The role of SMAD7 on epigenetic regulation of TGF-β targets in the metastasis of ovarian cancer
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PROVIDER: PRJNA1122794 | ENA |
REPOSITORIES: ENA
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Project description:Targeting TGF-β signaling and its downstream effectors, such as SMAD7, may offer promising therapeutic strategies for reversing epigenetic alterations and inhibiting metastatic progression in ovarian cancer.
2024-06-12 | GSE269632 | GEO
Project description:Repair of the infarcted heart requires TGFβ-Smad3 signaling in cardiac myofibroblasts. However, TGF-β-driven myofibroblast activation needs to be tightly regulated in order to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of the inhibitory Smad, Smad7 may restrain infarct myofibroblast activation, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of non-reperfused infarction, Smad3 activation triggered Smad7 synthesis in β-SMA+ infarct myofibroblasts, but not in β-SMA-/PDGFRα+ fibroblasts. Myofibroblast-specific Smad7 loss increased heart failure-related mortality, worsened dysfunction, and accentuated fibrosis in the infarct border zone and in the papillary muscles. Smad7 attenuated myofibroblast activation and reduced synthesis of structural and matricellular extracellular matrix proteins. Smad7 actions on TGF-β cascades involved de-activation of Smad2/3 and non-Smad pathways, without any effects on TGF-β receptor activity. Unbiased transcriptomic and proteomic analysis identified receptor tyrosine kinase signaling as a major target of Smad7. Smad7 interacted with Erbb2 in a TGF-independent manner and restrained Erbb1/Erbb2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins and CD44. Smad7 induction in myofibroblasts serves as an endogenous TGF-β-induced negative feedback mechanism that inhibits post-infarction fibrosis by restraining Smad-dependent and Smad-independent TGF-β responses, and by suppressing TGF-independent fibrogenic actions of Erbb2.
2021-11-11 | GSE185767 | GEO
Project description:Purpose：Cell division cycle associated 7 (CDCA7) is a copy number amplification gene that contributes to the metastasis and invasion of tumors, including esophageal squamous cell carcinoma (ESCC). This present study aimed at clarifying whether high expression of CDCA7 promotes the metastasis and invasion of ESCC cell lines and exploring the underlying mechanisms implicated in EMT of ESCC. Mehtod：We established KYSE150 cell lines in which target gene has been knocked down by shRNA and KYSE180 cell lines in which target gene has been ovexpressed by plasmid.We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cells.Each cell has three repetions. Result：KEGG pathway enrichment analysis on the data of RNA-seq showed that Wnt signaling pathway and TGF-β signaling pathway which are related to EMT process were screened out. Conclusion：CDCA7 was heavily involved in EMT by regulating the expression of Smad4 and Smad7 in TGF-β signaling pathway.
2023-01-11 | GSE201735 | GEO
Project description:Induction of the inhibitory Smad, Smad7 serves as a negative feedback mechanism that restrains TGF-b-mediated actions in injured tissues. In inflammatory cells, Smad7 has been suggested to exert both pro-inflammatory actions attributed to inhibition of TGF-b-induced suppression of inflammation, and anti-inflammatory effects due to disruption of the TAK-1/NF-kB system. Myocardial infarction triggers a macrophage-driven inflammatory response that plays a central role in cardiac repair, but also contributes to adverse remodeling and fibrosis. We hypothesized that Smad7 upregulation in infarct macrophages may play a modulatory role in cardiac repair, by restraining effects of TGF-b. To test the hypothesis, we investigated the response of Myeloid cell-specific Smad7 knockout mice (MyS7KO) following myocardial infarction protocols, and we examined the in vitro effects of Smad7 in isolated macrophages. Smad7 was upregulated in a subset of infarct macrophages, peaking 7 days after infarction. Myeloid cell-specific Smad7 loss did not affect baseline macrophage gene expression and had no significant effects on homeostatic functions. Although RNA-seq analysis predicted that, in the absence of Smad7, infarct macrophages may have attenuated activation of inflammatory pathways and suppressed TREM1 signaling, myeloid cell-specific Smad7 loss had no significant effects on ventricular dysfunction, adverse remodeling, scar remodeling and collagen deposition after myocardial infarction. In isolated macrophages, TGF-b attenuated pro-inflammatory cytokine and chemokine expression, modulated synthesis of matrix remodeling genes, and had profound effects on macrophage profile, inducing genes associated with activation of sphingosine-1 phosphate and integrin signaling pathways, and inhibiting cholesterol biosynthesis genes. However, RNA-seq and PCR array experiments showed that Smad7 loss has minimal effects on TGF-b-mediated macrophage responses, restraining synthesis of only a small fraction of TGF-b-induced genes, such as Itga5, Olfml3 and Fabp7. Smad7 absence did not affect the anti-inflammatory actions of TGF-b in TNF-stimulated cells. In conclusion, our findings suggest a limited role for macrophage Smad7 in regulation of post-infarction inflammation and repair, and demonstrate that the anti-inflammatory effects of TGF-b in macrophages are not restrained by endogenous Smad7 induction.
2022-04-29 | GSE189450 | GEO
Project description:Induction of the inhibitory Smad, Smad7 serves as a negative feedback mechanism that restrains TGF-b-mediated actions in injured tissues. In inflammatory cells, Smad7 has been suggested to exert both pro-inflammatory actions attributed to inhibition of TGF-b-induced suppression of inflammation, and anti-inflammatory effects due to disruption of the TAK-1/NF-kB system. Myocardial infarction triggers a macrophage-driven inflammatory response that plays a central role in cardiac repair, but also contributes to adverse remodeling and fibrosis. We hypothesized that Smad7 upregulation in infarct macrophages may play a modulatory role in cardiac repair, by restraining effects of TGF-b. To test the hypothesis, we investigated the response of Myeloid cell-specific Smad7 knockout mice (MyS7KO) following myocardial infarction protocols, and we examined the in vitro effects of Smad7 in isolated macrophages. Smad7 was upregulated in a subset of infarct macrophages, peaking 7 days after infarction. Myeloid cell-specific Smad7 loss did not affect baseline macrophage gene expression and had no significant effects on homeostatic functions. Although RNA-seq analysis predicted that, in the absence of Smad7, infarct macrophages may have attenuated activation of inflammatory pathways and suppressed TREM1 signaling, myeloid cell-specific Smad7 loss had no significant effects on ventricular dysfunction, adverse remodeling, scar remodeling and collagen deposition after myocardial infarction. In isolated macrophages, TGF-b attenuated pro-inflammatory cytokine and chemokine expression, modulated synthesis of matrix remodeling genes, and had profound effects on macrophage profile, inducing genes associated with activation of sphingosine-1 phosphate and integrin signaling pathways, and inhibiting cholesterol biosynthesis genes. However, RNA-seq and PCR array experiments showed that Smad7 loss has minimal effects on TGF-b-mediated macrophage responses, restraining synthesis of only a small fraction of TGF-b-induced genes, such as Itga5, Olfml3 and Fabp7. Smad7 absence did not affect the anti-inflammatory actions of TGF-b in TNF-stimulated cells. In conclusion, our findings suggest a limited role for macrophage Smad7 in regulation of post-infarction inflammation and repair, and demonstrate that the anti-inflammatory effects of TGF-b in macrophages are not restrained by endogenous Smad7 induction.
2022-04-29 | GSE187701 | GEO
Project description:We have identified a single miRNA, miR-181a, that can modulate TGF-β signaling to induce and maintain EMT, and effect further downstream events of tumour cell survival, altered response to chemotherapy, migration, invasion and dissemination in vivo. Our present study provides an understanding of how enhanced expression of miR-181a can confer malignant and invasive traits through the modulation of a canonical signaling pathway and a consequent maintenance of a mesenchymal state. Furthermore, inhibition of miR-181a led to a reversion of EMT and subsequent events through decreased TGF-β signaling. Our data confirmed Smad7 as a functional target through which TGF-β-mediated EMT occurs; re-expression of Smad7 lacking its 3'UTR was able to rescue miR-181a-mediated phenotypes, deeming Smad7 as a critical mediator of miR-181a-induced EMT. Other recent studies support the crucial role(s) that miRNAs play in mediating EMT and consequent aggressive disease traits. For example, the miR-106b-25 cluster has also been shown to target Smad7 and mediate TGF-β-induced EMT downstream to Six1 in breast cancer34. miR-9 directly targets E-cadherin and inhibition of miR-9 had led to an inhibition of metastasis35. Conversely, the miR-200 and -205 family was shown to target transcriptional repressors of E-cadherin, ZEB1 and SIP1, and re-expression of these miRNAs led to a mesenchymal-to-epithelial transition and prevented TGF-β -induced EMT36. A2780 ovarian cancer cell lines stably expressing either pBABE (control vector), p181a#1( clone 1 expressing miR-181a) or p181a#2( clone 2 expressing miR-181a)
2013-12-01 | E-GEOD-52077 | biostudies-arrayexpress
Project description:The transforming growth factor beta (TGF-β) superfamily proteins are potent regulators of cellular development and differentiation. Long non-coding RNAs (lncRNAs) play widespread roles in spatial-temporal regulation of early development. However, the roles of lncRNAs regulated by nodal/TGF-β signaling is still elusive. Here, we showed a nodal-driven Smad induced lncRNA in mouse embryonic stem cells (mESCs), lncRNA-Smad7, which is divergently transcribed to Smad7, regulates cell fate determination through repressing Bmp2. Depletion of lncRNA-Smad7 dramatically impairs cardiomyocyte differentiation in mESCs. Moreover, LncRNA-Smad7 represses Bmp2 expression and binds at the promoter region of Bmp2. Importantly, knock-down Bmp2 rescues the defect of cardiomyocyte differentiation. Hence, we showed that lncRNA-Smad7 is antagonistic to BMP signaling in mESCs. Furthermore, lncRNA-Smad7 regulates cell fate determination between osteocytes and myocytes formation in C2C12 cells by repressing Bmp2. Thus, we provide new insights regarding the antagonistic effects between nodal/TGF-β and BMP signaling via lncRNA-Smad7.
2022-10-19 | GSE178136 | GEO
Project description:Smad7 has been identified as a negative regulator of the transforming growth factor TGF-β pathway by direct interaction with the TGF-β type I receptor (TβR-I). Although Smad7 has also been shown to play TGF-β unrelated functions in the cytoplasm and in the nucleus, a comprehensive analysis of its nuclear function has not yet been performed. Here we show that in ESCs Smad7 is mainly nuclear and acts as a general transcription factor regulating a number of genes unrelated to the TGF-β pathway. Loss of Smad7 results in the downregulation of several key stemness master regulators, including Pou5f1 and Zfp42, and in the upregulation of developmental genes, with consequent loss of the stem phenotype. Integrative analysis of genome-wide mapping data for Smad7 and ESC self-renewal and pluripotency transcriptional regulators revealed that Smad7 co-occupies promoters of highly expressed key stemness regulators genes, by binding to a specific consensus response element NCGGAAMM. Altogether, our data establishes Smad7 as new integral component of the regulatory circuitry that controls ESC identity.
2022-01-05 | GSE185902 | GEO
Project description:Smad7 has been identified as a negative regulator of the transforming growth factor TGF-β pathway by direct interaction with the TGF-β type I receptor (TβR-I). Although Smad7 has also been shown to play TGF-β unrelated functions in the cytoplasm and in the nucleus, a comprehensive analysis of its nuclear function has not yet been performed. Here we show that in ESCs Smad7 is mainly nuclear and acts as a general transcription factor regulating a number of genes unrelated to the TGF-β pathway. Loss of Smad7 results in the downregulation of several key stemness master regulators, including Pou5f1 and Zfp42, and in the upregulation of developmental genes, with consequent loss of the stem phenotype. Integrative analysis of genome-wide mapping data for Smad7 and ESC self-renewal and pluripotency transcriptional regulators revealed that Smad7 co-occupies promoters of highly expressed key stemness regulators genes, by binding to a specific consensus response element NCGGAAMM. Altogether, our data establishes Smad7 as new integral component of the regulatory circuitry that controls ESC identity.
2022-01-05 | GSE185904 | GEO
Project description:Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Ovarian cancer cells are known to have diminished response to TGF-beta, but it remains unclear whether TGF-beta can modulate ovarian cancer cell growth in an indirect manner through cancer-associated fibroblasts (CAFs). Using transcriptome profiling analyses on TGF-beta-treated ovarian fibroblasts, we identified a TGF-beta-responsive gene signature in ovarian fibroblasts. Identifying TGF-beta-regulated genes in the ovarian microenvironment helps in understanding the role of TGF-beta in ovarian cancer progression. The human telomerase-immortalized ovarian fibroblast line NOF151 was treated with 5ng/mL of either TGF-beta-1 or TGF-beta-2. Total RNA was isolated from control samples and TGF-beta-treated fibroblasts samples at 48 hours post-treatment, followed by cDNA synthesis, IVT and biotin labeling. Samples were then hybridized onto Affymetrix Human Genome U133 Plus 2.0 microarrays. For each treatment group, three independent samples were prepared for the microarray experiment.
2013-12-31 | E-GEOD-40266 | biostudies-arrayexpress