single-step proteomics method can provide unique mechanistic insights into ECM remodelling and inflammatory mechanisms within plaques that correlate with clinical parameters, and help rationalize plaque destabilization. These data also provide an approach towards identifying biomarkers for individualized risk profiling of atherosclerosis.
PubMed: 38292008
DOI: 10.1016/j.mbplus.2024.100141 -
International Journal of Molecular... Jan 2024Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and...
Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and hyaluronan more prominent in eroded plaques. Following plaque disruption, the exposure of extracellular matrix (ECM) proteins triggers platelet adhesion and thrombus formation. In this study, the impact of differential plaque composition on platelet function and thrombus formation was investigated. Platelet adhesion, activation and thrombus formation under different shear stress conditions were assessed in response to individual proteoglycans and composites representing different plaque phenotypes. The results demonstrated that all the proteoglycans tested mediated platelet adhesion but not platelet activation, and the extent of adhesion observed was significantly lower than that observed with type I and type III collagens. Thrombus formation upon the rupture and erosion ECM composites was significantly reduced ( < 0.05) compared to relevant collagen alone, indicating that proteoglycans negatively regulate platelet collagen responses. This was supported by results demonstrating that the addition of soluble biglycan or decorin to whole blood markedly reduced thrombus formation on type I collagen ( < 0.05). Interestingly, thrombus formation upon the erosion composite displayed aspirin sensitivity, whereas the rupture composite was intensive to aspirin, having implications for current antiplatelet therapy regimes. In conclusion, differential platelet responses and antiplatelet efficacy are observed on ECM composites phenotypic of plaque rupture and erosion. Proteoglycans inhibit thrombus formation and may offer a novel plaque-specific approach to limit arterial thrombosis.
Topics: Humans; Biglycan; Decorin; Atherosclerosis; Plaque, Atherosclerotic; Extracellular Matrix Proteins; Aspirin; Collagen Type I; Thrombosis
PubMed: 38256024
DOI: 10.3390/ijms25020950