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: Not available
| S-EPMC10073300 | biostudies-literature
Project description:Identification of Driver Genes in Hepatocellular Carcinoma by Exome Sequencing
| PRJNA193570 | ENA
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: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: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:Background and aims: Insulin-like growth factor 2 (IGF2) is closely associated with the occurrence and development of primary and secondary muscle atrophy. This study investigates the role of IGF2 deficiency in inducing muscle atrophy using muscle-specific Igf2 knockout mice, aiming to provide theoretical basis and new concepts for growth hormone supplementation therapy in muscle atrophy. Methods: We analyzed Igf2 expression using the Tabula Muris single-cell database and generated muscle-specific Igf2 knockout mice using the Cre/LoxP system with Mck-cre transgenic mice. We characterized the phenotype and assessed muscle size and mass through external observation, dissection, H&E staining, and microCT scanning. Muscle function was evaluated using the Md3000 grip strength meter, treadmill tests for endurance and electromyography (EMG) for contraction force. Transcriptome sequencing was performed on muscle tissues to analyze the impact of Igf2 deletion on gene expression and pathways. Results: The Tabula Muris database confirmed high Igf2 expression in limb muscles, and we successfully developed muscle-specific Igf2 knockout (Igf2 cKO) mice. Analyses using MicroCT and H&E staining showed reduced muscle size, weight, and density in the gastrocnemius of Igf2 cKO mice versus controls. Grip strength tests using the Md3000 animal grip strength meter and treadmill tests assessing running endurance both indicated reduced physical performance in the Igf2 cKO group, with weakened grip strength and decreased running endurance distance and time. Electromyography (EMG) measurements disclosed a decrease in gastrocnemius muscle contraction force in the Igf2 cKO group. Transcriptome sequencing highlighted significant functional changes in muscle-related processes, RNA polymerase II transcription, and the PI3K pathway in the Igf2 cKO mice. Conclusions: Igf2 is highly expressed in skeletal muscle tissue. Muscle-specific Igf2 knockout mice exhibited reduced muscle size, weight, and density, weakened grip strength, decreased gastrocnemius muscle contraction force, and reduced running endurance distance and time. These findings suggest that IGF2 supplementation may be a potentially effective strategy for treating muscle atrophy.
2025-12-01 | GSE281658 | GEO
Project description:Chronic kidney disease (CKD) is prevalent in 10% of world’s adult population, with Estimated Glomerular filtration rate (eGFR) and albuminuria employed in diagnosis. Role of protein glycosylation in causal mechanisms of CKD progression is largely unknown. Aim of this study was to identify urinary O-linked glycopeptides in association to CKD for better characterization of CKD molecular manifestations. Urine samples from 2 healthy and 8 CKD subjects were analyzed by CE-MS/MS and glycopeptide analysis using Proteome Discoverer 1.4. Distribution of identi-fied glycopeptides and correlation with Age, eGFR and Albuminuria were evaluated in 3810 da-tasets. In total, 17 O-linked glycopeptides from 7 different proteins were identified, derived primarily from Insulin-like growth factor-II (IGF2). Glycosylation occurred at the surface ex-posed IGF2 Threonine 96 position. Three glycopeptides (DVStPPTVLPDNFPRYPVGKF, DVStPPTVLPDNFPRYPVG and DVStPPTVLPDNFPRYP) exhibited positive correlation with Age. Glycopeptide (tPPTVLPDNFPRYP) showed strong negative association with eGFR. These results suggest that with aging and deteriorating kidney function, alterations in IGF2 proteoforms take place; which may reflect changes in mature IGF2 protein. Our results corroborate this hypothesis as IGF2 increased plasma levels were observed in CKD patients. Protease predictions, consider-ing also available transcriptomics data, suggest activation of cathepsin S with CKD, meriting further investigation.
2023-05-10 | PXD039829 | Pride
Project description:Intergenic to H19 and Igf2, there is a previously identified centrally conserved domain (ccd ) that includes two sequences with high conservation between human and mouse. At one of these sequence elements there is DNAse1 Hypersentitivity sequence (HSS), CTCF binding and chromatic interaction/looping to sequence upstream of Igf2 on both parental alleles. In earlier studies, removal of ccd sequence from the maternal allele resulted in activation of the normally repressed maternal Igf2 in neonatal limb. We have generated an independent ccd (floxed) deletion allele. Deletion of ccd from both the maternal and paternal allele also results in elevated levels of Igf2 expression from the respective alleles in adult skeletal muscle. Capture C analysis of adult skeletal muscle nuclei uncovers new chromatin interactions in ccd deletion alleles.
2025-08-06 | GSE202669 | GEO
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