M6A reader IGF2BP2 promotes M2 macrophage polarization and malignant biological behavior of bladder cancer by stabilizing NRP1 mRNA expression
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ABSTRACT:
SUBMITTER: Fu D
PROVIDER: S-EPMC11251312 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate proinflammatory (M1) versus prohealing (M2) macrophages activation. Here, it is observed that insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 2 (IGF2BP2)-deleted macrophages exhibit enhanced M1 phenotype and promote dextran sulfate sodium induced colitis development. However, the IGF2BP2-/- macrophages are refractory to interleukin-4 (IL-4) induced activation and alleviate cockroach extract induced pulmonary allergic inflammation. Molecular studies indicate that IGF2BP2 switches M1 macrophages to M2 activation by targeting tuberous sclerosis 1 via an N6-methyladenosine (m6A)-dependent manner. Additionally, it is also shown a signal transducer and activators of transcription 6 (STAT6)-high mobility group AT-hook 2-IGF2BP2-peroxisome proliferator activated receptor-γ axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases.
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Project description:Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate pro-inflammatory (M1) versus pro-healing (M2) macrophages activation. Here, we observed that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) -deleted macrophages exhibited enhanced M1 phenotype and promoted DSS induced colitis development. However, the IGF2BP2-/- macrophages were refractory to IL4 induced activation and alleviated cockroach extract induced pulmonary allergic inflammation. Molecular studies indicated IGF2BP2 switched M1 macrophages to M2 activation by targeting tuberous sclerosis 1 (TSC1) via an N6-methyladenosine-dependent manner. Additionally, we also showed a signal transducer and activators of transcription 6 (STAT6) - high mobility group AT-hook 2 (HMGA2) -IGF2BP2-peroxisome proliferator activated receptor-γ (PPARγ) axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases.
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Project description:Alzheimer's disease, the most common form of dementia in the elderly, is a kind of neurodegenerative disease. However, its pathogenesis and diagnosis remain unclear. M6A is related to nervous system development and neurodegenerative diseases. Here in this study, using multiple RNA-seq datasets of Alzheimer's brain tissues, along with bioinformatic analysis, we innovatively found that m6A reader protein IGF2BP2 was abnormally highly expressed in Alzheimer's patients. After compared between Alzheimer's and normal brain samples, and between IGF2BP2- high and IGF2BP2- low subgroups of Alzheimer's patients, we took the shared differentially expressed genes as the relevant gene sets of IGF2PB2 affecting Alzheimer's disease occurrence for subsequent analysis. Then, weight gene correlation analysis was conducted and 17 functional modules were identified. The module that most positively correlated with Alzheimer's disease and IGF2PB2-high subgroups were mainly participated in ECM receptor interaction, focal adhesion, cytokine-cytokine receptor interaction, and TGF-beta signaling pathway. Afterwards, a hub gene-based model including 20 genes was constructed by LASSO regression and validated by ROC curve for Alzheimer diagnosis. Finally, we preliminarily elucidated that IGF2BP2 could bind with mRNAs in a m6A-dependent manner. This study first elucidates the pathogenic role of IGF2BP2 in Alzheimer's disease. IGF2BP2 and its relevant m6A modifications are potential to be new diagnostic and therapeutic targets for Alzheimer's patients.
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Project description:BackgroundImmunotherapy has brought new hope to gastric cancer (GC) patients. Exploring the immune infiltration pattern in GC and the key molecules is critical for optimizing the efficacy of immunotherapy. Aldo-keto reductase family 1 member B10 (AKR1B10) is an inflammatory regulator and is closely related to the prognosis of patients with GC. However, the function of AKR1B10 in GC remains unclear.MethodsIn the present study, the CIBERSORT algorithm was used to analyze the immune infiltration pattern in 373 samples in the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were seared by combing the TCGA database and the Gene Expression Omnibus (GEO) database, and the key molecule AKR1B10 was identified by weighted gene coexpression network analysis (WGCNA). The biological functions of AKR1B10 in stomach adenocarcinoma (STAD) were investigated in vitro.ResultsMacrophage polarization was the main immune infiltration pattern in GC, and the state of macrophage polarization was closely related to the pathological grading of GC and the clinical stage of patients. AKR1B10, MUC5AC, TFF2, GKN1, and PGC were significantly down-regulated in GC tissues. Low AKR1B10 expression induced M2 macrophage polarization and promoted the malignant phenotype of GC.ConclusionM2 macrophage polarization is the main immune infiltration pattern in GC. Low AKR1B10 expression induces M2 macrophage polarization and promotes the malignant transformation of GC.
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Project description:The present study aimed to explore the effects of key N6‑methyladenosine (m6A)‑related long non‑coding RNAs (lncRNAs) on the malignant behavior and macrophage polarization of gastric cancer cells, and their preliminary mechanisms. Gastric cancer‑related lncRNA datasets were downloaded from The Cancer Genome Atlas database, and m6A‑related differentially expressed lncRNAs (DElncRNAs) were analyzed. Subsequently, Cox regression and lasso regression analyses were used to screen the m6A‑related DElncRNAs associated with the prognosis of patients with gastric cancer. Additionally, reverse transcription‑quantitative polymerase chain reaction (qPCR) was employed to detect the expression levels of m6A‑related lncRNAs in normal gastric epithelial cells (GES‑1) and human gastric cancer cells (AGS and MKN‑45). In addition, the methylation levels of lncRNAs were measured using a methylated RNA immunoprecipitation qPCR assay kit, and the interaction between m6A‑related lncRNAs and m6A‑related proteins was observed by RNA pull‑down assay. Subsequently, m6A‑related lncRNAs and proteins were knocked down separately or simultaneously in gastric cancer cell lines. Bioinformatics analysis revealed that m6A‑related AC026691.1 was significantly associated with the prognosis of patients with gastric cancer and had a potential binding site for YT521‑B homology domain family member 2 (YTHDF2). The RNA pull‑down assay indicated that YTHDF2 not only had binding sites with AC026691.1 but could also markedly promote the degradation of m6A‑related AC026691.1. Furthermore, AC026691.1 was lowly expressed in gastric cancer cells, whereas YTHDF2 was highly expressed. Knockdown of YTHDF2 inhibited the proliferation, migration and epithelial‑mesenchymal transition of gastric cancer cells, and reduced M2 macrophage polarization. By contrast, knocking down AC026691.1 showed the opposite trend. Knockdown of YTHDF2 and AC026691.1 further confirmed the stable impact of YTHDF2 on AC026691.1. In conclusion, the degradation of AC026691.1 modified by YTHDF2‑mediated m6A may promote gastric cancer cell proliferation, migration, epithelial‑mesenchymal transition and M2 macrophage polarization.
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Project description:The human insulin-like growth factor 2 (IGF2) mRNA binding proteins 2 (IGF2BP2/IMP2) is an RNA-binding protein that regulates multiple biological processes. Previously, IGF2BP2 was thought to be a type 2 diabetes (T2D)-associated gene. Indeed IGF2BP2 modulates cellular metabolism in human metabolic diseases such as diabetes, obesity and fatty liver through post-transcriptional regulation of numerous genes in multiple cell types. Emerging evidence shows that IGF2BP2 is an N6-methyladenosine (m6A) reader that participates in the development and progression of cancers by communicating with different RNAs such as microRNAs (miRNAs), messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). Additionally, IGF2BP2 is an independent prognostic factor for multiple cancer types. In this review, we summarize the current knowledge on IGF2BP2 with regard to diverse human metabolic diseases and its potential for cancer prognosis.
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Project description:BackgroundLymph node metastasis is the main cause of poor prognosis of head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression, and as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression and metastasis. However, not much is currently known about the functional roles of IGF2BP2 in HNSCC, and whether IGF2BP2 regulates lymphatic metastasis through m6A modification in HNSCC remains to be determined.MethodsThe expression and overall survival (OS) probability of m6A-related regulators in HNSCC were analyzed with The Cancer Genome Atlas (TCGA) dataset and GEPIA website tool, respectively. The expression levels of IGF2BP2 were measured in HNSCC tissues and normal adjacent tissues. To study the effects of IGF2BP2 on HNSCC cell metastasis in vitro and in vivo, gain- and loss- of function methods were employed. RIP, MeRIP, luciferase reporter and mRNA stability assays were performed to explore the epigenetic mechanism of IGF2BP2 in HNSCC.ResultsWe investigated 20 m6A-related regulators in HNSCC and discovered that only the overexpression of IGF2BP2 was associated with a poor OS probability and an independent prognostic factor for HNSCC patients. Additionally, we demonstrated that IGF2BP2 was overexpressed in HNSCC tissues, and significantly correlated to lymphatic metastasis and poor prognosis. Functional studies have shown that IGF2BP2 promotes both HNSCC cell migration as well as invasion via the epithelial-mesenchymal transition (EMT) process in vitro, and IGF2BP2 knockdown significantly inhibited lymphatic metastasis and lymphangiogenesis in vivo. Mechanistic investigations revealed that Slug, a key EMT-related transcriptional factor, is the direct target of IGF2BP2, and essential for IGF2BP2-regulated EMT and metastasis in HNSCC. Furthermore, we demonstrated that IGF2BP2 recognizes and binds the m6A site in the coding sequence (CDS) region of Slug and promotes its mRNA stability.ConclusionsCollectively, our study uncovers the oncogenic role and potential mechanism of IGF2BP2, which serves as a m6A reader, in controlling lymphatic metastasis and EMT in HNSCC, suggesting that IGF2BP2 may act as a therapeutic target and prognostic biomarker for HNSCC patients with metastasis.
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Project description:BackgroundType 2 diabetes (T2D) is a common metabolic disease. Variants in human IGF2 mRNA binding protein 2 (IMP2/IGF2BP2) are associated with increased risk of T2D. IMP2 contributes to T2D susceptibility primarily through effects on insulin secretion. However, the underlying mechanism is not known.MethodsTo understand the role of IMP2 in insulin secretion and T2D pathophysiology, we generated Imp2 pancreatic β-cell specific knockout mice (βIMP2KO) by recombining the Imp2flox allele with Cre recombinase driven by the rat insulin 2 promoter. We further characterized metabolic phenotypes of βIMP2KO mice and assessed their β-cell functions.ResultsThe deletion of IMP2 in pancreatic β-cells leads to reduced compensatory β-cell proliferation and function. Mechanically, IMP2 directly binds to Pdx1 mRNA and stimulates its translation in an m6A dependent manner. Moreover, IMP2 orchestrates IGF2-AKT-GSK3β-PDX1 signaling to stable PDX1 polypeptides. In human EndoC-βH1 cells, the over-expression of IMP2 is capable to enhance cell proliferation, PDX1 protein level and insulin secretion.ConclusionOur work therefore reveals IMP2 as a critical regulator of pancreatic β-cell proliferation and function; highlights the importance of posttranscriptional gene expression in T2D pathology.
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Project description:Pancreatic adenocarcinoma (PC), one of the most fatal diseases, usually generates a poor prognosis in advanced stages. N6-methyladenosine modification has emerged as a crucial participant in tumor development and recurrence. Methyltransferase-like 14 (METTL14), as a core member of methyltransferases, is involved in tumor progression and metastasis. However, the potential mechanism by which METTL14 regulates long noncoding RNAs (lncRNAs) in PC remains unclear. RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation quantitative PCR (MeRIP-qPCR), and fluorescence in situ hybridization (FISH) were used to explore the underlying mechanisms. In our study, we found that METTL14 expression was upregulated in PC patients, and was associated with poor prognosis. In vitro and in vivo experiments, knocking down METTL14 suppressed tumor metastasis. RNA-seq and bioinformatics analyses were used to identify LINC00941 as the downstream target of METTL14. Mechanistically, LINC00941 was upregulated by METTL14 in an m6A-dependent way. LINC00941 was recruited and recognized by IGF2BP2. METTL14 enhanced the affinity of IGF2BP2 for LINC00941, while IGF2BP2 promoted the stabilization of LINC00941, which contributed to the migration and invasion of PC cells. Overall, our research revealed that METTL14 promoted the metastasis of PC through m6A modification of LINC00941. Targeting the METTL14-LINC00941-IGF2BP2 axis may provide promising therapeutic approaches for PC.
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