IGF2 is an epi-driver and therapeutic target in hepatocellular carcinoma
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ABSTRACT:
PROVIDER: PRJNA338010 | ENA |
REPOSITORIES: ENA
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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:Identification of Driver Genes in Hepatocellular Carcinoma by Exome Sequencing
| PRJNA193570 | ENA
Project description:The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.
2016-09-05 | GSE64073 | GEO
Project description:We identified an enhancer element near IGF2 locus that is possibly involved with dopamine function and schizophrenia. A knockout mouse was generated for the enhancer element in the IGF2 locus. We then characterized the striatal synaptosomes ( i.e. biological fraction representing pre- post synaptic nerve terminal)by mass spectometry from WT and Igf2 enhancer KO mice.
2019-05-31 | PXD012786 | Pride
Project description:Hypoxia is a common feature of tumor microenvironment (TME), which promotes tumor progression, metastasis and therapeutic drug resistance via a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical studies with this approach are lacking in hepatocellular carcinoma (HCC). From a genome-wide CRISPR/Cas9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as a master driver for HCC cell growth under hypoxia. To delineate the functional implications of ALDOA in HCC, transcriptome sequencing is performed to interrogate the differential gene expression in ALDOA-knockdown HepG2 cells under hypoxia.
2021-06-28 | GSE168544 | GEO
Project description:This study will evaluate longitudinal performance of Epi proColon with respect to test positivity, longitudinal adherence to Epi proColon screening, adherence to follow-up colonoscopy and diagnostic yield, as well as assay failure rates.
| 2249389 | ecrin-mdr-crc
Project description:The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5′-GGCTCG-3′ in intron 1 of Igf2. Deletion of this motif (Igf2ΔGGCT) or complete ablation of Zbed6 leads to ~20-fold up-regulation of IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Zbed6-/- and Igf2ΔGGCT myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Zbed6-/- myoblasts. Both Zbed6-/- and Igf2ΔGGCT myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O2 consumption rate, due to IGF2 up-regulation. Transcriptome analysis revealed ~30% overlap between differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with an enrichment of up-regulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Zbed6-/- and Igf2ΔGGCT myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study suggests that the interaction between ZBED6-Igf2 may be a therapeutic target for human diseases where anabolism is impaired.
2020-07-07 | PXD012758 | Pride
Project description:The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5′-GGCTCG-3′ in intron 1 of Igf2. Deletion of this motif (Igf2ΔGGCT) or complete ablation of Zbed6 leads to ~20-fold up-regulation of IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Zbed6-/- and Igf2ΔGGCT myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Zbed6-/- myoblasts. Both Zbed6-/- and Igf2ΔGGCT myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O2 consumption rate, due to IGF2 up-regulation. Transcriptome analysis revealed ~30% overlap between differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with an enrichment of up-regulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Zbed6-/- and Igf2ΔGGCT myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study suggeststhat the interaction between ZBED6-Igf2 may be a therapeutic target for human diseases where anabolism is impaired.
2020-07-07 | PXD012789 | Pride
Project description:Background and aims: Metabolic diseases, including diabetes, obesity, and dyslipidemia, are significant public health concerns worldwide. The insulin-like growth factor 2 (IGF2) gene have been implicated in various physiological processes, but its specific role in lipid metabolism remains unclear. We aim to elucidate the role of IGF2 in regulating lipid metabolism in adipose tissues and its association with metabolic syndrome (MetS). Methods: The research employed a multidisciplinary approach to investigate the role of IGF2 in lipid metabolism. We investigated the correlation between genetic variations within the IGF2 gene and metabolic parameters. We conduct a cross-sectional human study to evaluate relationships between varying IGF2 serum concentrations and the incidence of MetS. Additionally, manipulation of IGF2 expression levels in mouse and cell models via overexpression and knockdown to assess impacts on lipid metabolism in adipose tissue, specifically lipid accumulation, insulin resistance, and the balance between lipogenesis and lipolysis. Furthermore, the study employs metabolomics techniques to scrutinize the broader metabolic profiles in adipose tissues in response to IGF2 modulation. Results: Multiple SNP loci in the IGF2 gene were significantly associated with BMI, HbA1c, and diabetes. Insufficient or excessive expression of IGF2 was identified as a risk factor for hyperlipidemia, low HDL-c, and central obesity in MetS. We observed that IGF2 was mainly concentrated in adipose tissues and adipocytes. Enhanced IGF2 expression stimulated adipogenesis and lipid accumulation, whereas IGF2 knockdown hindered lipolysis, exacerbating ectopic lipid accumulation and insulin resistance. There is a substantial enlargement of pancreatic tissue and heightened insulin generation in mice deficient in IGF2. Activation of the PI3K/Akt pathway through IGF1R in IGF2 excess or INSR in conditions of IGF2 scarcity, along with inhibition of AMPK, implies a common downstream process that favors lipid accumulation and metabolic reprogramming in adipocytes. Conclusions: Our study demonstrated that upregulation of IGF2 enhanced adipogenesis and lipogenesis, while knockdown of IGF2 inhibited lipolysis, which resulting in accelerating lipid accumulation through PI3K/Akt-AMPK pathway.
2024-08-08 | GSE273546 | GEO
Project description:We identified and characterized a rice epigenetic mutant Epi-df which exhibits a dwarf stature and various floral defects that are inherited in a dominant fashion. We demonstrated that Epi-df participates in Polycomb repressive complex 2 (PRC2) mediated gene silencing. Epigenetic mutations results in ectopic expression of Epi-df and pleiotropic developmental defects in mutant plants. Moreover, ectopic expression of Epi-df leads to mis-regulated H3K27me3 and changed expression of hundreds of genes involved in a wide range of biological processes. We used microarrays to identify differentially expressed genes in Epi-df. For genome-wide expression analysis of Epi-df, three replicates of WT and Epi-df samples (RNA from 3-week-old seedlings) were analyzed on Affymetrix Genechip® Rice Genome arrays by an Affymetrix service facility (CapitalBio Corporation) according to the manufacturer’s protocols. Genes showing a 2-fold change with a q-value ≤ 0.05 were considered to be differentially expressed.
2012-07-12 | E-GEOD-39298 | biostudies-arrayexpress