Cadmium exposure induces SNAIL1 expression via downregulation of miR-30e in human bronchial epithelial cells
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ABSTRACT:
PROVIDER: PRJNA526901 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8723520.fastq.gz | Fastqsanger.gz | |||
| SRR8723521.fastq.gz | Fastqsanger.gz | |||
| SRR8723522.fastq.gz | Fastqsanger.gz | |||
| SRR8723523.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: To understand the molecular mechanisms underlying Cd exposure-induced diseases. Methods: Immortalized human bronchial epithelial cells (BEAS-2B) were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM, Cellgro) supplemented with 1% Penicillin Streptomycin and 10% Fetal Bovine Serum (FBS, Atlanta Biologicals) at 37 degree C and 5 % CO2. For Cd exposure, 0, 2.5, 5 and 10 µM of CdCl2 was added to the media and the cells were cultured for 72h. Results: This study shows that cadmium exposure induces SNAIL1 expression via miR-30e downregulation and the cells undergo epithelial-mesenchymal transition.
2019-06-16 | GSE128263 | GEO
Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF Analysis of 7 overexpression MDCK cells each of them using biological rpelicates (MDCK-E47, Snail2, Snail1, Twist1, Tiwst2, Zeb1, Zeb2)
2014-09-09 | E-GEOD-61217 | biostudies-arrayexpress
Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF
2014-09-09 | GSE61217 | GEO
Project description:Snail1 is a transcriptional repressor required for a correct embryonic development. In cancer, Snail1 promotes the epithelial to mesenchymal transition in tumorigenic epithelial cells. In this work, we have analyzed the control of Snail1 in the differentiation of the 3T3-L1 cell line derived from murine embryo cells. The activation by snail of 3T3-L1 induced typical markers of cancer-activated fibroblasts as S100A4 or CD44. We generated 3T3-L1 cells stably over expressing Snail1 (3T3L1/Snail1) and control (3T3-L1/control) cells. We used SILAC quantitative approach to identify and characterize protein alterations induced by Snail1. Cells were fractionated in 5 subcellular fractions. The nuclear fraction of the cells was separated by 10% SDS-PAGE. Gels with forward and reverse experiments were stained with Coomassie Blue and cut into 18 slices prior to reduction, alkylation and digestion with trypsin. Tryptic peptides were scanned and fragmented with a linear ion trap-Orbitrap Velos (ThermoScientific). We identified a total of 3108 proteins, with 2572 quantified proteins, and 565 proteins modulated >1.5-fold by Snail1 overexpression. Among them, we found interesting up-regulated proteins associated to early differentiation of adipogenesis (C/EBPβ) and down-regulated proteins implicated in the final stages of differentiation to adipocytes (Fatty acid-binding protein or Fatty acid synthase). We also observed as down-regulated proteins important mediators of PPARγ pathway. We also observed downregulation of proteins implicated in mTOR, SRC and JAK/STAT pathway. We validated these proteomics data by western blot and qPCR in 3T3-L1 cells and other types of fibroblasts with capable to differentiate to terminal mesenchymal phenotypes, as well as in mesenchymal stem cells (MSC). This work provided insight into novel proteins with potential roles in the regulation of differentiation of the 3T3-L1 and MSCs as Nr2F6, ASC-1, Prrx1 or Cbx6. These candidates are down regulated due to the overexpression of Snail1 in 3T3-L1 cells. We next investigated the potential binding of Snail1 to promoter of these candidates. In silico analysis with MatInspector program revealed various putative E-box consensus motifs for Snail1. We performed ChIP and Luciferase assay to validate Snail1 binds to different E-box motifs of our candidates. Additionally, we analyzed the ability to prevent the differentiation to adipocytes of the 3T3-L1 cells using siRNAs. This work provided insight into novel proteins with potential roles in the regulation of differentiation to adipocytes of the 3T3-L1 and mMSC cells as Nr2F6, ASC-1, Prrx1 or Cbx6 controlled by Snail1.
2015-01-06 | PXD001529 | Pride
Project description:At the molecular level, epithelial-to-mesenchymal transition (EMT) necessitates extensive transcriptional reprogramming which is orchestrated by a small group of gene regulatory proteins. The transcription factor SNAIL1 is a zinc-finger DNA-binding protein and well-known master regulator of EMT. However, knowledge of its immediate target genes is incomplete. Here, we performed ChIP-seq to chart genome-wide SNAIL1 chromosomal binding sites and to identify genes directly regulated by SNAIL1. For this we used the colorectal adenocarcinoma cell line LS174T which was engineered to express hemagglutinin epitope-tagged murine SNAIL1 in a doxycycline inducible fashion. In total, 1501 SNAIL1-HA ChIP-seq peaks were mapped which were linked to 1307 genes based on nearest neighbor relationships. The vast majority of SNAIL1-HA binding events occurred within 1 kb upstream of transcriptional start sites (44%), and in intergenic regions and promoter-distal introns (46%). De novo motif deduction showed that nearly all ChIP-seq peak regions harbored at least one sequence element corresponding to the cognate SNAIL1 DNA-recognition motif 5’-CAGGTG-3’. SNAIL1-HA ChIP-seq peaks included previously determined SNAIL1 binding sites at the FOXA1, EPHB3, ITGB4 and CLDN3 genes, thus validating the ChIP-Seq results. When comparing the genomic distribution of SNAIL1-HA to that of the intestinal stem cell (ISC) transcription factors ASCL2 and TCF7L2, we observed a significant overlap. Furthermore, SNAIL1-HA ChIP-seq peaks are associated with a substantial fraction of ISC signature genes. In two colorectal cancer cell lines, we verified that SNAIL1 decreases ISC marker expression. Likewise, SNAIL1-HA was found to occupy multiple regulatory elements at the proto-oncogene MYB, and the long non-coding RNA (lncRNA) WiNTRLINC1, a recently described regulator of ASCL2. Occupancy of the MYB and WiNTRLINC1 regulatory elements by SNAIL1-HA correlated with the downregulation of the two genes. We propose that SNAIL1-mediated repression of MYB and ISC markers like WiNTRLINC1 contributes to the decrease in proliferation known to be associated with EMT, while simultaneously abrogating stemness features of colorectal cancer cells.
2019-08-26 | GSE127183 | GEO
Project description:Snail1 transcriptional factor is essential for triggering epithelial-to-mesenchymal transition (EMT) and inducing tumor cell invasion. We report here that Snail1 plays also a key role in tumor associated fibroblasts since is necessary for enhancement by these cells on epithelial cells tumor invasion. Snail1 expression in fibroblast requires signals derived from tumor cells such as TGF-b; reciprocally, in fibroblasts Snail1 organizes a complex program that favors collective invasion of epithelial cells at least in part by the secretion of diffusible signaling molecules, such as prostaglandin E2. The capability of human or murine tumor-derived cancer associated fibroblasts to promote tumor invasion is associated to Snail1 expression and obliterated by Snail1 depletion. In vivo experiments show that tumor cells co-transplanted with Snail1 depleted fibroblasts show lower invasion than those xenografted with control fibroblasts. Finally Snail1 depletion in mice prevents the formation of breast tumors and decreased their invasion. Therefore, these results demonstrate that the role of Snail1 in tumor invasion is not limited to its effect in EMT but dependent on its expression in stromal fibroblasts where it orchestrates its activation and the crosstalk with epithelial cells.
2016-12-22 | GSE74057 | GEO
Project description:Snail1 transcriptional factor is essential for triggering epithelial-to-mesenchymal transition (EMT) and inducing tumor cell invasion. We report here that Snail1 plays also a key role in tumor associated fibroblasts since is necessary for enhancement by these cells on epithelial cells tumor invasion. Snail1 expression in fibroblast requires signals derived from tumor cells such as TGF-b; reciprocally, in fibroblasts Snail1 organizes a complex program that favors collective invasion of epithelial cells at least in part by the secretion of diffusible signaling molecules, such as prostaglandin E2. The capability of human or murine tumor-derived cancer associated fibroblasts to promote tumor invasion is associated to Snail1 expression and obliterated by Snail1 depletion. In vivo experiments show that tumor cells co-transplanted with Snail1 depleted fibroblasts show lower invasion than those xenografted with control fibroblasts. Finally Snail1 depletion in mice prevents the formation of breast tumors and decreased their invasion. Therefore, these results demonstrate that the role of Snail1 in tumor invasion is not limited to its effect in EMT but dependent on its expression in stromal fibroblasts where it orchestrates its activation and the crosstalk with epithelial cells.
2016-12-22 | GSE74056 | GEO
Project description:The transcription factor SNAIL1 is a master regulator of epithelial-to-mesenchymal transition, a process entailing massive gene expression changes. To better understand SNAIL1-induced transcriptional reprogramming we performed time-resolved transcriptome analysis upon conditional SNAIL1 expression in colorectal cancer cells. Bioinformatic analyses indicated that SNAIL1 strongly affected Wnt/β-Catenin pathway activity. This correlated with upregulation of LEF1, a nuclear binding partner of β-Catenin. Several tumour entities, including aggressive mesenchymal colorectal cancers, exhibit positively correlated LEF1 and SNAIL1 expression, and elevated LEF1 levels parallel increased colorectal cancer patient mortality. Comparative gene expression profiling suggested that 35% of Snail1-induced transcriptional changes are attributable to LEF1. LEF1 stimulates Wnt/β-Catenin pathway feedback inhibitor expression, causes cell-cycle arrest in vitro, and retards xenograft tumour growth. Conversely, LEF1-deficiency and preventing the β-Catenin-LEF1 interaction impaired the ability of SNAIL1 to alter Wnt/β-catenin target gene expression and to induce cancer cell invasion. Although LEF1 did not autonomously induce epithelial-mesenchymal transition, LEF1 is a critical factor acting downstream of SNAIL1. Apparently, SNAIL1 employs LEF1 as alternative effector to redirect Wnt/β-catenin pathway activity towards anti-proliferative and pro-invasive gene expression.
2019-08-15 | GSE115716 | GEO
Project description:Tumor growth requires elevated ribosome biogenesis. Targeting ribosomes is an important strategy for cancer therapy. The ribosome inhibitor, homoharringtonine (HHT), is used for the clinical treatment of leukemia, yet it is ineffective for the treatment of solid tumors, the reasons for which remain unclear. Here we show that Snail1, a key factor in the regulation of epithelial-to-mesenchymal transition, plays a pivotal role in cellular surveillance response upon ribotoxic stress. Mechanistically, ribotoxic stress activates the JNK-USP36 signaling to stabilize Snail1 in the nucleolus, which facilitates ribosome biogenesis and tumor cell survival. Furthermore, we show that HHT activates the JNK-USP36-Snail1 axis in solid tumor cells, but not in leukemia cells, resulting in solid tumor cell resistance to HHT. Importantly, a combination of HHT with the inhibition of the JNK-USP36-Snail1 axis synergistically inhibits solid tumor growth. Together, this study provides a rationale for targeting the JNK-USP36-Snail1 axis in ribosome inhibition-based solid tumor therapy.
2023-09-26 | PXD045622 | Pride
Project description:Converting epithelial into mesenchymal cells through epithelial-mesenchymal transition (EMT) requires massive changes in gene expression. How this is brought about is currently not clear. Here we examined the impact of the EMT master regulator SNAIL1 on the FOXA family of transcription factors which are distinguished by their particular competence to induce chromatin reorganization for the activation of transcriptional enhancer elements. We show that the expression of SNAIL1 and FOXA genes is anti-correlated in transcriptomes of colorectal tumors and cell lines. In two cellular EMT models, ectopically expressed Snail1 downregulates FOXA factors and directly represses FOXA1. To elucidate how FOXA factors contribute to the control of epithelial gene expression, we determined by ChIP-seq data analysis FOXA chromosomal distribution in relation to chromatin structural features characterizing distinct states of transcriptional activity. This revealed a preferential localization of FOXA1 and FOXA2 to transcriptional enhancers at signature genes that distinguish epithelial from mesenchymal colon tumors. To validate the significance of this association, we investigated the impact of FOXA factors on structure and function of transcriptional enhancers at the epithelial genes CDH1, CDX2 and EPHB3. Expression of dominant negative FOXA2 led to chromatin condensation at these enhancer elements. Site- directed mutagenesis of FOXA binding sites in reporter gene constructs and by genome- editing in situ impaired enhancer activity and completely abolished the active chromatin state of the EPHB3 enhancer. Conversely, expression of FOXA factors in cells with inactive CDX2 and EPHB3 enhancers led to chromatin opening and de novo deposition of the H3K4me1 and H3K27ac marks. These findings establish the pioneer function of FOXA factors at enhancer regions of epithelial genes and demonstrate their essential role in maintaining enhancer structure and function. Thus, by repressing FOXA family members, Snail1 targets transcription factors at strategically important positions in gene-regulatory hierarchies which may facilitate transcriptional reprogramming during EMT.
2017-11-10 | GSE106073 | GEO