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Journal of Orthopaedic Research :... Jul 2021Musculoskeletal malignancy is often accompanied by aberrant bone remodeling, leading to tumor cell invasion into skeletal tissues and causing severe pain. BMPs, FGF-2,...
Musculoskeletal malignancy is often accompanied by aberrant bone remodeling, leading to tumor cell invasion into skeletal tissues and causing severe pain. BMPs, FGF-2, and RANKL have been identified as promising regulators in physiological bone remodeling. In this study, we explored the expressional profile of BMPs, FGF-2, and RANKL in 1361 patients with 22 varieties of musculoskeletal tumors. Notably, the expression of FGF-2 and RANKL was under detected in all patients. Among BMP1 to BMP15, we found that BMP1, BMP2, BMP4, BMP5, BMP6, and BMP7 were prevalent. In comparison with normal bones, osteosarcoma highly expressed BMP1, BMP2, BMP4, and BMP7 with statistical significance. Synovial sarcoma upregulated BMP4, BMP5, and BMP7; rhabdomyosarcoma increased BMP1 and BMP4; and alveolar soft part sarcoma upregulated BMP1, BMP4, and BMP7. To visualize the BMP-oriented interactions in a bone tumor microenvironment, we have developed novel software that analyzes numerous cell-to-cell and ligand-to-receptor interactions, that is, Environmentome, delineating that osteosarcoma-secreted BMP-4 and synovial sarcoma-secreted BMP7 potently interact with osteoblasts, osteocytes, osteoclast precursors, and mature osteoclasts. Specifically, quantification analysis revealed that the relationship between osteosarcoma and mature osteoclast/precursor, BMP4-BMPR2 and BMP4-ACVR2A interactions were most potent. Regarding the association between osteosarcoma and osteocyte/osteoblast, BMP4-ACVR1 and BMP4-BMPR2 were the key interactions. In the connection between synovial sarcoma and mature osteoclast/precursor, BMP7-ACVR2A and BMP7-BMPR2 interactions were most remarkable. With regard to the cellular link between synovial sarcoma and osteocyte/osteoblast, BMP7-BMPR2 was identified as a potent interaction. In conclusion, our new outlook suggests delivering the pathological events that clinically underlie behind severe skeletal pain or fracture in musculoskeletal tumors.
Topics: Bone Morphogenetic Proteins; Bone Neoplasms; Bone Remodeling; Bone and Bones; Chondrosarcoma; Fibroblast Growth Factors; Humans; Multiple Myeloma; Muscle Neoplasms; Osteosarcoma; RANK Ligand; Tumor Microenvironment
PubMed: 33034913
DOI: 10.1002/jor.24879 -
Bulletin Du Cancer Apr 2022This study aims to elucidate the characteristic and expression level of miR-1226 in non-small cell lung cancer (NSCLC) tissue samples and cell lines, and its potential...
OBJECTIVE
This study aims to elucidate the characteristic and expression level of miR-1226 in non-small cell lung cancer (NSCLC) tissue samples and cell lines, and its potential influence on the malignant progression of NSCLC.
METHODS
The expression level of miR-1226 in tumor tissue and paracancerous tissue of NSCLC patients was detected by qRT-PCR. The influences on clinical features of NSCLC patients were analyzed. The proliferation and metastasis ability in H1299 and SPC-A1 cells were examined by CCK-8 and Transwell assay, respectively. Subsequently, the binding relationship between miR-1226 and FGF2 was verified by dual-luciferase reporter assay. The upstream regulatory factor ASCL1 was identified through database prediction, and the co-regulation on NSCLC cell lines was explored via rescue experiments.
RESULTS
miR-1226 was down-regulated in NSCLC tissue samples and cell lines, which suggested that miR-1226 was associated with tumor stage and lymph node metastasis. The transfection of miR-1226 mimic inhibited the proliferation and migration in H1299 and SPC-A1 cells. In addition, the overexpression of miR-1226 suppressed tumor growth in vivo. FGF2 was the downstream target binding miR-1226, which was up-regulated in NSCLC tissue samples. Moreover, ASCL1 was found to be a potential regulator of miR-1226. Finally, the tumor suppressive effect of miR-1226 was reversed by its downstream FGF2 and upstream factor ASCL1.
CONCLUSIONS
miR-1226, which was regulated by ASCL1, inhibited tumor growth and migration by targeting FGF2, indicating that the ASCL1/miR-1226/FGF2 axis could be a potential therapeutic target for NSCLC.
Topics: Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Fibroblast Growth Factor 2; Fibroblast Growth Factors; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MicroRNAs
PubMed: 35164915
DOI: 10.1016/j.bulcan.2021.11.017 -
Human Molecular Genetics Jan 2023Asthma is a heterogeneous common respiratory disease that remains poorly understood. The established genetic associations fail to explain the high estimated...
BACKGROUND
Asthma is a heterogeneous common respiratory disease that remains poorly understood. The established genetic associations fail to explain the high estimated heritability, and the prevalence of asthma differs between populations and geographic regions. Robust association analyses incorporating different genetic ancestries and whole-genome sequencing data may identify novel genetic associations.
METHODS
We performed family-based genome-wide association analyses of childhood-onset asthma based on whole-genome sequencing (WGS) data for the 'The Genetic Epidemiology of Asthma in Costa Rica' study (GACRS) and the Childhood Asthma Management Program (CAMP). Based on parent-child trios with children diagnosed with asthma, we performed a single variant analysis using an additive and a recessive genetic model and a region-based association analysis of low-frequency and rare variants.
RESULTS
Based on 1180 asthmatic trios (894 GACRS trios and 286 CAMP trios, a total of 3540 samples with WGS data), we identified three novel genetic loci associated with childhood-onset asthma: rs4832738 on 4p14 ($P=1.72\ast{10}^{-9}$, recessive model), rs1581479 on 8p22 ($P=1.47\ast{10}^{-8}$, additive model) and rs73367537 on 10q26 ($P=1.21\ast{10}^{-8}$, additive model in GACRS only). Integrative analyses suggested potential novel candidate genes underlying these associations: PGM2 on 4p14 and FGF20 on 8p22.
CONCLUSION
Our family-based whole-genome sequencing analysis identified three novel genetic loci for childhood-onset asthma. Gene expression data and integrative analyses point to PGM2 on 4p14 and FGF20 on 8p22 as linked genes. Furthermore, region-based analyses suggest independent potential low-frequency/rare variant associations on 8p22. Follow-up analyses are needed to understand the functional mechanisms and generalizability of these associations.
Topics: Humans; Genome-Wide Association Study; Genetic Predisposition to Disease; Asthma; Genetic Loci; Whole Genome Sequencing; Polymorphism, Single Nucleotide; Fibroblast Growth Factors
PubMed: 36255742
DOI: 10.1093/hmg/ddac258 -
Brain : a Journal of Neurology Mar 2021Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations...
Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10-5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (odds ratio 0.73, 95% confidence interval 0.60-0.89, P = 1.161 × 10-3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.
Topics: Adult; Aged; Female; Fibroblast Growth Factors; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mutation; Parkinson Disease; Polymorphism, Single Nucleotide; Synaptotagmins
PubMed: 33349842
DOI: 10.1093/brain/awaa401 -
Genes Apr 2021Parkinson's disease (PD) is a neurodegenerative disease with the pathological hallmark of Lewy bodies and Lewy neurites composed of α-synuclein. The SNP rs591323 is one... (Meta-Analysis)
Meta-Analysis
Parkinson's disease (PD) is a neurodegenerative disease with the pathological hallmark of Lewy bodies and Lewy neurites composed of α-synuclein. The SNP rs591323 is one of the risk loci located near the gene that has been implicated in PD. The variation of in the 3' untranslated region was shown to increase α-synuclein expression. We examined the association of rs591323 with the risk of PD in a Taiwanese population and conducted a meta-analysis, including our study and two other studies from China, to further confirm the role of this SNP in Taiwanese/Chinese populations. A total of 586 patients with PD and 586 health controls (HCs) were included in our study. We found that the minor allele (A) and the AA + GA genotype under the dominant model are significantly less frequent in PD than in controls. The meta-analysis consisted of 1950 patients with PD and 2073 healthy controls from three studies. There was significant association between rs591323 and the risk of PD in the additive (Z = -3.96; < 0.0001) and the dominant models (Z = -4.01; < 0.0001). Our study results and the meta-analysis support the possible protective role of the rs591323 A allele in PD in Taiwanese/Chinese populations.
Topics: China; Fibroblast Growth Factors; Humans; Parkinson Disease; Polymorphism, Single Nucleotide; Taiwan
PubMed: 33947140
DOI: 10.3390/genes12050674 -
Biomedicine & Pharmacotherapy =... Nov 2021The pathology of cerebrovascular disorders takes an important role in traumatic brain injury (TBI) by increasing intracranial pressure. Fibroblast growth factor 20...
The pathology of cerebrovascular disorders takes an important role in traumatic brain injury (TBI) by increasing intracranial pressure. Fibroblast growth factor 20 (FGF20) is a brain-derived neurotrophic factor, that has been shown to play an important role in the survival of dopaminergic neurons and the treatment of Parkinson's disease (PD). However, little is known about the role of FGF20 in the treatment of TBI and its underlying mechanism. The purpose of this study was to evaluate the protective effect of recombinant human FGF20 (rhFGF20) on protecting cerebral blood vessels after TBI. In this study, we indicated that rhFGF20 could reduce brain edema, Evans blue penetration and upregulated the expression of blood-brain barrier (BBB)-related tight junction (TJ) proteins, exerting a protective effect on the BBB in vivo after TBI. In the TBI repair phase, rhFGF20 promoted angiogenesis, neurological and cognitive function recovery. In tumor necrosis factor-α (TNF-α)-induced human brain microvascular endothelial cells (hCMEC/D3), an in vitro BBB disruption model, rhFGF20 reversed the impairment in cell migration and tube formation induced by TNF-α. Moreover, in both the TBI mouse model and the in vitro model, rhFGF20 increased the expression of β-catenin and GSK3β, which are the two key regulators in the Wnt/β-catenin signaling pathway. In addition, the Wnt/β-catenin inhibitor IWR-1-endo significantly reversed the effects of rhFGF20. These results indicate that rhFGF20 may prevent vascular repair and angiogenesis through the Wnt/β-catenin pathway.
Topics: Angiogenesis Inducing Agents; Animals; Behavior, Animal; Blood-Brain Barrier; Brain Edema; Brain Injuries, Traumatic; Capillary Permeability; Cell Movement; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Fibroblast Growth Factors; Humans; Intracranial Pressure; Male; Memory; Mice, Inbred C57BL; Morris Water Maze Test; Motor Activity; Neovascularization, Physiologic; Recombinant Proteins; Rotarod Performance Test; Tight Junction Proteins; Tight Junctions; Wnt Signaling Pathway; Mice
PubMed: 34649342
DOI: 10.1016/j.biopha.2021.112200 -
PloS One 2015Nonalcoholic fatty liver disease (NAFLD) is a risk factor for Hepatocellular carcinoma (HCC), but he transition from NAFLD to HCC is poorly understood. Feature selection...
Nonalcoholic fatty liver disease (NAFLD) is a risk factor for Hepatocellular carcinoma (HCC), but he transition from NAFLD to HCC is poorly understood. Feature selection algorithms in human and genetically modified mice NAFLD and HCC microarray data were applied to generate signatures of NAFLD progression and HCC differential survival. These signatures were used to study the pathogenesis of NAFLD derived HCC and explore which subtypes of cancers that can be investigated using mouse models. Our findings show that: (I) HNF4 is a common potential transcription factor mediating the transcription of NAFLD progression genes (II) mice HCC derived from NAFLD co-cluster with a less aggressive human HCC subtype of differential prognosis and mixed etiology (III) the HCC survival signature is able to correctly classify 95% of the samples and gives Fgf20 and Tgfb1i1 as the most robust genes for prediction (IV) the expression values of genes composing the signature in an independent human HCC dataset revealed different HCC subtypes showing differences in survival time by a Logrank test. In summary, we present marker signatures for NAFLD derived HCC molecular pathogenesis both at the gene and pathway level.
Topics: Animals; Biomarkers; Carcinoma, Hepatocellular; Disease Progression; Fibroblast Growth Factors; Hepatocyte Nuclear Factor 4; Humans; Insulin Resistance; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Liver; Liver Neoplasms; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Risk Factors; p38 Mitogen-Activated Protein Kinases
PubMed: 25993042
DOI: 10.1371/journal.pone.0124544 -
CNS Neuroscience & Therapeutics Jan 2022
Topics: Asian People; Female; Fibroblast Growth Factors; GTP Cyclohydrolase; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Parkinson Disease; Synaptotagmins
PubMed: 34674384
DOI: 10.1111/cns.13745 -
The Journal of Neuroscience : the... Apr 2010We explored the effect of single-nucleotide polymorphisms (SNPs) in the fibroblast growth factor 20 gene (FGF20) associated with risk for Parkinson's disease on brain...
We explored the effect of single-nucleotide polymorphisms (SNPs) in the fibroblast growth factor 20 gene (FGF20) associated with risk for Parkinson's disease on brain structure and function in a large sample of healthy young-adult human subjects and also in elderly subjects to look at the interaction between genetic variations and age (N = 237; 116 men; 18-87 years). We analyzed high-resolution anatomical magnetic resonance images using voxel-based morphometry, a quantitative neuroanatomical technique. We also measured FGF20 mRNA expression in postmortem human brain tissue to determine the molecular correlates of these SNPs (N = 108; 72 men; 18-74 years). We found that the T allele carriers of rs12720208 in the 3'-untranslated region had relatively larger hippocampal volume (p = 0.0059) and diminished verbal episodic memory (p = 0.048) and showed steeper decreases of hippocampal volume with normal aging (p = 0.026). In postmortem brain, T allele carriers had greater expression of hippocampal FGF20 mRNA (p = 0.037), consistent with a previously characterized microRNA mechanism. The C allele matches a predicted miR-433 microRNA binding domain, whereas the T allele disrupts it, resulting in higher FGF20 protein translation. The strong FGF20 genetic effects in hippocampus are presumably mediated by activation of the FGFR1 (FGF receptor 1), which is expressed in mammalian brain most abundantly in the hippocampus. These associations, from mRNA expression to brain morphology to cognition and an interaction with aging, confirm a role of FGF20 in human brain structure and function during development and aging.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Alleles; Cognition; Female; Fibroblast Growth Factors; Genotype; Hippocampus; Humans; Male; MicroRNAs; Middle Aged; Organ Size; Polymorphism, Single Nucleotide; RNA, Messenger; Receptor, Fibroblast Growth Factor, Type 1; Young Adult
PubMed: 20427658
DOI: 10.1523/JNEUROSCI.5773-09.2010 -
Developmental Cell Jun 2012The identity of niche signals necessary to maintain embryonic nephron progenitors is unclear. Here we provide evidence that Fgf20 and Fgf9, expressed in the niche, and...
The identity of niche signals necessary to maintain embryonic nephron progenitors is unclear. Here we provide evidence that Fgf20 and Fgf9, expressed in the niche, and Fgf9, secreted from the adjacent ureteric bud, are necessary and sufficient to maintain progenitor stemness. Reduction in the level of these redundant ligands in the mouse led to premature progenitor differentiation within the niche. Loss of FGF20 in humans, or of both ligands in mice, resulted in kidney agenesis. Sufficiency was shown in vitro where Fgf20 or Fgf9 (alone or together with Bmp7) maintained isolated metanephric mesenchyme or sorted nephron progenitors that remained competent to differentiate in response to Wnt signals after 5 or 2 days in culture, respectively. These findings identify a long-sought-after critical component of the nephron stem cell niche and hold promise for long-term culture and utilization of these progenitors in vitro.
Topics: Animals; Bone Morphogenetic Protein 7; Cell Differentiation; Congenital Abnormalities; Female; Fibroblast Growth Factor 9; Fibroblast Growth Factors; Humans; Kidney; Kidney Diseases; Male; Mesenchymal Stem Cells; Mice; Mutation; Nephrons; Organ Culture Techniques; Stem Cell Niche; Wnt Signaling Pathway
PubMed: 22698282
DOI: 10.1016/j.devcel.2012.04.018