Insulin-like Growth Factor Binding Protein-7 (IGFBP7) regulation in Hepatocellular Carcinoma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE85427 | GEO | 2019/08/01
REPOSITORIES: GEO
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Project description:Our previous study reported that IGFBP7 plays a role in maintaining mRNA stability of oncogenic lncRNA UBE2CP3 by RNA-RNA interaction. Clinical cohort studies had implied an oncogenic role of IGFBP7 in GC. However, the molecular mechanism of IGFBP7 in driving gastric cancer (GC) progression remains unknown. In this study, clinical analysis based on two independent cohort showed that IGFBP7 was positively associated with poor prognosis and macrophage infiltration in GC. Loss-of-function studies confirmed the oncogenic properties of IGFBP7 in regulating GC cell proliferation and invasion. Mechanismly, IGFBP7 was induced by epithelial-to-mesenchymal transition (EMT) signaling, since its expression was increased by TGF-beta treatment and reduced by overexpression of OVOL2 in GC. RNA sequencing, qRT-PCR, ELISA assay showed that IGFBP7 positively regulating FGF2 expression and secretion. Transcriptome analysis revealed that FGFR1 was downregulated in M1 macrophages but upregulated in M2 macrophages. Exogenous recombinant IGFBP7 protein in macrophages and GC cells further identified that IGFBP7 promotes macrophage polarization towards to a M2/TAM phenotype via FGF2/FGFR1/PI3K/AKT axis. Our finding highlights that IGFBP7 promotes GC by enhancing TAM infiltration through FGF2/FGFR1/PI3K/AKT axis.
2022-07-08 | GSE207373 | GEO
Project description:Previous study has demonstrated that HCC827/gef cells are resistant to gefitinib-induced aspoptosis. To investigate the regulators contributed to gefitinib resistance in lung cancer, we analyzed the gene expression profiles between HCC827 andHCC827/gef cells. Reduced IGFBP7 in TKI-resistant cells reversed resistance to EGFR-TKIs, and increased EGFR-TKI-induced apoptosis through up-regulation of BIM and activation of caspases. Suppression of IGFBP7 attenuated phosphorylation of IGF-IR and downstream AKT in TKI-resistant cells.
2019-02-07 | GSE122005 | GEO
Project description:Insulin like growth factor binding protein 7, Igfbp7, is a secreted protein that in addition to modulating insulin and insulin-like growth factor signaling, it acts as a tumor suppressor gene in breast and other cancers. To elucidate the role of Igfbp7 in regulating the proliferation and differentiation of mammary epithelial cells, we examined the growth and differentiation of mammary gland through different stages of its development in Igfbp7-null mice. Using transcriptome profiling in addition to functional assays we demonstrate that loss of Igfbp7 leads to diminished luminal cell differentiation and expansion of the luminal progenitors. These studies identify the endocrine factor Igfbp7, as a key regulator of luminal progenitor functions in the mammary gland. Mammary gland mRNA profiles of lactation day 3 wild type (WT) and Igfbp7-/- (KO) mice were generated by deep sequencing using SOLiD5500xl
2014-09-02 | E-GEOD-45118 | biostudies-arrayexpress
Project description:Insulin like growth factor binding protein 7, Igfbp7, is a secreted protein that in addition to modulating insulin and insulin-like growth factor signaling, it acts as a tumor suppressor gene in breast and other cancers. To elucidate the role of Igfbp7 in regulating the proliferation and differentiation of mammary epithelial cells, we examined the growth and differentiation of mammary gland through different stages of its development in Igfbp7-null mice. Using transcriptome profiling in addition to functional assays we demonstrate that loss of Igfbp7 leads to diminished luminal cell differentiation and expansion of the luminal progenitors. These studies identify the endocrine factor Igfbp7, as a key regulator of luminal progenitor functions in the mammary gland.
2014-09-02 | GSE45118 | GEO
Project description:Background & Aims: Hepatocellular carcinoma (HCC) is a major health problem. Most patients are diagnosed at advanced stages when the only approved therapy is sorafenib. Consequently, there is an urgent need to develop effective treatments. IGF-signaling is aberrantly activated in HCC, but there is no clear understanding on the molecular drivers and potential therapeutic targets within the pathway. Since IGF2-ligand is overexpressed in HCC, we aimed to elucidate its mechanism of overexpression, assess its oncogenic potential in vitro and in vivo and determine the antitumoral efficacy of molecular therapies against IGF2. Methods: Expression profiling, miRNAs expression and methylation were analyzed in 228 HCCs focusing on IGF2. Stable HCC cell lines with knock-down and ectopic overexpression of IGF2 were generated. A chemically-induced mouse model of HCC, and genetically-engineered mouse models (GEMM) overexpressing IGF2 in the liver were generated to assess IGF2 oncogenicity. The therapeutic potential of the monoclonal antibody against IGF-ligands (IGF1/2-mAb) and its combination with sorafenib was tested in vitro and in a xenograft model. Results: IGF2-overexpression occurred in 15% of HCC patients as a result of the epigenetic reactivation of IGF2-fetal promoters, mainly through loss of promoter methylation. Re-expression of IGF2 was associated with progenitor cell-like and poorly differentiated HCCs, and with poor prognosis (p<0.0001). In the GEMM model, IGF2-overexpression accelerated HCC progression and reduced survival (p=0.02). Conversely, IGF2-blockage using IGF1/2- mAbs delayed tumor growth and increased survival in vivo (p<0.0001), through antiproliferative and antiangiogenic mechanisms. Conclusions: We propose IGF2 as the first actionable epi-driver in HCC, and IGF1/2-mAbs as a potential targeted therapy in a defined subset of HCC patients. Keywords: IGF2, HCC, epidriver, IGF-pathway, monoclonal antibody, BI 836845.
2019-08-05 | GSE85274 | GEO
Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.
2016-06-16 | E-GEOD-73571 | biostudies-arrayexpress
Project description:Introduction: Hepatocellular carcinoma (HCC) is one of the most aggressive solid tumors and oncogenic pathways (e.g Akt, IGF signaling) are often activated in high proliferating HCC. Among several genetic alterations, epigenetic changes seem to be involved in the development and progression of HCC. DNA hypermethylation of promoter regions is almost always associated with transcriptional silencing and can lead to inactivation of tumor suppressor genes (TSG) in cancer cells. Aim: (1) To identify genes differently methylated in a subclass of HCC associated with proliferation and, (2) To correlate methylation changes with activation of molecular pathways. Methods: gDNA of 20 HCC, 8 cirrhotic and 8 normal liver samples was extracted and the methylation status was detected by the Illumina HumanMethylation27 BeadChip and immunohistochemistry of p-AKT, pIGF IR, p-S6 was analyzed. Results: Unsupervised clustering clearly classified normal livers, cirrhosis and HCC in 3 different groups. 961 genes were significantly hypermethylated in HCC compared to cirrhotic and 3942 genes showed hypermethylation in cirrhotic compared to normal liver tissue. 163 genes showed stepwise significant hypermethylation from normal to cirrhotic to HCC, including well described (p16, SOCS2, SFRP5, RBP1) and potential (SRD5A2, PCDH8, IGF-1R, UCHL1) TSGs, and the miR-10a. 133 genes were specifically hypermethylated in HCC. Among them the transcription factors GATA2, DLX1, and KLF14, all significantly inversely correlated to gene expression (p=0.003, p=0.03, and p=0.007, respectively). The methylation status of SOCS2 (p=0.025) and DLX1 (p=0.025) was significantly correlated to phosphorylation of IGFR1. Samples with RBP1 hypermethylation showed significantly higher AFP serum levels (p=0.018). Conclusion: Whole genome methylation analysis markedly classifies normal, cirrhotic and HCC samples. 8 TSGs play a key role in this stepwise progression of hypermethylation in the development of HCC and could be a promising point of action in anticancer therapy. Genomic DNA extracted from fresh frozen tissue specimens and cell lines was hybridized to genome-wide mthylation beadarray after bisulphite treatment. Keywords: DNA methylation, hepatocellular carcinoma, tissue, cell line
2013-09-27 | E-GEOD-44970 | biostudies-arrayexpress
Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.
2016-06-16 | GSE73571 | GEO
Project description:Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.
2022-03-03 | GSE168742 | GEO
Project description:Introduction: Hepatocellular carcinoma (HCC) is one of the most aggressive solid tumors and oncogenic pathways (e.g Akt, IGF signaling) are often activated in high proliferating HCC. Among several genetic alterations, epigenetic changes seem to be involved in the development and progression of HCC. DNA hypermethylation of promoter regions is almost always associated with transcriptional silencing and can lead to inactivation of tumor suppressor genes (TSG) in cancer cells. Aim: (1) To identify genes differently methylated in a subclass of HCC associated with proliferation and, (2) To correlate methylation changes with activation of molecular pathways. Methods: gDNA of 20 HCC, 8 cirrhotic and 8 normal liver samples was extracted and the methylation status was detected by the Illumina HumanMethylation27 BeadChip and immunohistochemistry of p-AKT, pIGF IR, p-S6 was analyzed. Results: Unsupervised clustering clearly classified normal livers, cirrhosis and HCC in 3 different groups. 961 genes were significantly hypermethylated in HCC compared to cirrhotic and 3942 genes showed hypermethylation in cirrhotic compared to normal liver tissue. 163 genes showed stepwise significant hypermethylation from normal to cirrhotic to HCC, including well described (p16, SOCS2, SFRP5, RBP1) and potential (SRD5A2, PCDH8, IGF-1R, UCHL1) TSGs, and the miR-10a. 133 genes were specifically hypermethylated in HCC. Among them the transcription factors GATA2, DLX1, and KLF14, all significantly inversely correlated to gene expression (p=0.003, p=0.03, and p=0.007, respectively). The methylation status of SOCS2 (p=0.025) and DLX1 (p=0.025) was significantly correlated to phosphorylation of IGFR1. Samples with RBP1 hypermethylation showed significantly higher AFP serum levels (p=0.018). Conclusion: Whole genome methylation analysis markedly classifies normal, cirrhotic and HCC samples. 8 TSGs play a key role in this stepwise progression of hypermethylation in the development of HCC and could be a promising point of action in anticancer therapy.
2013-09-27 | GSE44970 | GEO