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Proceedings of the National Academy of... Sep 2021Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we...
Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we show that fibroblast growth factor-2 (FGF-2) not only stimulates muscle growth but also promotes intramuscular adipogenesis. Using multiple screening assays upstream and downstream of microRNA (miR)-29a signaling, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. Genetic deletions in muscle cells and adeno-associated virus-mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of fibro/adipogenic progenitors in vitro and intramuscular adipose tissue (IMAT) formation in vivo. Skeletal muscle from human donors aged >75 y versus <55 y showed activation of FGF-2-dependent signaling and increased IMAT. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a pathway to combat fat accumulation in aged human skeletal muscle.
Topics: Adipogenesis; Adipose Tissue; Aged; Cell Differentiation; Fibroblast Growth Factor 2; Humans; MicroRNAs; Muscle, Skeletal; Osteonectin; Proto-Oncogene Proteins c-fos; Signal Transduction
PubMed: 34493647
DOI: 10.1073/pnas.2021013118 -
Cellular and Molecular Life Sciences :... Mar 2018Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies, with approximately 20-30% of PDAC patients receiving the surgical resection... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies, with approximately 20-30% of PDAC patients receiving the surgical resection with curative intent. Although many studies have focused on finding ideal "drug chaperones" that facilitate and/or potentiate the effects of gemcitabine (GEM) in pancreatic cancer, a significant benefit in overall survival could not be demonstrated for any of these combination therapies in PDAC. Given that pancreatic cancer is characterized by desmoplasia and the dual biological roles of stroma in pancreatic cancer, we reassess the importance of stroma in GEM-based therapeutic approaches in light of current findings. This review is focused on understanding the role of stromal components in the extrinsic resistance to GEM and whether anti-stroma therapies have a positive effect on the GEM delivery. This work contributes to the development of novel and promising combination GEM-based regimens that have achieved significant survival benefits for the patients with pancreatic cancer.
Topics: Albumins; Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Hyaluronic Acid; Osteonectin; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Pyridines; Stromal Cells; Survival Analysis; Treatment Outcome; Gemcitabine
PubMed: 28993833
DOI: 10.1007/s00018-017-2678-7 -
Scientific Reports May 2019Gastric adenocarcinoma (GAC), also known as stomach adenocarcinoma (STAD), is one of the most lethal malignancies in the world. It is vital to classify and detect the...
Gastric adenocarcinoma (GAC), also known as stomach adenocarcinoma (STAD), is one of the most lethal malignancies in the world. It is vital to classify and detect the hub genes and key pathways participated in the initiation and progression of GAC. In this study, we collected and sequenced 15 pairs of GAC tumor tissues and the adjacent normal tissues. Differentially expressed genes (DEGs) were analyzed and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analysis were used to annotate the unique biological significance and important pathways of enriched DEGs. Moreover, we constructed the protein-protein interaction (PPI) network by Cytoscape and conducted KEGG enrichment analysis of the prime module. We further applied the TCGA database to start the survival analysis of these hub genes by Kaplan-Meier estimates. Finally, we obtained total 233 DEGs consisted of 64 up-regulated genes and 169 down-regulated genes. GO enrichment analysis found that DEGs most significantly enriched in single organism process, extracellular region, and extracellular region part. KEGG pathway enrichment analysis suggested that DEGs most significantly enriched in Protein digestion and absorption, Gastric acid secretion, and ECM-receptor interaction. Furthermore, the PPI network showed that the top 10 hub genes in GAC were IL8, COL1A1, MMP9, SST, COL1A2, TIMP1, FN1, SPARC, ALDH1A1, and SERPINE1 respectively. The prime gene interaction module in PPI network was enriched in protein digestion and absorption, ECM receptor interaction, the PI3K-Akt signaling pathway, and pathway in cancer. Survival analysis based on the TCGA database found that the expression of the FN1, SERPINE1, and SPARC significantly predicted poor prognosis of GAC. Collectively, we identified several hub genes and key pathways associated with GAC initiation and progression by analyzing the microarray data on DEGs, which provided a detailed molecular mechanism underlying GAC occurrence and progression.
Topics: Adenocarcinoma; Adult; Aged; Biomarkers, Tumor; Carcinogenesis; Computational Biology; Disease Progression; Female; Fibronectins; Gastric Mucosa; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Osteonectin; Plasminogen Activator Inhibitor 1; Prognosis; Protein Interaction Mapping; Protein Interaction Maps; Signal Transduction; Stomach Neoplasms; Young Adult
PubMed: 31127138
DOI: 10.1038/s41598-019-43924-x -
Cells Jun 2020The silencing of (secreted protein acid and rich in cysteine) gene through methylation of its promoter region represents a common event in many solid tumors and it is...
The silencing of (secreted protein acid and rich in cysteine) gene through methylation of its promoter region represents a common event in many solid tumors and it is frequently associated with tumor progression and an aggressive clinical outcome. Anyhow, the data concerning the epigenetic mechanism of deregulation and its prognostic value in lung cancer are still incomplete. We explored the aberrant methylation of and its effects in 4 non-small cell lung cancer (NSCLC) cell lines and 59 NSCLC tissues and correlated the methylation levels with clinical-pathological features and disease outcome of patients. In 3 out of 4 tumor cell lines high methylation levels were observed. An inverse correlation between the epigenetic silencing and SPARC expression was confirmed by 5-Aza-2'-deoxycytidine ((5-Aza-CdR) treatment that also significantly induced a reduction in cell viability, proliferation and tumor cell migration. In tissues, the DNA methylation levels of the gene were significantly lower in paired non-neoplastic lungs (NLs) and normal lungs distant from tumor (NLDTs) than in NSCLCs ( = 0.002 and = 0.0034 respectively). A promoter hypermethylation was detected in 68% of squamous cell carcinoma (SqCCs, 17/25) and 56% of adenocarcinoma (ADCs, 19/34), with SqCC showing the highest levels of methylation. Higher methylation levels were significantly associated with higher mortality risk both in all NSCLCs early stage patients (Hazard Ratio, HR = 1.97; 95% Confidence Interval, CI: 1.32-2.93; = 0.001) and in those with SqCC (HR = 2.96; 95% CI: 1.43-6.12; = 0.003). Promoter methylation of gene should represent an interesting prognostic biomarker in NSCLC, with potential application in the squamous early-stage context. Further research in this setting on larger independent cohorts of lung patients with different histologies and stages of disease are warranted.
Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; DNA Methylation; Humans; Lung Neoplasms; Osteonectin; Prognosis
PubMed: 32580473
DOI: 10.3390/cells9061523 -
Communications Biology Oct 2021Runx2 is an essential transcription factor for bone formation. Although osteocalcin, osteopontin, and bone sialoprotein are well-known Runx2-regulated bone-specific...
Runx2 is an essential transcription factor for bone formation. Although osteocalcin, osteopontin, and bone sialoprotein are well-known Runx2-regulated bone-specific genes, the skeletal phenotypes of knockout (KO) mice for these genes are marginal compared with those of Runx2 KO mice. These inconsistencies suggest that unknown Runx2-regulated genes play important roles in bone formation. To address this, we attempted to identify the Runx2 targets by performing RNA-sequencing and found Smoc1 and Smoc2 upregulation by Runx2. Smoc1 or Smoc2 knockdown inhibited osteoblastogenesis. Smoc1 KO mice displayed no fibula formation, while Smoc2 KO mice had mild craniofacial phenotypes. Surprisingly, Smoc1 and Smoc2 double KO (DKO) mice manifested no skull, shortened tibiae, and no fibulae. Endochondral bone formation was also impaired at the late stage in the DKO mice. Collectively, these results suggest that Smoc1 and Smoc2 function as novel targets for Runx2, and play important roles in intramembranous and endochondral bone formation.
Topics: Animals; Calcium-Binding Proteins; Core Binding Factor Alpha 1 Subunit; Gene Expression Regulation, Developmental; Mice; Mice, Knockout; Osteogenesis; Osteonectin
PubMed: 34667264
DOI: 10.1038/s42003-021-02717-7 -
The Journal of Investigative Dermatology Jul 2021Immunoregulatory effects of IL-4 and IL-13 and alterations of keratinocyte (KC) differentiation are important factors in the pathogenesis of atopic dermatitis. This...
Immunoregulatory effects of IL-4 and IL-13 and alterations of keratinocyte (KC) differentiation are important factors in the pathogenesis of atopic dermatitis. This study investigated the role of IL-4 and IL-13 in KC responses to changes in extracellular calcium (Ca) and analyzed differentiation signals elicited via a Ca sensor, SMOC1. Real-time dynamics of transmembrane Ca influx were assessed in live KCs by flow cytometry and microscopy. Exposure of KCs to a high Ca environment (1.3 mM) triggered a rapid intracellular Ca influx, whereas IL-4- and IL-13-treated cells exhibited a significant decrease in the peak amplitude of Ca influx (P < 0.01). IL-17A and IL-22 did not elicit such responses. Evaluation of intracellular Ca dynamics by microscopy confirmed these observations and revealed heterogeneity of individual KC responses. IL-4 and IL-13 significantly inhibited the expression of Ca-binding protein SMOC1 (P < 0.001). Inhibition of epidermal differentiation markers were also observed in SMOC1 small interfering RNA-transfected KCs. Concurrently, the deletion of SMOC1 increased the amplitude of Ca peak response (P < 0.05). In conclusion, our results provide innovative data that IL-4 and IL-13 regulate KC sensitivity to microenvironmental Ca changes and inhibit Ca-induced KC differentiation signals. SMOC1 inhibition by IL-4 and IL-13 alters Ca transport in KCs and inhibits differentiation, suggesting a new target for treatment of atopic dermatitis.
Topics: Calcium; Cell Differentiation; Cell Proliferation; Cells, Cultured; Dermatitis, Atopic; Gene Expression Profiling; Humans; Interleukin-13; Interleukin-4; Intravital Microscopy; Keratinocytes; Osteonectin; Primary Cell Culture; Single-Cell Analysis
PubMed: 33484701
DOI: 10.1016/j.jid.2020.12.026 -
International Journal of Molecular... Jun 2021Matricellular proteins (MCPs) are defined as extracellular matrix (ECM) associated proteins that are important regulators and integrators of microenvironmental signals,... (Review)
Review
Matricellular proteins (MCPs) are defined as extracellular matrix (ECM) associated proteins that are important regulators and integrators of microenvironmental signals, contributing to the dynamic nature of ECM signalling. There is a growing understanding of the role of matricellular proteins in cellular processes governing tissue development as well as in disease pathogenesis. In this review, the expression and functions of different MP family members (periostin, CCNs, TSPs, SIBLINGs and others) are presented, specifically in relation to craniofacial development and the maintenance of orofacial tissues, including bone, gingiva, oral mucosa, palate and the dental pulp. As will be discussed, each MP family member has been shown to have non-redundant roles in development, tissue homeostasis, wound healing, pathology and tumorigenesis of orofacial and dental tissues.
Topics: Animals; CCN Intercellular Signaling Proteins; Cell Adhesion Molecules; Extracellular Matrix Proteins; Head and Neck Neoplasms; Humans; Mouth; Osteonectin; Tenascin; Thrombospondins; Wound Healing
PubMed: 34205668
DOI: 10.3390/ijms22126626 -
PloS One 2019MicroRNAs (miRNAs) are small noncoding RNAs that critically regulate gene expression. Their abundance and function have been linked to a range of physiologic and...
MicroRNAs (miRNAs) are small noncoding RNAs that critically regulate gene expression. Their abundance and function have been linked to a range of physiologic and pathologic processes. In aged monkey muscle, miR-451a and miR-144-3p were far more abundant than in young monkey muscle. This observation led us to hypothesize that miR-451a and miR-144-3p may influence muscle homeostasis. To test if these conserved microRNAs were implicated in myogenesis, we investigated their function in the mouse myoblast line C2C12. The levels of both microRNAs declined with myogenesis; however, only overexpression of miR-451a, but not miR-144-3p, robustly impeded C2C12 differentiation, suggesting an inhibitory role for miR-451a in myogenesis. Further investigation of the regulatory influence of miR-451a identified as one of the major targets Sparc mRNA, which encodes a secreted protein acidic and rich in cysteine (SPARC) that functions in wound healing and cellular differentiation. In mouse myoblasts, miR-451a suppressed Sparc mRNA translation. Together, our findings indicate that miR-451a is downregulated in differentiated myoblasts and suggest that it decreases C2C12 differentiation at least in part by suppressing SPARC biosynthesis.
Topics: 3' Untranslated Regions; Animals; Cell Line; Cell Proliferation; Mice; MicroRNAs; Muscle Development; Myoblasts; Osteonectin; Polyribosomes; Protein Biosynthesis
PubMed: 30925184
DOI: 10.1371/journal.pone.0214301 -
Journal of Alzheimer's Disease : JAD 2019Alzheimer's disease (AD) is an age-related progressive form of dementia that features neuronal loss, intracellular tau, and extracellular amyloid-β (Aβ) protein...
Alzheimer's disease (AD) is an age-related progressive form of dementia that features neuronal loss, intracellular tau, and extracellular amyloid-β (Aβ) protein deposition. Neurodegeneration is accompanied by neuroinflammation mainly involving microglia, the resident innate immune cell population of the brain. During AD progression, microglia shift their phenotype, and it has been suggested that they express matricellular proteins such as secreted protein acidic and rich in cysteine (SPARC) and Hevin protein, which facilitate the migration of other immune cells, such as blood-derived dendritic cells. We have detected both SPARC and Hevin in postmortem AD brain tissues and confirmed significant alterations in transcript expression using real-time qPCR. We suggest that an infiltration of myeloid-derived immune cells occurs in the areas of diseased tissue. SPARC is highly expressed in AD brain and collocates to Aβ protein deposits, thus contributing actively to cerebral inflammation and subsequent tissue repair, and Hevin may be downregulated in the diseased state. However, further research is needed to reveal the exact roles of SPARC and Hevin proteins and associated signaling pathways in AD-related neuroinflammation. Nevertheless, normalizing SPARC/Hevin protein expression such as interdicting heightened SPARC protein expression may confer a novel therapeutic opportunity for modulating AD progression.
Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Brain Injuries; Calcium-Binding Proteins; Extracellular Matrix Proteins; Female; Humans; Laser Capture Microdissection; Male; Middle Aged; Osteonectin
PubMed: 30883351
DOI: 10.3233/JAD-181032 -
International Journal of Molecular... Jul 2017Secreted protein acidic and rich in cysteine (SPARC) is a secreted protein which is involved in various biological processes. SPARC expression is associated with tumor...
Secreted Protein Acidic and Rich in Cysteine (SPARC) Enhances Cell Proliferation, Migration, and Epithelial Mesenchymal Transition, and SPARC Expression is Associated with Tumor Grade in Head and Neck Cancer.
Secreted protein acidic and rich in cysteine (SPARC) is a secreted protein which is involved in various biological processes. SPARC expression is associated with tumor metastasis and poor prognosis in several types of cancer. However, the SPARC-induced signaling pathway was not fully understood in head and neck cancer. In this study, our results showed that SPARC treatment promoted cell proliferation and migration in head and neck cancer cell lines FaDu and Detroit 562. In addition, SPARC induced expression of epithelial mesenchymal transition (EMT) regulators, including Slug, Snail, and Twist in Detroit 562. The results of phospho-kinase array analysis showed that SPARC treatment increased phosphorylation of some molecules including protein kinase B (PKB/AKT), ribosomal S6 kinase (RSK), and extracellular signal-regulated kinases (ERK). The expression of SPARC-induced EMT regulator Slug was suppressed by AKT inhibitor, but not ERK and RSK inhibitors. The SPARC expression in grade IV tumor samples is higher when compared to that in grade I-III tumor samples. Our results suggest that SPARC treatment enhances the EMT signaling pathway via activation of AKT, and exogenous SPARC and tumor expressing SPARC might be associated with tumor progression in head and neck cancers.
Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Models, Biological; Neoplasm Grading; Osteonectin; Phenotype; Signal Transduction
PubMed: 28718842
DOI: 10.3390/ijms18071556