IGF2BP3 enhances ferroptosis resistance in colon cancer by stabilizing SLC7A11 mRNA and is regulated by miR-98-5p
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ABSTRACT:
PROVIDER: PRJNA1224454 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32362963_1.fastq.gz | Fastqsanger.gz | |||
| SRR32362963_2.fastq.gz | Fastqsanger.gz | |||
| SRR32362964_1.fastq.gz | Fastqsanger.gz | |||
| SRR32362964_2.fastq.gz | Fastqsanger.gz | |||
| SRR32362965_1.fastq.gz | Fastqsanger.gz |
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Project description:Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, with increasing incidence and mortality rates. Resistance to cell death is a hallmark of cancer, and ferroptosis, a form of non-apoptotic cell death, has emerged as a critical factor in tumor suppression. The RNA-binding protein IGF2BP3, which plays a significant role in colon cancer progression, has been shown to modulate various oncogenic processes. However, its involvement in ferroptosis regulation in colon cancer remains largely unexplored. This study investigates the role of IGF2BP3 in ferroptosis regulation and its potential as a therapeutic target in colon cancer. Our data show that IGF2BP3 is upregulated in colon cancer tissues and correlates with poor prognosis. Knockdown of IGF2BP3 in colon cancer cell lines enhances sensitivity to ferroptosis induction, evidenced by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, which are reversed by the ferroptosis inhibitor ferrostatin-1. Mechanistically, IGF2BP3 regulates ferroptosis by stabilizing SLC7A11 mRNA, a key ferroptosis regulator, through its interaction with the mRNA. Additionally, miR-98-5p directly targets IGF2BP3, enhancing ferroptosis sensitivity. In vivo studies confirm that IGF2BP3 knockdown suppresses tumor growth, highlighting its potential as a therapeutic target. Overall, our findings suggest that IGF2BP3 plays a pivotal role in regulating ferroptosis in colon cancer, offering new avenues for therapeutic strategies in colon cancer treatment.
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Project description:Purpose: Increases in galactose-deficient IgA1 (Gd-IgA1) play a crucial role in the pathogenesis of IgA nephropathy (IgAN), and several recent experiments have shown that microRNAs (miRNAs) are involved in regulating the development and physiological function of the kidney. The aims of this study were to identify miRNAs that can affect the pathogenesis of IgAN and reveal the underlying regulatory mechanism of IgA1 glycosylation in peripheral blood Methods: The differentially expressed miRNAs in peripheral blood mononuclear cells (PBMCs) between IgAN patients and healthy controls were screened by high-throughput sequencing. The miRNA targets were predicted and verified by dual-luciferase reporter assays. We also explored the miRNA regulation of Gd-IgA1 through the transfection of miRNA mimics and related plasmids Results: The high-throughput sequencing results showed that miR-98-5p was highly expressed in the PBMCs of IgAN patients compared with healthy controls, and the luciferase reporter gene system confirmed that miR-98-5p might target chemokine ligand 3 (CCL3). The transfection of si-CCL3 confirmed that a decrease in CCL3 can affect the expression of interleukin-6 (IL-6) and C1GALT1. The overexpression of miR-98-5p in PBMCs via the transfection of miR-98-5p mimic reduced the CCL3 and C1GALT1 levels and increased the IL-6 levels. However, these changes in PBMCs were attenuated by cotransfection with the CCL3 plasmid. Conclusion: The results showed that miR-98-5p in PBMCs can target CCL3 to decrease its expression, which increased the IL-6 levels and the resulting increase in IL-6 can decrease C1GALT1 expression. Therefore, miR-98-5p might be involved in the development of IgAN.
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Project description:With obesity as a risk factor for atherosclerotic disease, recent research suggests that adipose tissue in obese animal models and humans can generate endocrine-like molecules that affect arterial health. Previous studies showed that microRNA-30e (miR-30e) level is elevated in atherosclerosis and solute carrier family 7 member 11 (SLC7A11), a cystine/glutamate transporter, is involved in atherogenesis. However, whether an endocrine-like link between the adipose-derived miR-30e-5p and SLC7A11 in the vascular endothelium can lead to obesity-caused atherosclerosis is unknown.MiRNA data mining and RT-PCR validations were used to demonstrate the positive association among serum level of miR-30e-5p, obesity, and coronary arterial disease in human patients. Transcriptomics (bulk RNA-seq and single-nucleus RNA-seq), metabolomics, and in silico analysis were used to establish a miR-30e-5p–SLC7A11 regulation of central carbon metabolism, mitochondrial and endothelial cell (EC) function. Mouse models with EC-specific Slc7a11 knockout (EC-Slc7a11-/-) and gain- or loss-of- function of miR-30e-5p were used to elucidate the detrimental role of this endocrine-like axis in obesity-related atherosclerosis.Our multi-omics approaches demonstrate that the adipose-derived miR-30e-5p downregulated SLC7A11 mRNA in ECs via tissue crosstalk. The resulting EC dysfunction led to obesity-related atherosclerosis in mice. These findings underscore a causality between obesity and atherosclerosis in the context of cardiovascular-kidney-metabolic syndrome.
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Project description:PGK1 acts as a non-catalytic gatekeeper of ferroptosis by stabilizing SLC7A11
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Project description:Objective. Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system with heterogenous clinical course, lacking non-invasive biomarkers for early phenotype differentiation. This study aimed to identi-fy circulating extracellular vesicle (EV)-derived miRNA signatures and as-sociated disease-specific molecular markers capable of distinguishing stable relapsing-remitting MS (RRMS) from secondary progressive MS (SPMS). Materials and methods. Plasma samples were collected from patients with stable RRMS, SPMS, and healthy controls (HC), followed by EVs isolation and characterization using transmission electron microscopy, dynamic light scattering, and flow cytometry. RNA was extracted from EVs, and miRNA profiles were ana-lyzed via RNA sequencing and RT-qPCR. Cytokine and neurodegeneration marker levels were quantified using the BioPlex® multiplex system and ELISA. Functional enrichment and network analyses of miRNA targets were performed, alongside logistic regression modeling to assess diagnostic utility. Results. Four EV-derived miRNAs (miR-760, miR-98-5p, miR-301a-3p, and miR-223-3p) showed significant differences between stable RRMS and SPMS. The integrative model incorporating these miRNAs with FGF basic protein achieved excellent discrimination between MS phenotypes (AUC = 0.97). Moreover, miR-760 emerged as the most robust predictive biomarker for stable RRMS classification. In turn, miR-98-5p showed the highest up-regulation in both stable RRMS and SPMS relative to HC. miRNA targets network analysis further revealed distinct immunoregulatory patterns for stable RRMS and SPMS. Conclusions. Plasma-derived EV-miRNAs, particularly miR-760 and miR-98-5p, showed strong potential as non-invasive biomarkers for stable RRMS and SPMS phenotypes. Integrating EV-miRNA profiling with protein bi-omarkers enhances diagnostic precision and may support personalized management strategies in MS.
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Project description:Ferroptosis is restrained by layered antioxidant defenses, yet whether glycolytic enzymes directly constitute ferroptosis-defense machinery remains unclear. Here we identify phosphoglycerate kinase 1 (PGK1) as a non-canonical suppressor of ferroptosis that functions independently of its glycolytic kinase activity. Across pan-cancer bulk and single-cell transcriptomes, glycolysis inversely associates with ferroptosis programs, with PGK1 emerging as a prognostic hub. PGK1 loss in multiple tumor models elicits hallmark ferroptotic features, elevates lipid peroxidation and labile iron, and suppresses xenograft growth, all of which are reversed by liproxstatin-1. Mechanistically, PGK1 physically binds the C-terminal tail of SLC7A11 (aa 471-501) and shields it from ubiquitin-proteasome degradation, thereby sustaining cystine-driven glutathione synthesis and redox homeostasis. This scaffolding role is preserved in a kinase-dead PGK1 mutant, establishing a strict separation between metabolic and ferroptosis-regulatory functions. Restoring SLC7A11 rescues PGK1-deficient tumor growth, whereas a rationally designed competing peptide SLC7A11471-501 (FP-01) disrupts the PGK1-SLC7A11 interface, depletes SLC7A11/GSH, triggers ferroptosis, and suppresses tumor progression in vivo. Collectively, the PGK1-SLC7A11 interaction represents a druggable ferroptosis vulnerability that enables selective ferroptosis induction while sparing essential glycolysis.
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Project description:Accumulating evidence indicates that N6-methyladenosine (m6A) modification of circular RNAs (circRNAs) plays a pivotal role in regulating cancer progression. However, in head and neck squamous cell carcinoma (HNSCC), the biological functions and underlying mechanisms of m6A modification in circRNAs remain insufficiently elucidated. In this study, we demonstrated that IGF2BP3, an upstream m6A reader, is associated with poor clinical outcomes. IGF2BP3 stabilizes circHECTD2 through binding, and m6A modification enhances this interaction. Mechanistic investigations revealed that IGF2BP3 binds to and stabilizes circHECTD2, which functions as a sponge for hsa-miR-4310 and hsa-miR-7157-5p, thereby preventing the degradation of SMAD2 mRNA and promoting tumor proliferation, invasion, and metastasis in HNSCC. Collectively, these findings suggest that IGF2BP3 and circHECTD2 may serve as promising prognostic biomarkers and therapeutic targets for HNSCC.
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Project description:Ferroptosis is restrained by layered antioxidant defenses, yet whether glycolytic enzymes directly constitute ferroptosis-defense machinery remains unclear. Here we identify phosphoglycerate kinase 1 (PGK1) as a non-canonical suppressor of ferroptosis that functions independently of its glycolytic kinase activity. Across pan-cancer bulk and single-cell transcriptomes, glycolysis inversely associates with ferroptosis programs, with PGK1 emerging as a prognostic hub. PGK1 loss in multiple tumor models elicits hallmark ferroptotic features, elevates lipid peroxidation and labile iron, and suppresses xenograft growth, all of which are reversed by liproxstatin-1. Mechanistically, PGK1 physically binds the C-terminal tail of SLC7A11 (aa 471-501) and shields it from ubiquitin-proteasome degradation, thereby sustaining cystine-driven glutathione synthesis and redox homeostasis. This scaffolding role is preserved in a kinase-dead PGK1 mutant, establishing a strict separation between metabolic and ferroptosis-regulatory functions. Restoring SLC7A11 rescues PGK1-deficient tumor growth, whereas a rationally designed competing peptide SLC7A11471-501 (FP-01) disrupts the PGK1-SLC7A11 interface, depletes SLC7A11/GSH, triggers ferroptosis, and suppresses tumor progression in vivo. Collectively, the PGK1-SLC7A11 interaction represents a druggable ferroptosis vulnerability that enables selective ferroptosis induction while sparing essential glycolysis.
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