Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA292864 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2163160_1.fastq.gz | Fastqsanger.gz | |||
| SRR2163160_2.fastq.gz | Fastqsanger.gz | |||
| SRR2163170.fastq.gz | Fastqsanger.gz | |||
| SRR2163161_1.fastq.gz | Fastqsanger.gz | |||
| SRR2163161_2.fastq.gz | Fastqsanger.gz |
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Project description:Oral squamous cell carcinoma (OSCC) is a lethal malignancy characterized by frequent metastasis. Utilizing a 4-NQO-induced murine model and single-cell RNA sequencing, we identified a distinct Collagen Type I Alpha 1 Chain (Col1a1+) epithelial subpopulation that is significantly expanded in OSCC, exhibits the highest epithelial-mesenchymal transition (EMT) signature, and correlates with poor patient survival. Functional studies demonstrated that Col1a1 knockdown in OSCC cell lines (HSC3) attenuated TGF-β-induced EMT, impaired migration and invasion in vitro, and reduced tumor burden in a conditional knockout mouse model. Transcriptomic profiling following Col1a1 silencing revealed the suppression of TGF-β signaling and ECM-receptor interaction pathways. We further identified BMP1 as a key downstream effector, demonstrating a direct physical interaction between COL1A1 and BMP1, and showed that COL1A1 potentiates BMP1's proteolytic activity. Rescue experiments confirmed that BMP1 is essential for COL1A1-driven tumor growth, metastasis, and TGF-β pathway activation in vivo. Furthermore, we uncovered an immunomodulatory role for the COL1A1-BMP1 axis, whereby it promotes M2 macrophage polarization via TGF-β secretion to foster an immunosuppressive tumor microenvironment. This effect was reversible using either BMP1 knockdown or TGF-β neutralization. In conclusion, our study establishes a novel COL1A1-BMP1-TGF-β signaling cascade that drives OSCC progression by autonomously enhancing tumor cell malignancy and non-autonomously reprogramming the immune landscape, nominating this axis as a promising therapeutic target.
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Project description:Our group is interested in epithelial-to-mesenchymal transition (EMT), in particular, TGF-beta induced EMT. TGF-beta signalling has been shown to be an important factor in the induction of EMT and it has been demonstrated that adding TGF-beta to epithelial cells in culture is a convenient way to study the process of EMT. In response to TGF-beta, Smad2 and 3 are activated, and form complexes with Smad4, which then regulate transcription of target genes through interactions with other DNA binding transcription factors. In the induction of EMT, the activated Smads mediate transcriptional regulation through three families of transcription factors, resulting in repression of epithelial marker gene expression and activation of mesenchymal gene expression (Xu J, et al. 2009) <br></br> Also investigated in this study is the role of H2A.Z in EMT. H2A.Z is an evolutionary conserved and a metazoan essential histone variant of the H2A class. Mice deficient in H2A.Z die during early development but the reason for this is unknown (Faast et al. 2001). Previously, our laboratory showed that the loss of H2A.Z in Xenpous laevis impaired cell movement required for the formation of the mesoderm and neural crest (Ridgway et al. 2004). Given that mesoderm formation is critically dependent upon EMT, we therefore wondered whether H2A.Z might be a chromatin regulator of EMT. We transfected MDCK cells with a lentiviral vector to express a construct encoding an shRNA targeting canine H2A.Z as we wanted to test the hypothesis that H2A.Z is involved in the maintenance of cellular identity and that its loss might trigger de-differentiation. <br></br> In order to investigate changes in histone variant H2A.Z occupancy associated with TGF-beta induced epithelial-to-mesenchymal transition (EMT) we performed H2A.Z ChIP-Seq in untreated and TGFb-treated MDCK cells. The MDCK cell line has been extensively used as a model system for EMT because they convert fully from the epithelial to the mesenchymal state in response to TGF-beta. <br></br>Please note that RNA-seq data generated in conjunction to this ChIP-seq data set were also deposited at ArrayExpress under accession number E-MTAB-5628 ( https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5628 ).
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Project description:Recently, we found that a novel Traf2- and Nck-interacting kinase (TNIK) inhibitor, named NCB-0846, was capable of attenuating tumor-initiating cells among human colorectal cancer. The cross link between EMT and cancer stemness has been revealed in several studies and other group showed another TNIK inhibitor named KY-05009 had inhibited the TGF-β-induced EMT. Therefore we evaluated whether this small-molecule compound could have efficacy to inhibit TGF-β-induced EMT. NCB-0846 reduced the expression of mesenchymal markers (Vimentin and N-cadherin) and upregulated the expression of epithelial marker E-cadherin in A549 and H2228 non-small cell lung cancer cells. NCB-0846 suppressed the phosphorylation and nuclear translocation of Smad proteins and also inhibited migration, invasion, and metastasis. NCB-0846 inhibited TGF-β1-induced EMT through the down-regulation of TGF-β receptor-1 (TβRI) in mRNA levels. MiR-186-5p and miR-320 family were identified as candidate miRNAs that could target TβRI and we found that miR-186-5p and miR-320s inhibited TβRI expression. NCB-0846 might be a novel therapeutics drugs that targets the invasion and metastasis through inhibiting TGF-β-induced EMT in lung cancer.
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Project description:Transforming growth factor-β (TGF-β) signaling stimulates cell movement and plasticity by inducing epithelial-to-mesenchymal transition (EMT). This process is aberrantly activated in cancer and facilitates tumor cell migration, invasion, metastasis, and therapy resistance. In this study, we identified the lncRNA eSNAI1 (SCREEM2) as a potent activator of TGF-β/SMAD signaling and SNAI1 expression. eSNAI1 depletion reduces TGF-β-induced EMT, migration, in vivo extravasation, stemness, and chemotherapy resistance of breast cancer cells. eSNAI1 promotes TGF-β/SMAD signaling by inhibiting TGF-β type I receptor polyubiquitination and proteasomal degradation. eSNAI1 stimulates the expression of the nearby gene SNAI1, which encodes the EMT transcription factor SNAI1 that facilitates TGF-β/SMAD signaling by retaining the inhibitory SMAD7 in the nucleus. Mechanistically, eSNAI1 acts as an enhancer RNA (eRNA) to potentiate SNAI1 expression through in-cis regulation. Furthermore, we uncovered that eSNAI1 interacts with and reinforces the binding of the co-activator bromodomain-containing protein 4 (BRD4) to the H3 lysine 27 acetylation (H3K27ac)-enriched SNAI1 enhancer region. Our findings identify eSNAI1 as a potent activator of TGF-β signaling and a promising therapeutic target to mitigate overactive TGF-β signaling and EMT in cancer cells.
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Project description:Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMTs) occurring in wound healing processes and the cancer stem cell-like compartment of tumors, including TGF-β-dependence, we investigated the role of a Grainyhead gene (GRHL2) in oncogenic EMT. Grainyhead was specifically down-regulated in the claudin-low subclass of mammary tumors and in the basal-B subclass of breast cancer cell lines. Functionally, GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis-sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated, in part, by its suppression of ZEB1 expression, through direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription, and up-regulated mir200b/c as well as the TGF-β receptor antagonist, BMP2. The expression of GRHL2 in the breast cancer cell line MDA-MB-231 triggered a mesenchymal-to-epithelial transition and sensitized the cells to anoikis. These results indicate that GRHL2 is a suppressor of the oncogenic EMT. 3 biologic replicates for each cell line. Comparison of HMLE+Twist-ER cells expressing GRHL2/pMIG vs. HMLE+Twist-ER cells expressing empty pMIG.
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Project description:Activation of the transforming growth factor β (TGF-β) signaling leads to established hallmarks of cancer such as the epithelial-to-mesenchymal transition (EMT), initiating cancer dissemination and increasing chemoresistance. TGF-β signal by binding to its type I and II receptors, leading to parallel activation of SMAD proteins, ubiquitin ligases and protein kinases. Here, using a panel of tumor cells we show that TGF-β activation induces the expression of the mammalian nuclear long non-coding RNA (lncRNA) VIM-AS1 (Vimentin antisense RNA 1) variant 2 (v.2) via the formation of a complex among the transcriptional factors GATA6-SMAD-SPI1. Furthermore, transcriptomic analysis indicated VIM-AS1 enhancing TGF-β signaling and EMT, as further validated by functional gain or loss assays. Mechanistically, the TGF-β-induced VIM-AS1 v.2 enhanced SMAD nucleocytoplasmic shuttling by interacting with the N-terminus domain of the nucleoporin RanBP2 (Nup358), whereby acting as a scaffold molecule, facilitates the binding of RanBP2 with SMAD2/3 and its further nuclear import. Finally, VIM-AS1 increases invasion and motility of tumor cells and emerges as a promising therapeutic target to sensitize cancer cells to chemotherapeutic drugs. Hence, we delineated a novel signaling mechanism for VIM-AS1 v.2 facilitating TGF-β response in tumor cells via SMAD nucleocytoplasmic shuttling.
2026-01-26 | PXD057186 | Pride
Project description:In this project we evaluated the proteomic profiling with TGF-β stimuli at 24h in a CRISPR-Cas9 model for ALMS1 gene in HeLa cells. Proteomic results showed a majority inhibition of downstream regulated pathways by the TGF-β, associating the protein coding genes (PCG) with processes like focal adhesion or cell-substrate adherens junction. Finally, EMT biomarkers like VIM, DSP, EDIL3 and SNAI1 had the opposite pattern to what would be expected when activating the EMT. In conclusion, seems that the depletion of ALMS1 could be inhibiting the signals transduction through the TGF -β and the routes regulated downstream by it such as the EMT.
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Project description:Inappropriate activation of developmental pathways is a well-recognized tumor-promoting mechanism. Here we show that overexpression of the homeoprotein Six1, normally a developmentally restricted transcriptional regulator, increases Transforming Growth Factor-beta (TGF-beta) signaling in mammary carcinoma cells and induces an epithelial to mesenchymal transition (EMT) that is in part dependent on its ability to increase TGF-beta signaling. TGF-beta signaling and EMT have been implicated in metastatic dissemination of carcinoma. Using spontaneous and experimental metastasis mouse models, we demonstrate that Six1 overexpression promotes breast cancer metastasis. In addition, we show that, like its induction of EMT, Six1-induced experimental metastasis is dependent on its ability to activate TGF-beta signaling. Importantly, in human breast cancers Six1 significantly correlates with nuclear Smad3, and thus increased TGF-beta signaling. Further, breast cancer patients whose tumors overexpress Six1 have a shortened time to relapse and metastasis, and an overall decrease in survival. Finally, we show that the effects of Six1 on tumor progression likely extend beyond breast cancer, since its overexpression correlates with adverse outcomes in numerous other cancers, including brain, cervical, prostate, colon, kidney, and liver, amongst others. Our findings argue that Six1, acting through TGF-beta signaling and EMT, is a powerful and global promoter of cancer metastasis.
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Project description: Not available
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