Pharmacological inhibition of LIFR impairs ovarian cancer progression by blocking LIF/LIFR autocrine loop
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236743 | GEO | 2024/05/29
REPOSITORIES: GEO
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Project description:Pharmacological inhibition of LIFR impairs ovarian cancer progression by blocking LIF/LIFR autocrine loop
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Project description:We examined the transcriptional changes modulated by ESR2 agonist liquiritigenin by perfroming global transcriptome analysis. ES2 cells were treated with either vehicle or liquiritigenin for 24 h and the isolated RNA was utilized for RNA-seq analysis. Our results demonstrated that liquiritigenin modulated several genes that are involved in NF-kB signaling, inflammation, NRF2 mediated oxidative stress response, and MMP signaling.
2017-09-18 | GSE93807 | GEO
Project description:Dlx3 over-expression in mouse embryonic fibroblasts changed the expression level of numerous genes involved in osteogenesis and embryonic stem cell-related pathways as revealed by microarray analysis. From the list of Dlx3 modulated genes we focused our attention on the study of two candidates, Lifr and Chrdl1. Chromatin immunoprecipitation demonstrated the recruitment of Dlx3 transcription factor to the promoters of Lifr and Chrdl1, and luciferase assays confirmed the role of Dlx3 in the regulation of Lifr expression. Over-expression of Dlx3 in mouse embryonic stem cells stimulated Lifr and Chrdl1 expression and inhibited expression of Id proteins and Bmp4. We show that Dlx3 increases the expression of both soluble and transmembrane forms of Lifr. Soluble Lifr may regulate extracellular Lif levels via solution binding, while transmembrane Lifr mediates the signal transduction pathway. The data suggests that Dlx3 may be involved in stem cell differentiation in a dosage dependent way through its interaction with Lifr and with Chrdl1, a known antagonist of Bmp4. We speculate that Dlx3 may also be involved in osteoblast differentiation through interactions involving Lifr, Bmp, and Id proteins and signaling via the JAK/STAT and MAPK pathways. In summary, our data suggests that Dlx3 proteins play a significant role in a highly tuned network in early embryogenesis. Keywords: treated vs.untreated Stable and Transient transfection of Dlx3 in MEF. Total of 4 hybridizations including biological replicates.
2009-08-15 | E-GEOD-11727 | biostudies-arrayexpress
Project description:Dlx3 over-expression in mouse embryonic fibroblasts changed the expression level of numerous genes involved in osteogenesis and embryonic stem cell-related pathways as revealed by microarray analysis. From the list of Dlx3 modulated genes we focused our attention on the study of two candidates, Lifr and Chrdl1. Chromatin immunoprecipitation demonstrated the recruitment of Dlx3 transcription factor to the promoters of Lifr and Chrdl1, and luciferase assays confirmed the role of Dlx3 in the regulation of Lifr expression. Over-expression of Dlx3 in mouse embryonic stem cells stimulated Lifr and Chrdl1 expression and inhibited expression of Id proteins and Bmp4. We show that Dlx3 increases the expression of both soluble and transmembrane forms of Lifr. Soluble Lifr may regulate extracellular Lif levels via solution binding, while transmembrane Lifr mediates the signal transduction pathway. The data suggests that Dlx3 may be involved in stem cell differentiation in a dosage dependent way through its interaction with Lifr and with Chrdl1, a known antagonist of Bmp4. We speculate that Dlx3 may also be involved in osteoblast differentiation through interactions involving Lifr, Bmp, and Id proteins and signaling via the JAK/STAT and MAPK pathways. In summary, our data suggests that Dlx3 proteins play a significant role in a highly tuned network in early embryogenesis. Keywords: treated vs.untreated
2009-08-15 | GSE11727 | GEO
Project description:Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR activate oncogenic signaling pathways including JAK/STAT3 as immediate effectors and MAPK, AKT, mTOR further downstream. LIF/LIFR signaling plays a key role in tumor growth, progression, metastasis, stemness and therapy resistance. Many solid cancers show overexpression of LIF and autocrine stimulation of the LIF/LIFR axis; these are associated with a poorer relapse-free survival. LIF/LIFR signaling also plays a role in modulating multiple immune cell types present in tumor micro environment (TME). Recently, two targeted agents that target LIF (humanized anti-LIF antibody, MSC-1) and LIFR inhibitor (EC359) were under development. Both agents showed effectivity in preclinical models and clinical trials using MSC-1 antibody are in progress. This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.
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Project description:We examined the mechanisms by which adiposity regulates EEC progression. EEC cells were incubated with or without adipocyte conditioned medium (ADP-CM), and total RNA was isolated for RNA-seq analysis. Our results demonstrated that ADP-CM stimulated EEC cells showed upregulation of several LIF/LIFR modulated pathways including Jak/STAT and cytokine pathways.
2022-11-16 | GSE214872 | GEO
Project description:The poly(rC) binding protein 1 gene (PCBP1) encodes the heterogenous nuclear ribonucleoprotein E1 (hnRNPE1), a nucleic acid binding protein that plays a tumor-suppressive role in mammary epithelium by regulating phenotypic plasticity and cell fate. Following loss of PCBP1 function, the FAM3C gene (encoding the Interleukin-like EMT inducer, or “ILEI” protein) and the leukemia inhibitory factor receptor (LIFR) gene are upregulated. Interaction between FAM3C and LIFR in the extracellular space induces phosphorylation of the signal transducer and activator of transcription 3 (pSTAT3). The overexpression and/or hyperactivity of STAT3 has been detected in 40% of breast cancer cases and is associated with poor prognosis. Herein, we characterize feed-forward regulation of LIFR expression in response to FAM3C/LIFR/pSTAT3 signaling in mammary epithelial cells, and show that PCBP1 upregulates LIFR transcription through FAM3C, involving activity at the LIFR promoter. Additionally, our bioinformatic analysis reveals a signature of transcriptional regulation associated with FAM3C/LIFR interaction and identifies the TWIST1 transcription factor as a downstream effector that participates in maintenance of LIFR expression. Finally, we characterize the effect of LIFR expression in cell-based experiments that demonstrate promotion of invasion, migration, and breast cancer stem cell (BCSC) self-renewal, consistent with previous studies that link LIFR expression to tumor initiation and metastasis in mammary epithelial cells.
2023-06-13 | GSE234882 | GEO
Project description:MCF7 cells were infected with lentiviral particles containing LIFR-targeted shRNAs then chemically selected to create a stable pooled population of shLIFR MCF7 cells. The goal of the study was to determine the downstream targets of LIFR in human MCF7 breast cancer cells.
2024-05-03 | GSE174592 | GEO
Project description:Super-enhancers (SEs) have been recognized as key epigenetic regulators underlying cancer stemness and malignant traits by aberrant transcriptional control and promising therapeutic targets against human cancers. However, the SE landscape and their roles during head and neck squamous cell carcinoma (HNSCC) development especially in cancer stem cells (CSCs) maintenance remain underexplored yet. Here, we identified leukemia inhibitory factor (LIF)-SE as a representative oncogenic SE to activate LIF transcription in HNSCC. LIF secreted from cancer cells and cancer-associated fibroblasts promotes cancer stemness by driving SOX2 transcription in an autocrine or paracrine manner, respectively. Mechanistically, enhancer elements E1, 2, 4 within LIF-SE recruited SOX2/SMAD3/BRD4/EP300 to facilitate LIF transcription; LIF activated downstream LIFR-STAT3 signaling to drive SOX2 transcription, thus forming a previously unknown regulatory feedback loop (LIF-SE-LIF/LIFR-STAT3-SOX2) to maintain LIF overexpression and CSCs stemness. Clinically, increased LIF abundance in clinical samples correlated with malignant clinicopathological features and patient prognosis; higher LIF concentrations in presurgical plasma were negatively associated with patient survival and dramatically diminished following cancer eradication. Therapeutically, pharmacological targeting LIF-SE-LIF/LIFR-STAT3 significantly impaired tumor growth and reduced CSC subpopulations in HNSCC xenograft and PDX models. Our findings reveal a hitherto uncharacterized LIF-SE-mediated auto-regulatory loop in regulating HNSCC stemness and highlight LIF as a novel non-invasive biomarker and potential therapeutic target for HNSCC.
2024-11-06 | GSE274995 | GEO
Project description:Super-enhancers (SEs) have been recognized as key epigenetic regulators underlying cancer stemness and malignant traits by aberrant transcriptional control and promising therapeutic targets against human cancers. However, the SE landscape and their roles during head and neck squamous cell carcinoma (HNSCC) development especially in cancer stem cells (CSCs) maintenance remain underexplored yet. Here, we identified leukemia inhibitory factor (LIF)-SE as a representative oncogenic SE to activate LIF transcription in HNSCC. LIF secreted from cancer cells and cancer-associated fibroblasts promotes cancer stemness by driving SOX2 transcription in an autocrine or paracrine manner, respectively. Mechanistically, enhancer elements E1, 2, 4 within LIF-SE recruited SOX2/SMAD3/BRD4/EP300 to facilitate LIF transcription; LIF activated downstream LIFR-STAT3 signaling to drive SOX2 transcription, thus forming a previously unknown regulatory feedback loop (LIF-SE-LIF/LIFR-STAT3-SOX2) to maintain LIF overexpression and CSCs stemness. Clinically, increased LIF abundance in clinical samples correlated with malignant clinicopathological features and patient prognosis; higher LIF concentrations in presurgical plasma were negatively associated with patient survival and dramatically diminished following cancer eradication. Therapeutically, pharmacological targeting LIF-SE-LIF/LIFR-STAT3 significantly impaired tumor growth and reduced CSC subpopulations in HNSCC xenograft and PDX models. Our findings reveal a hitherto uncharacterized LIF-SE-mediated auto-regulatory loop in regulating HNSCC stemness and highlight LIF as a novel non-invasive biomarker and potential therapeutic target for HNSCC.
2024-11-06 | GSE274994 | GEO