Multi-omics profiling reveals key signaling pathways in ovarian cancer controlled by STAT3
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA554895 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9694250.fastq.gz | Fastqsanger.gz | |||
| SRR9694260.fastq.gz | Fastqsanger.gz | |||
| SRR9694251.fastq.gz | Fastqsanger.gz | |||
| SRR9694261.fastq.gz | Fastqsanger.gz | |||
| SRR9694252.fastq.gz | Fastqsanger.gz |
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Project description:Inhibiting STAT3 signaling reduces tumor progression, metastases and chemoresistance, however the precise molecular mechanism has not been fully delineated in ovarian cancer. Methods: In this study, we generated STAT3 knockout (KO) ovarian cancer cell lines. Effect of STAT3 KO on cell proliferation, migration and spheroid formation was assessed in vitro and effect on in vivo tumor growth was tested using several tumor xenograft models. We used multi-omic genome-wide profiling to identify multi-level (Bru-Seq, RNA-Seq, and MS Proteomic) expression signatures of STAT3 KO ovarian cancer cells.
2019-07-17 | GSE134375 | GEO
Project description:Inhibiting STAT3 signaling reduces tumor progression, metastasis and chemoresistance, however the precise molecular mechanism has not been fully delineated in ovarian cancer. METHODS:In this study, we generated STAT3 knockout (KO) ovarian cancer cell lines. Effects of STAT3 KO on cell proliferation, migration and spheroid formation were assessed in vitro and effects on in vivo tumor growth were tested using several tumor xenograft models. We used multi-omic genome-wide profiling to identify multi-level (Bru-Seq, RNA-Seq, and MS Proteomic) expression signatures of STAT3 KO ovarian cancer cells. RESULTS:We observed that deletion of STAT3 blocked cell proliferation and migration in vitro and suppressed tumor growth in mice. Deletion of STAT3 transcriptionally suppressed key genes involved in EMT, cell cycle progression, E2F signaling, and altered stemness markers. Notably, KO of STAT3 resulted in modulation of the expression of other STAT family members. CONCLUSION:Our study presents a rich, multi-faceted summary of the molecular mechanisms impacted by STAT3 deletion and provides new insight for STAT3's potential as a therapeutic target in ovarian cancer.
| S-EPMC6735387 | biostudies-literature
Project description:In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. We demonstrate that adherent glioma CSCs exhibit characteristics previously described for CSCs grown in suspension culture. The expression of CD133, Sox2 and Nestin increased when compared to glioma cells grown in monolayer, and the adherent CSCs were ~100 times more tumorigenic in vivo than monolayer cultured glioma cells. We also found that while the STAT3 and NF-κB signaling pathways are constitutively activated in glioma lines, these pathways are dramatically activated in glioma CSCs. Treatment with STAT3 inhibitors led to a loss of nuclear activation of STAT3 signaling and suppression of growth in both monolayer and CSC conditions. There was a markedly greater growth suppressive effect on glioma CSCs, suggesting that targeted therapy of these key pathways in glioma CSCs may be possible. To further investigate potential biomarkers in glioma CSCs, microarray analysis was performed and revealed deregulation of the Notch signaling pathway. This constitutive activation of STAT3, NF-κB, and Notch pathways in glioma CSCs helps identify novel therapeutic targets for the treatment of glioma. GBM6 cells were continuously maintained as subcutaneous xenografts in NSG mice, and monolayer and CSC cultures were derived from freshly harvested tumor tissue. A total of 6 samples were subjected to microarray analysis, with three biological replicates for each experimental condition.
2013-06-19 | E-GEOD-48079 | biostudies-arrayexpress
Project description:Ovarian carcinoma (OC) is the fifth leading cause of death among women in the United States. Persistent activation of signal transducer and activator of transcription (STAT3) is frequently detected in OC. STAT3 is activated by Janus family kinases (JAK) via cytokine receptors, growth factor receptor and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses anti-tumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on OC cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration and adhesion of OC cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity and immune cell populations in a transgenic mouse model of OC. AZD1480-treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured OC cells and ovarian tumor growth rate, volume and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal tumor microenvironment of tumor-bearing mice than control mice. Taken together, our results show pharmacological inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy. 8 female C57BL/6JTgMISIIR-TAg mice with ovarian tumors of ~500 mm3 were used. 4 vehicle-treated mice (0.5% hypermellose/0.1%Tween 80);4 drug-treated mice (30 mg/kg AZD1480 in 0.5% hypermellose/0.1%Tween 80).
2015-02-01 | E-GEOD-63092 | biostudies-arrayexpress
Project description:The activated B cell-like (ABC) subgroup of diffuse large B cell lymphoma (DLBCL) is characterized by constitutive activation of the NF-êB pathway. Here we show that the NF- êB pathway induces the expression of the cytokines IL-6 and IL-10 in ABC DLBCL cell lines, which also have high levels of total and phosphorylated STAT3 protein, suggesting autocrine signaling. Using RNA interference for STAT3, we defined a gene expression signature of IL-6 and IL-10 signaling through STAT3. Based on this signature, we constructed a molecular predictor of STAT3 signaling that defined a subset of ABC DLBCL tumors with high expression of STAT3, IL-6 and/or IL-10, and their downstream targets. Although the STAT3-high and STAT3-low subsets had equivalent expression of genes that distinguish ABC DLBCL from GCB DLBCL, STAT3-high ABC DLBCLs had higher expression of signatures that reflected NF-kB activity, proliferation, and glycolysis. A smallmolecule inhibitor of JAK signaling, which blocked STAT3 signature expression, was toxic only for ABC DLBCL lines, and synergized with an inhibitor of NF-kB signaling. These findings suggest that the biological interplay between the STAT3 and NF-kB pathways may be exploited for the treatments of a subset of ABC DLBCLs. Activated B cell-like (ABC) subgroup of diffuse large B cell lymphoma (DLBCL) cell lines were used as model systems to study the cytokine pathways in these cells. We expressed inducible IkB super-repressor for 1 to 24 hours to identify NF-kB target genes in OCI-Ly3 and OCI-Ly10 cells for a total of 13 arrays with replicates of each time point. We treated OCI-Ly3 cells with IL-10 for 1 to 96 hours for a total of 10 arrays with replicates of each time point. We treated OCI-Ly10 cells with IL-6 for 30 minutes to 24 hours for a total of 8 arrays with replicates of each time point. OCI-Ly10 cells transfected with no siRNA versus STAT3-siRNA for 8, 24, or 48 hours for a total of 5 arrays with replicates for 24 and 48 hours. We treated OCI-Ly10 cells with JAK inhibitor I for 3 and 6 hours for a total of 4 arrays with replicates of each time point.
2010-05-27 | E-GEOD-10009 | biostudies-arrayexpress
Project description:In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. We demonstrate that adherent glioma CSCs exhibit characteristics previously described for CSCs grown in suspension culture. The expression of CD133, Sox2 and Nestin increased when compared to glioma cells grown in monolayer, and the adherent CSCs were ~100 times more tumorigenic in vivo than monolayer cultured glioma cells. We also found that while the STAT3 and NF-κB signaling pathways are constitutively activated in glioma lines, these pathways are dramatically activated in glioma CSCs. Treatment with STAT3 inhibitors led to a loss of nuclear activation of STAT3 signaling and suppression of growth in both monolayer and CSC conditions. There was a markedly greater growth suppressive effect on glioma CSCs, suggesting that targeted therapy of these key pathways in glioma CSCs may be possible. To further investigate potential biomarkers in glioma CSCs, microarray analysis was performed and revealed deregulation of the Notch signaling pathway. This constitutive activation of STAT3, NF-κB, and Notch pathways in glioma CSCs helps identify novel therapeutic targets for the treatment of glioma.
2013-06-19 | GSE48079 | GEO
Project description:RNA interference (RNAi) holds tremendous potential as a therapeutic approach, especially in the treatment of malignant tumors. However, efficient and biocompatible delivery methods are needed for systemic delivery of siRNA. To achieve this goal, we have established a novel formulation of siRNA by incorporating it into reconstituted high density lipoprotein (rHDL) nanoparticles. Here, we demonstrate that rHDL nanoparticles facilitate highly efficient systemic delivery of siRNA in vivo, mediated by the scavenger receptor type B1 (SR-B1). Moreover, in therapeutic proof-of-concept studies, these nanoparticles were effective in targeting either signal transducer and activator of transcription 3 (STAT3) or focal adhesion kinase (FAK) expression in orthotopic mouse models of ovarian and colorectal cancer. These data indicate that an rHDL nanoparticle is a novel and highly efficient siRNA carrier, and therefore this novel technology could serve as the foundation for new cancer therapeutic approaches. To identify the role of STAT3 in ovarian cancer cell, we performed microarray after knocking down STAT3 in ovarican cancer cells (3 siCon and 3 siSTAT3).
2011-12-22 | E-GEOD-20597 | biostudies-arrayexpress
Project description:Many patients have cancers that have increased activity of a protein called STAT3 that contributes critically to the development and growth of their cancer. Despite our knowledge of STAT3’s importance to cancer, scientists and doctors have not developed a drug that targets it and that patients can take to treat their cancer more effectively than treatments that are now available. Tvardi Therapeutics, Incorporated has developed a compound, TTI-101, which can be given by mouth and acts as a direct inhibitor of STAT3. Administration of TTI-101 to mice demonstrated that it blocked growth of cancers of the breast, head and neck, lung, and liver and it was safe when administered at high doses to mice, rats, and dogs. In this application, Tvardi is proposing to further develop TTI-101 for treatment of solid tumors for which the prognosis is dismal. The investigators will determine how safe it is when administered to patients with cancer, determine whether an adequate dose can be administered to patients with cancer that will block STAT3 in their cancer, and determine whether treatment with TTI-101 leads to reduced growth of their cancer.
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Project description:Characterizing the Key Metabolic Pathways of the Neonatal Mouse Heart Using a Quantitative Combinatorial Omics Approach
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Project description:Signal-transducer-and-activator-of-transcription-3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding a zinc-finger transcription factor. Wildtype-ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindred. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.
2018-05-02 | GSE107719 | GEO