Inhibition of the autocrine loop IL6-JAK2-STAT3-Calprotectin as targeted therapy for HR-/HER2+ breast cancers
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE62251 | GEO | 2015/09/03
SECONDARY ACCESSION(S): PRJNA263583
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-09-03 | E-GEOD-62251 | biostudies-arrayexpress
Project description:HER2-positive (HER2(+)) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR(-)/HER2(+) tumors, eliciting tumor dependency in these cells. Mechanistically, HR(-)/HER2(+) cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6-Janus kinase 2 (JAK2)-STAT3-calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR(-)/HER2(+) breast cancers, opening novel targeted therapeutic opportunities.
| S-EPMC4536311 | biostudies-literature
Project description:Inhibition of the autocrine loop IL6-JAK2-STAT3-Calprotectin as targeted therapy for HR-/HER2+ breast cancers
| PRJNA263583 | ENA
Project description:Metastasis is the most important reason for the poor prognosis of gastric cancer (GC) patients, and the mechanism urgently needs to be clarified. Here, we explored a prognostic model for the estimation of tumor-associated mortality in GC patients and revealed the RNA-binding protein RBMS1 as a candidate promoter gene for GC metastasis by analyzing GOBO and Oncomine high-throughput sequencing datasets for 408 GC patients. Additionally, RBMS1 was observed with overexpression in 85 GC patient clinical specimens by IHC staining and further be verified its role in GC metastasis via inducing EMT process both in in vitro and in vivo experiments. Moreover, we identified that IL-6 was predicted to be one of the most significant upstream cytokines in the RBMS1 overexpression gene set based on the Ingenuity Pathway Analysis (IPA) algorithm. Most importantly, we also revealed that RBMS1 could promote migration and invasion through IL6 transactivation and JAK2/STAT3 downstream signaling pathway activation by influencing histone modification in the promoter regions after binding with the transcription factor MYC in the HGC-27 and SGC-7901 GC cell lines. Hence, we shed light on the potential molecular mechanisms of RBMS1 in the promotion of GC metastasis, which suggests that RBMS1 may be a potential therapeutic target for GC patients.
| S-EPMC8971453 | biostudies-literature
Project description:Glioma, a prevalent primary tumor of the central nervous system, is targeted by molecular therapies aiming to intervene in specific genes and signaling pathways to inhibit tumor growth and spread. Our previous bioinformatics study revealed that significant CDC6 overexpression in gliomas was closely correlated with poor patient prognosis. Through qPCR, western blotting, and immunohistochemistry, we will further validate CDC6 expression in clinical glioma specimens, while the effects of silencing and overexpressing CDC6 in the U87 and LN229 glioma cell lines on malignancy will be assessed through MTS, EdU, transwell, and migration assays. Luciferase reporter assays, ChIP, qPCR, and western blotting were used to explore the upstream and downstream molecular mechanisms of CDC6. Our study confirmed the abnormal overexpression of CDC6 in gliomas, particularly in glioblastomas. CDC6 promotes glioma cell activity, proliferation, invasion, and migration by activating the IL6-mediated JAK2/STAT3 signaling pathway. The transcription Factor E2F8 directly regulates CDC6 transcription, playing a crucial role in its abnormal overexpression in gliomas. This research provides vital evidence supporting CDC6 as a molecular target for glioma therapy.
| S-EPMC11301287 | biostudies-literature
Project description:The activation of JAK2/STAT3 pathway has been reported to have critical roles in several solid tumors. The present study aimed to evaluate the correlation between JAK2/STAT3 activation and clinicopathological parameters in ovarian cancer types. Tissue microarrays made from the patients treated at the National Defense Medical College Hospital between 1984 and 2008 were evaluated using immunohistochemical (IHC) stainings. Medical charts of these patients including IHC results were retrospectively analyzed, and prognostic factors for progression-free survival and overall survival were evaluated. Among 341 enrolled patients, positive expression of p-STAT3 was observed in 95 cases (28%). Positive p-STAT3 was an independent worse prognostic factor for overall survival in all the cases. Additionally, p-STAT3 expression was related with overall survival in patients with clear-cell histology, but not in serous histology. The effect of an inhibitor of STAT3, niclosamide, was evaluated in ovarian clear-cell cancer cells, and niclosamide treatment decreased expression of p-STAT3, leading to increased apoptosis in a dose-dependent manner in vitro. The activation of JAK2/STAT3 pathway had significant impact on survival of ovarian cancers, especially for the cases with clear-cell histology. Although further analyses are needed, suppression of this pathway could be a candidate for the treatment of ovarian cancers.
| S-EPMC5840758 | biostudies-other
Project description:BackgroundGlioma is the most common and malignant tumor of central nervous system. The tumor initiation, self-renewal, and multi-lineage differentiation abilities of glioma stem cells (GSCs) are responsible for glioma proliferation and recurrence. Although circular RNAs (circRNAs) play vital roles in the progression of glioma, the detailed mechanisms remain unknown.MethodsqRT-PCR, western blotting, immunohistochemistry, and bioinformatic analysis were performed to detect the expression of circATP5B, miR-185-5p, HOXB5, and SRSF1. Patient-derived GSCs were established, and MTS, EDU, neurosphere formation, and limiting dilution assays were used to detect the proliferation of GSCs. RNA-binding protein immunoprecipitation, RNA pull-down, luciferase reporter assays, and chromatin immunoprecipitation assays were used to detect these molecules' regulation mechanisms.ResultsWe found circATP5B expression was significantly upregulated in GSCs and promoted the proliferation of GSCs. Mechanistically, circATP5B acted as miR-185-5p sponge to upregulate HOXB5 expression. HOXB5 was overexpressed in glioma and transcriptionally regulated IL6 expression and promoted the proliferation of GSCs via JAK2/STAT3 signaling. Moreover, RNA binding protein SRSF1 could bind to and promote circATP5B expression and regulate the proliferation of GSCs, while HOXB5 also transcriptionally regulated SRSF1 expression.ConclusionsOur study identified the SRSF1/circATP5B/miR-185-5p/HOXB5 feedback loop in GSCs. This provides an effective biomarker for glioma diagnosis and prognostic evaluation.
| S-EPMC8051130 | biostudies-literature
Project description:Tumor-associated macrophages have emerged as crucial factors for metastases. Microglia are indispensable components of the brain microenvironment and play vital roles in brain metastasis (BM). However, the underlying mechanism of how activated microglia promote brain metastasis of non-small cell lung cancer (NSCLC) remains elusive. Here, we purified cell lines with brain-metastatic tropism and employed a co-culture system to reveal their communication with microglia. By single-cell RNA-sequencing and transcriptome difference analysis, we identified IL6 as the key regulator in brain-metastatic cells (A549-F3) to induce anti-inflammatory microglia via JAK2/STAT3 signaling, which in turn promoted the colonization process in metastatic A549-F3 cells. In our clinical samples, patients with higher levels of IL6 in serum showed higher propensity for brain metastasis. Additionally, the TCGA (The Cancer Genome Atlas) data revealed that NSCLC patients with a lower level of IL6 had a longer overall survival time compared to those with a higher level of IL6. Overall, our data indicate that the targeting of IL6/JAK2/STAT3 signaling in activated microglia may be a promising new approach for inhibiting brain metastasis in NSCLC patients.
| S-EPMC8864012 | biostudies-literature
Project description:Aurora kinase A is a frequently amplified and overexpressed gene in upper gastrointestinal adenocarcinomas (UGCs). Using in vitro cell models of UGCs, we investigated whether AURKA can regulate Signal Transducer and Activator of Transcription 3 (STAT3). Our data indicate that overexpression of AURKA in FLO-1 and AGS cells increase STAT3 phosphorylation at the Tyr705 site, whereas AURKA genetic depletion by siRNA results in decreased phosphorylation levels of STAT3 in FLO-1 and MKN45 cells. Immunofluorescence analysis showed that AURKA overexpression enhanced STAT3 nuclear translocation while AURKA genetic knockdown reduced the nuclear translocation of STAT3 in AGS and FLO-1 cells, respectively. Using a luciferase reporter assay, we demonstrated that AURKA expression induces transcriptional activity of STAT3. Pharmacological inhibition of AURKA by MLN8237 reduced STAT3 phosphorylation along with down-regulation of STAT3 pro-survival targets, BCL2 and MCL1. Moreover, by using clonogenic cells survival assay, we showed that MLN8237 single dose treatment reduced the ability of FLO-1 and AGS cells to form colonies. Additional experiments utilizing cell models of overexpression and knockdown of AURKA indicated that STAT3 upstream non-receptor tyrosine kinase Janus kinase 2 (JAK2) is mediating the effect of AURKA on STAT3. The inhibition of JAK2 using JAK2-specific inhibitor AZD1480 or siRNA knockdown, in presence of AURKA overexpression, abrogated the AURKA-mediated STAT3 activation. These results confirm that the AURKA-JAK2 axis is the main mechanism by which AURKA regulates STAT3 activity. In conclusion, we report, for the first time, that AURKA promotes STAT3 activity through regulating the expression and phosphorylation levels of JAK2. This highlights the importance of targeting AURKA as a therapeutic approach to treat gastric and esophageal cancers.
| S-EPMC4254172 | biostudies-literature
Project description:BackgroundLung cancer is one of the most common tumors in the world, and metastasis is one of the major causes of tumor-related death in lung cancer patients. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and are frequently associated with tumor metastasis in human cancers. However, the regulatory mechanisms of TAMs in lung cancer metastasis remain unclear.MethodsSingle-cell sequencing analysis of lung cancer and normal tissues from public databases and from 14 patients who underwent surgery at Zhongshan Hospital was performed. In vitro co-culture experiments were performed to evaluate the effects of TAMs on lung cancer migration and invasion. Changes in the expression of IL-6, STAT3, C/EBPΒ, and EMT pathway were verified using RT-qPCR, western blotting, and immunofluorescence. Dual luciferase reporter assays and ChIP were used to reveal potential regulatory sites on the transcription factor sets. In addition, the effects of TAMs on lung cancer progression and metastasis were confirmed by in vivo models.ResultsTAM infiltration is associated with tumor progression and poor prognosis. IL-6 secreted by TAMs can activate the JAK2/STAT3 pathway through autocrine secretion, and STAT3 acts as a transcription factor to activate the expression of C/EBPβ, which further promotes the transcription and expression of IL-6, forming positive feedback loops for IL6-STAT3-C/EBPβ-IL6 in TAMs. IL-6 secreted by TAMs promotes lung cancer progression and metastasis in vivo and in vitro by activating the EMT pathway, which can be attenuated by the use of JAK2/STAT3 pathway inhibitors or IL-6 monoclonal antibodies.ConclusionsOur data suggest that TAMs promote IL-6 expression by forming an IL6-STAT3-C/EBPβ-IL6 positive feedback loop. Released IL-6 can induce the EMT pathway in lung cancer to enhance migration, invasion, and metastasis. The use of IL-6-neutralizing antibody can partially counteract the promotion of LUAD by TAMs. A novel mechanism of macrophage-promoted tumor progression was revealed, and the IL6-STAT3-C/EBPβ-IL6 signaling cascade may be a potential therapeutic target against lung cancer.
| S-EPMC10903044 | biostudies-literature