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Silicosis is a chronic occupational pulmonary disease characterized by persistent inflammation and irreversible fibrosis. Considerable evidences now indicate that S100 calcium-binding protein A4 (S100A4) has been associated with fibrotic diseases. However, the role of S100A4 in silicosis is still unclear.
Colorectal cancer (CRC) is the world's second most common cause of cancer-related death. Novel treatments are still urgently needed. S100 calcium-binding protein A4 (S100A4) was demonstrated to be an anticancer therapeutic target. Herein, we found that higher S100A4 expression was associated with a poorer prognosis in publicly available cohorts and a Taiwanese CRC patient cohort. To identify repurposed S100A4 inhibitors, we mined the Connectivity Map (CMap) database for clinical drugs mimicking the S100A4-knockdown gene signature. Ingenol mebutate, derived from the sap of the plant Euphorbia peplus, is approved as a topical treatment for actinic keratosis. The CMap analysis predicted ingenol mebutate as a potent S100A4 inhibitor. Indeed, both messenger RNA and protein levels of S100A4 were attenuated by ingenol mebutate in human CRC cells. In addition, CRC cells with higher S100A4 expressions and/or the wild-type p53 gene were more sensitive to ingenol mebutate, and their migration and invasion were inhibited by ingenol mebutate. Therefore, our results suggest the repurposing of ingenol mebutate for treating CRC by targeting S100A4.
Vitamin C, a key antioxidant in the central nervous system, cycles between ascorbic acid and dehydroascorbic acid under pathophysiological conditions. Clinical evidence supports that the absence of vitamin C may be linked to depressive symptoms, but much less is known about the mechanism. Herein, we show that chronic stress disrupts the expression of ascorbic acid transporter, sodium-dependent vitamin C transport 2, and induces a deficiency in endogenous ascorbic acid in the medial prefrontal cortex, leading to depressive-like behaviors by disturbing redox-dependent DNA methylation reprogramming. Attractively, ascorbic acid (100 mg/kg-1000 mg/kg, intraperitoneal injection, as bioequivalent of an intravenous drip dose of 0.48 g-4.8 g ascorbic acid per day in humans) produces rapid-acting antidepressant effects via triggering DNA demethylation catalyzed by ten-eleven translocation dioxygenases. In particular, the mechanistic studies by both transcriptome sequencing and methylation sequencing have shown that S100 calcium binding protein A4, a potentially protective factor against oxidative stress and brain injury, mediates the antidepressant activity of ascorbic acid via activating erb-b2 receptor tyrosine kinase 4 (ErbB4)-brain derived neurotrophic factor (BDNF) signaling pathway. Overall, our findings reveal a novel nutritional mechanism that couples stress to aberrant DNA methylation underlying depressive-like behaviors. Therefore, application of vitamin C may be a potential strategy for the treatment of depression.
The aim of the present study was to examine the protective effects and mechanisms of S100 calcium-binding protein A4 (S100A4) on endothelial cell apoptosis induced by oxidative stress injury. Endothelial cells were cultured and divided into control and oxidative stress injury groups, with the latter state induced by H2O2. Endothelial cells in every group were incubated with or without 50 or 100 µM S100A4. The cell viability and amounts of malondialdehyde, nitric oxide and lactate dehydrogenase in the culture medium were measured. The apoptotic index was detected by TUNEL staining. Western blot and immunoprecipitation analyses were used to detect the expression levels and the association between S100A4 and P53. H2O2 treatment led to oxidative stress injury in the cultured vascular endothelial cells, a decrease in the cell viability and an increase in the rate of apoptosis of vascular endothelial cells compared with the negative control group. Exogenous S100A4 serves a significant function against oxidative stress injury (P<0.05), increasing the viability and attenuating the apoptotic rate of endothelial cells. Western blotting results suggested that the protein levels of S100A4 and P53 increased subsequent to oxidative stress injury and that exogenous S100A4 increased the expression of P53 in the cytoplasm and decreased the expression of P53 in nucleus. The immunoprecipitation assay results revealed a protein-protein interaction between S100A4 and P53. These results suggested that rat recombinant S100A4 serves an anti-apoptotic function in oxidative stress injury. This effect of S100A4 is mediated, at least in part, via the inhibition of the translocation of P53 to the nucleus.
Acute exacerbation (AE) of interstitial pneumonia (IP) is the most fatal complication after lung resection for lung cancer. To improve the prognosis of lung cancer with IP, the risk factors of AE of IP after lung resection should be assessed. S100 calcium-binding protein A4 (S100A4) is a member of the S100 family of proteins and is a known marker of tissue fibrosis. We examined the usefulness of S100A4 in predicting AE of IP after lung resection for lung cancer.
The onset of distal metastasis, which underlies the high mortality of breast cancers, warrants substantial studies to depict its molecular basis. Nuclear factor of activated T cells 5 (NFAT5) is upregulated in various malignancies and is critically involved in migration and invasion of neoplastic cells. Nevertheless, the metastasis-related events potentiated by this transcriptional factor and the mechanism responsible for NFAT5 elevation in carcinoma cells remain to be fully elucidated.
We have previously shown that decreased expression of CCAAT/enhancer binding protein β (C/EBPβ) inhibits the growth of glioblastoma cells and diminishes their transformation capacity and migration. In agreement with this, we showed that C/EBPβ depletion decreases the mRNA levels of different genes involved in metastasis and invasion. Among these, we found S100 calcium binding protein A4 (S100A4) to be almost undetectable in glioblastoma cells deficient in C/EBPβ. Here, we have evaluated the possible role of S100A4 in the observed effects of C/EBPβ in glioblastoma cells and the mechanism through which S100A4 levels are controlled by C/EBPβ. Our results show that C/EBPβ suppression significantly reduced the levels of S100A4 in murine GL261 and human T98G glioblastoma cells. By employing an S100A4-promoter reporter, we observed a significant induction in the transcriptional activation of the S100A4 gene by C/EBPβ. Furthermore, overexpression of S100A4 in C/EBPβ-depleted glioblastoma cells reverses the enhanced migration and motility induced by this transcription factor. Our data also point to a role of S100A4 in glioblastoma cell invasion and suggest that the C/EBPβ gene controls the invasive potential of GL261 and T98G cells through direct regulation of S100A4. Finally, this study indicates a role of C/EBPβ on the maintenance of the stem cell population present in GL261 glioblastoma cells.
Background Carotid plaques with expansive arterial remodeling are closely related to cerebral ischemic events. Although S100A4 (S100 calcium-binding protein A4) is expressed in atherosclerotic lesions, its role in atherosclerotic plaque progression remains unknown. In this study, we examined the association between carotid arterial expansive remodeling and S100A4 expression. Methods and Results Preoperative high-resolution magnetic resonance imaging was used to assess luminal stenosis and vascular remodeling in patients undergoing carotid endarterectomy. To examine murine carotid atherosclerosis, we induced experimental lesions by flow cessation in apolipoprotein E-deficient mice fed a high-fat diet. The role of S100A4 in plaque formation and smooth muscle cell proliferation was investigated in vivo and in vitro, respectively. Human carotid arterial expansive remodeling showed positive correlations with the expression of S100A4, MMP2, and MMP9. S100A4 mRNA levels were positively correlated with those of MMP2, MMP9, and MMP13. S100A4 was expressed in vascular smooth muscle cells (VSMCs) and VSMC-derived foam cells in the plaque shoulder and marginal areas. S100A4 expression increased concomitantly with plaque formation in our animal model. Exogenous recombinant S100A4 protein enhanced the levels of Mmp2, Mmp9, and Mmp13 and the cell proliferation ability in VSMCs. A chemotaxis assay indicated that extracellular S100A4 functions as a chemoattractant for VSMCs. Conclusions S100A4 expression was elevated in human carotid plaques and showed a positive correlation with the degree of expansive remodeling. S100A4-positive VSMC-derived cells are considered to play an important role in carotid expansive remodeling.
Orf virus (ORFV), a member of Parapoxvirus, has evolved various strategies to modulate the immune responses of host cells. The ORFV-encoded protein ORFV002, a regulator factor, has been found to inhibit the acetylation of NF-κB-p65 by blocking phosphorylation of NF-κB-p65 at Ser(276) and also to disrupt the binding of NF-κB-p65 and p300. To explore the mechanism by which ORFV002 regulates NF-κB signaling, the understanding of ORFV002 potential binding partners in host cells is critical. In this study, ovine S100 calcium binding protein A4 (S100A4), prolyl endopeptidase-like (PREPL) and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 8 (NDUFA8) were found to interact with ORFV002 based on the yeast two-hybrid (Y2H) assay using a cDNA library derived from primary ovine fetal turbinate cells (OFTu). GST pull-down and bidirectional co-immunoprecipitation assay results demonstrate that ORFV002 interacts with S100A4 directly. Following the pEGFP-ORFV002 (p002GFP) transfection, we found that cytoplasmic S100A4 translocates into the nucleus and co-localizes with ORFV002. Furthermore, the inhibitory effect of ORFV002 on NF-κB signaling was significantly restored by S100A4 knock-down phenotype, suggesting that ovine S100A4 participates in the ORFV002-mediated NF-κB signaling. These data demonstrate that ORFV002 inhibits the NF-κB activation through its interaction with S100A4 along with its nucleus translocation.
Our previous study revealed that metastasis‑associated protein 1 (MTA1), which is expressed in vascular endothelial cells, acts as a tube formation promoting factor. The present study aimed to clarify the importance of MTA1 expression in tube formation using MTA1‑knockout (KO) endothelial cells (MTA1‑KO MSS31 cells). Tube formation was significantly suppressed in MTA1‑KO MSS31 cells, whereas MTA1‑overexpression MTA1‑KO MSS31 cells regained the ability to form tube‑like structures. In addition, western blotting analysis revealed that MTA1‑KO MSS31 cells showed significantly higher levels of phosphorylation of non‑muscle myosin heavy chain IIa, which resulted in suppression of tube formation. This effect was attributed to a decrease of MTA1/S100 calcium‑binding protein A4 complex formation. Moreover, inhibition of tube formation in MTA1‑KO MSS31 cells could not be rescued by stimulation with vascular endothelial growth factor (VEGF). These results demonstrated that MTA1 may serve as an essential molecule for angiogenesis in endothelial cells and be involved in different steps of the angiogenic process compared with the VEGF/VEGF receptor 2 pathway. The findings showed that endothelial MTA1 and its pathway may serve as promising targets for inhibiting tumor angiogenesis, further supporting the development of MTA1‑based antiangiogenic therapies.
Idiopathic pulmonary fibrosis (IPF) is a progressive and devastating interstitial lung disease. The origin of myofibroblasts is still to be elucidated and the existence of epithelial-mesenchymal transition (EMT) in IPF remains controversial. Hence, it is important to clarify the origin of fibroblasts by improving modeling and labeling methods and analyzing the differentiation pathway of alveolar epithelial cells (AEC) in pulmonary fibrosis with cell tracking technology. In the present study, adult transgenic mice with SPC-rtTA +/- /tetO 7 -CMV-Cre +/- /mTmG +/- were induced with doxycycline for 15 days. The gene knockout phenomenon occurred in type II AECs in the lung and the reporter gene cell membrane-localized enhanced green fluorescence protein (mEGFP) was expressed in the cell membrane. The expression of Cre recombinase and SPC was analyzed using immunohistochemical (IHC) staining to detect the labeling efficiency. A repetitive intraperitoneal bleomycin-induced pulmonary fibrosis model was established, and the mice were sacrificed on day 28. The co-localization of mEGFP and mesenchymal markers α-smooth muscle actin (α-SMA) and S100 calcium binding protein A4 (S100A4) were detected by multiple IHC staining. The results revealed that Cre was expressed in the airway and AECs in the lung tissue of adult transgenic mice with SPC-rtTA +/- /tetO 7 -CMV-Cre +/- /mTmG +/- induced by doxycycline; the labeling efficiency in the peripheral lung tissue was 63.27±7.51%. mEGFP was expressed on the membrane of type II AECs and their differentiated form of type I AECs. Expression of mEGFP was mainly observed in the fibrotic region in bleomycin-induced pulmonary fibrosis; 1.94±0.08% of α-SMA-positive cells were mEGFP-positive and 9.68±2.06% of S100A4-positive cells were mEGFP-positive in bleomycin-induced pulmonary fibrosis. In conclusion, the present results suggested that while EMT contributes to the pathogenesis of pulmonary fibrosis, it is not the major causative factor of this condition.
The irreversible loss of cardiomyocytes in the adult heart following cardiac injury leads to adverse cardiac remodeling and ventricular dysfunction. However, the role of B cells in cardiomyocyte proliferation and heart regeneration has not been clarified. Here, we found that the neonatal mice with B cell depletion showed markedly reduced cardiomyocyte proliferation, leading to cardiac dysfunction, fibrosis scar formation, and the complete failure of heart regeneration after apical resection. B cell depletion also significantly impaired heart regeneration and cardiac function in neonatal mice following myocardial infarction (MI). However, B cell depletion in adult mice suppressed tissue inflammation, inhibited myocardial fibrosis, and improved cardiac function after MI. Interestingly, B cell depletion partially restricted cardiomyocyte proliferation in adult mice post-MI. Single-cell RNA sequencing showed that cardiac B cells possessed a more powerful ability to inhibit inflammatory responses and enhance angiogenesis in the postnatal day 1 (P1) mice compared with P7 and adult mice. Besides, the proportion of cardioprotective B cell clusters with high expression levels of S100a6 (S100 calcium-binding protein A6) and S100a4 (S100 calcium-binding protein A4) was greatly decreased in adult heart tissues compared with neonatal mice after cardiac damage. Thus, our study discovers that cardiac B cells in neonatal mice are required for cardiomyocyte proliferation and heart regeneration, while adult B cells promote inflammation and impair cardiac function after myocardial injury.
Canines are useful in mammalian preclinical studies because they are larger than rodents and share many diseases with humans. Canine fetal fibroblast cells (CFFs) are an easily accessible source of somatic cells. However, they are easily driven to senescence and become unusable with continuous in vitro culture. Therefore, to overcome these deficiencies, we investigated whether tetracycline-inducible L-myc gene expression promotes self-renewal activity and tumorigenicity in the production of induced conditional self-renewing fibroblast cells (iCSFCs). Here, we describe the characterization of a new iCSFC line immortalized by transduction with L-myc that displays in vitro self-renewal ability without tumorigenic capacity. We established conditionally inducible self-renewing fibroblast cells by transducing CFF-3 cells with L-myc under the tetracycline-inducible gene expression system. In the absence of doxycycline, the cells did not express L-myc or undergo self-renewal. The iCSFCs had a fibroblast-like morphology, normal chromosome pattern, and expressed fibroblast-specific genes and markers. However, the iCSFCs did not form tumors in a soft agar colony-forming assay. We observed higher expression of three ES modules (core pluripotency genes, polycomb repressive complex genes (PRC), and MYC-related genes) in the iCSFCs than in the CFF-3 cells; in particular, the core pluripotency genes (OCT4, SOX2, and NANOG) were markedly up-regulated compared with the PRC and MYC module genes. These results demonstrated that, in canine fetal fibroblasts, L-myc tetracycline-inducible promoter-driven gene expression induces self-renewal capacity but not tumor formation. This study suggests that L-myc gene-induced conditional self-renewing fibroblast cells can be used as an in vitro tool in a variety of biomedical studies related to drug screening.
Vascular calcification is an active process that increases cardiovascular disease (CVD) risk. There is still no consensus on an appropriate biomarker for vascular calcification. We reasoned that the biomarker for vascular calcification is the collection of all blood components that can be sensed and integrated into a calcification response by human vascular smooth muscle cells (hVSMCs).
ΔFosB is a member of the family of transcription factor activating proteins-1 (AP-1) and is known to play important roles in Ca(2+) metabolism processes of osteoblast formation and differentiation in humans and rodents. The postpartum mammary gland is one of the significant organs for Ca(2+) metabolism processes. However, very little information is available on the role of ΔFosB in goat mammary gland. In this investigation, the full-length cDNA of ΔFosB from Xinong Saanen dairy goats was cloned, which contains an open-reading frame (ORF) of 723 bp encoding 240 amino acids. The amino acid sequence is highly homologous with cattle (99.17%). Quantitative real time PCR (QRT-PCR) and western blotting assays showed that ΔFosB was expressed in goat heart, liver, lung, and breast, but little in the hypophysis and spleen. The fluorescence signals revealed that the Ca(2+) was decreased in goat mammary epithelial cells (GMECs) over-expressed ΔFosB at 72h. Consistently, intracellular Ca(2+) was increased in GMECs suppressing expressed ΔFosB at 72 h. QRT-PCR assay showed that ΔFosB positively regulated the mRNA expression of runt related transcription factor 2 (Runx2), SMAD family member 4 (Smad4), S100 calcium binding protein A4 (S100A4) and S100 calcium binding protein A13 (S100A13) genes in GMECs, which had been proven to be relative to calcium metabolism in humans and rodents. Ca(2+) could induce a dose-dependent increase of the ΔFosB mRNA expression and a dose-dependent decrease in cell viability when the GMECs were treated with CaCl2. Suppressing ΔFosB expression in GMECs also inhibited the cell viability. These discoveries suggest that ΔFosB plays important roles in regulating Ca(2+) release and proliferation of the GMECs, which may prove useful in regulation of milk production.
As a key transcription factor required for bone formation, osterix (OSX) has been reported to be overexpressed in various cancers, however, its roles in breast cancer progression remain poorly understood. In this study, we demonstrated that OSX was highly expressed in metastatic breast cancer cells. Moreover, it could upregulate the expression of S100 calcium binding protein A4 (S100A4) and potentiate breast cancer cell migration and tumor angiogenesis in vitro and in vivo. Importantly, inhibition of S100A4 impaired OSX-induced cell migration and capillary-like tube formation. Restored S100A4 expression rescued OSX-short hairpin RNA-suppressed cell migration and capillary-like tube formation. Moreover, the expression levels of OSX and S100A4 correlated significantly in human breast tumors. Our study suggested that OSX acts as an oncogenic driver in cell migration and tumor angiogenesis, and may serve as a potential therapeutic target for human breast cancer treatment.
Lung metastasis is the leading cause of breast cancer-related death. The tumor microenvironment contributes to the metastatic colonization of tumor cells in the lungs. Tumor secretory factors are important mediators for the adaptation of cancer cells to foreign microenvironments. Here, we report that tumor-secreted stanniocalcin 1 (STC1) promotes the pulmonary metastasis of breast cancer by enhancing the invasiveness of tumor cells and promoting angiogenesis and lung fibroblast activation in the metastatic microenvironment. The results show that STC1 modifies the metastatic microenvironment through its autocrine action on breast cancer cells. Specifically, STC1 upregulates the expression of S100 calcium-binding protein A4 (S100A4) by facilitating the phosphorylation of EGFR and ERK signaling in breast cancer cells. S100A4 mediates the effect of STC1 on angiogenesis and lung fibroblasts. Importantly, S100A4 knockdown diminishes STC1-induced lung metastasis of breast cancer. Moreover, activated JNK signaling upregulates STC1 expression in breast cancer cells with lung-tropism. Overall, our findings reveal that STC1 plays important role in breast cancer lung metastasis.
Metastasis-associated in colon cancer 1 (MACC1) and S100 calcium-binding protein A4 (S100A4) are prominent inducers of tumor progression and metastasis. For the first time, we systematically tracked circulating serum levels of MACC1 and S100A4 transcripts in the course of surgery and chemotherapy and analyzed their clinical relevance for ovarian cancer. MACC1 and S100A4 transcripts were quantified in a total of 318 serum samples from 79 ovarian cancer patients by RT-qPCR and digital droplet PCR, respectively. MACC1 and S100A4 transcripts were significantly elevated in serum of ovarian cancer patients, compared to healthy controls (P = 0.024; P < 0.001). At primary diagnosis, high levels of MACC1 or S100A4 correlated with advanced FIGO stage (P = 0.042; P = 0.008), predicted suboptimal debulking surgery and indicated shorter progression-free survival (PFS; P = 0.003; P = 0.001) and overall survival (OS; P = 0.001; P = 0.002). This is the first study in ovarian cancer to propose circulating MACC1 and S100A4 transcripts as potential liquid biopsy markers.
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