SPTLC2 mediates EGFR/STAT3 pathway regulates the biological function of Ovarian Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1090419 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28408380_1.fastq.gz | Fastqsanger.gz | |||
| SRR28408380_2.fastq.gz | Fastqsanger.gz | |||
| SRR28408381_1.fastq.gz | Fastqsanger.gz | |||
| SRR28408381_2.fastq.gz | Fastqsanger.gz | |||
| SRR28408382_1.fastq.gz | Fastqsanger.gz |
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Project description:Serine Palmitoyltransferase (SPTLC2) was positively correlated with the invasion ability of ovarian cancer cells, its down-regulation inhibited the migrative, invasive and cloning capacity of cancer cells in vitro and suppressed the tumor proliferation and intraperitoneal diffusion in vivo, while its up-regulation did the opposite. Moreover, SPTLC2 could bind to EGFR to induce PD-L1 regulation in ovarian cancer, which was caused by the activation of EGFR/STAT3 signaling. Afatinib combined with trametinib had an obvious effect of inhibiting the intraperitoneal diffusion of ovarian cancer cells, especially in the group with low expression of SPTLC2, while overexpression of PD-L1 could reverse this phenomenon.
2024-12-17 | GSE262115 | GEO
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:SPTLC2 mediates AKT pathway and regulates the biological function of Ovarian Cancer
| PRJNA1089504 | ENA
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.
2015-02-01 | GSE63092 | GEO
Project description:Background: Among all gynecologic malignancies, epithelial ovarian cancer has the highest case-to-fatality ratio. Most patients are diagnosed at advanced stages and recurrence is common and accounts for disease-related mortality. Spleen tyrosine kinase (SYK) is an emerging cancer-associated kinase upregulated in recurrent tumors and is amenable for inhibition using small compounds that have been studied in clinical trials for autoimmune diseases. Our previous proteomic analysis identified several novel SYK substrates including EGFR and ERBB2. Here, we investigated the cross-talk between these pathways in ovarian carcinomas. Methods: Immunohistochemistry and immunoblotting were utilized to assess SYK and EGFR phosphorylation in ovarian serous carcinomas. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. To study its role in EGFR signaling, SYK activity was modulated using a small molecule inhibitor, a syngeneic knockout, and an active kinase inducible system. We applied RNA-seq to investigate the SYK-regulated EGF-induced transcriptome. Results: Intense immunoreactivity of active pSYK(Y525/526) correlated with poor overall survival in two independent ovarian cancer cohorts. SYK directly phosphorylated EGFR and ERBB2, while knockout of SYK reduces their phosphorylation. Phosphorylation levels of SYK(Y525/526) positively correlated with EGFR(Y1187) and STAT3(Y705). Active SYK reduced sensitivity to the EGFR/ERBB2 inhibitor, lapatinib, and SYK non-phosphorylatable EGFR mutant was more sensitive to paclitaxel. SYK modulated the EGF-induced transcriptome, supporting its involvement in EGFR/ERBB2-regulated transcriptional activity. Conclusions: Our findings suggest an upstream role of SYK in regulating the EGFR/ERBB2 signaling, and provide a biological rationale for targeting SYK in ovarian cancer therapy.
2020-11-08 | GSE106716 | GEO
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:Dimerization is believed necessary for receptor tyrosine kinases (RTKs) activation. Here we report that monomeric epidermal growth factor receptor (EGFR) directly phosphorylates the signal transducer and activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25 (hereafter referred to as TAMER (Transmembrane protein Antagonizing Monomeric EGF Receptor signaling) to reflect its molecular function). We identified TAMER as a checkpoint for the monomeric-EGFR/STAT3 signaling, and downregulation of TAMER in triple-negative breast cancer (TNBC) results in a persistent activation of STAT3 that is required for TNBC progression, which gives a good explanation why targeting EGFR dimerization by antibodies showed no significant benefit to TNBC patients in clinical trials. Remarkably, supply of TAMER strongly suppressed TNBC progression, presenting a promising targeted therapy for TNBC. Hence, our study demonstrated the first RTK monomer-mediated signaling pathway, introducing an unprecedented pattern of RTK signaling that may play key roles in certain physiological or pathological contexts, which might need to be inspected for therapeutically targeting RTKs in the future.In this paper, RNA-seq were used to identify different gene expression in WT and TMEM25 knockout MDA-MB-231 cells.
2024-07-28 | GSE180989 | 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:Ovarian cancer is a leading cause of death among gynecologic malignancies. This disappointing prognosis is closely related to intrinsic or acquired resistance to conventional platinum-based chemotherapy, which can affect a third of patients. As such, investigating relevant molecular targets is crucial in the fight against this disease. So far, many mutations involved in ovarian cancer pathogenesis have been identified. Among them, a few pathways were implicated. One such pathway is the P13K/AKT/mTOR with abnormalities found in many cases. This pathway is considered to have an instrumental role in proliferation, migration, invasion and, more recently, in chemotherapy resistance. Serine Palmitoyltransferase (SPTLC2) have been found to influence P13K/AKT/mTOR pathway with different potential role in tumor genesis behavior. In particular, their biological function was recently investigated as regards chemoresistance, therefore, leading to the identification of potential specific indirect biomarker of platinum sensitivity in ovarian cancer
2024-12-17 | GSE261885 | GEO
Project description:Although the oncogenic signalings driven by amplification and mutations of EGF receptor (EGFR) gene play a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59), acting as a new downstream effector of EGFR signaling, regulates STAT3 activation in glioblastoma. EGFR signaling leads to TRIM59 upregulation through SOX9 that results in enhancing TRIM59 interaction with STAT3 in nucleus, and inhibiting STAT3 association with TC45 (the nuclear form of T cell protein tyrosine phosphatase TC-PTP), thereby maintaining STAT3 phosphorylation and activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumorigenesis of GBM cells. Moreover, evaluation of GBM patient samples reveals an association among EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR-STAT3 signaling and a potential therapeutic target for GBM patients with EGFR activation.
2019-03-26 | GSE106557 | GEO