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PubMed2026

Circulating IGF2BP3 enables risk stratification and predicts treatment response in Ewing sarcoma.

Ewing sarcoma (EWS), the second most common pediatric bone tumor, presents with a markedly heterogeneous clinical spectrum and optimal risk stratification is therefore crucial for improving treatment outcomes. The RNA-binding protein IGF2BP3 is a critical oncogenic driver of EWS malignancy. This study evaluates the clinical utility of circulating IGF2BP3 as a biomarker to predict treatment response and risk of disease progression in patients with EWS. Plasma samples from 60 patients with EWS diagnosed and treated at the IRCCS Rizzoli Orthopedic Institute (Bologna, Italy) were collected at diagnosis before treatment initiation and/or after induction chemotherapy. For 51 of these patients, blood was collected at diagnosis, prior to any treatments. For 25 patients, blood samples were available at diagnosis and before surgical intervention, allowing longitudinal analysis in the same patient. For 9 patients, blood was collected only after preoperative chemotherapy, before surgical intervention. Circulating IGF2BP3 levels were quantified using a highly specific and sensitive ELISA assay. Plasma samples from healthy donors served as controls. IGF2BP3 plasma levels were correlated with IGF2BP3 tumor tissue expression, established clinical risk factors, and cumulative incidence of relapse using univariable and multivariable analyses. Plasma IGF2BP3 levels were significantly elevated in patients with EWS compared with healthy controls, with a subset of patients (22/51, 43.2%) exhibiting clinically relevant concentrations. Circulating IGF2BP3 levels reflected tumor expression of the molecule and provided additional prognostic information beyond standard clinicopathologic features. The prognostic impact of circulating IGF2BP3 was primarily observed in patients with localized disease, in whom elevated levels were identified as a significant adverse prognostic factor for disease-specific survival (hazard ratio, 10.63; 95% CI, 1.27-88.62; P = 0.029). Longitudinal monitoring demonstrated that persistence of IGF2BP3 in plasma after induction chemotherapy was a strong predictor of poor clinical outcomes. Circulating IGF2BP3 represents a valuable biomarker for early risk stratification in EWS, particularly in patients with localized disease. Although this is single-marker assay, the expression of the molecule may impact on the fate of many mRNAs. We present an accurate, simple, cost-effective and easy clinical applicable tool to support risk-adapted therapeutic interventions. The limited number of employed patients warrants the need of larger cohorts for validation.

Humans↗

PubMed2025

Proteins that recognize unique features of U7 snRNA and may substitute for Gemin5 in the assembly of U7-specific Sm ring.

U7 snRNA is a 60 nucleotide component of U7 snRNP, a multisubunit endonuclease that cleaves precursors of metazoan replication-dependent histone mRNAs at the 3' end, hence generating mature histone mRNAs. The Sm site in U7 snRNA differs from the Sm site in spliceosomal snRNAs and promotes the assembly of a unique Sm ring containing Lsm10 and Lsm11 instead of the spliceosomal SmD1 and SmD2 proteins. While the spliceosomal-type Sm site is recognized by Gemin5, a subunit of the SMN complex, the identity of the protein that recognizes the unusual Sm site of U7 snRNA resulting in the incorporation of Lsm10 and Lsm11 has not been determined. Here, we looked for proteins in mammalian extracts that interact with U7 snRNA and identified polypyrimidine tract-binding protein 1 (PTBP1) and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) as two major proteins with this characteristic. The binding of PTBP1 and IGF2BP3 to U7 snRNA depends on its unique Sm site and on the upstream CUCUUU motif that base-pairs with histone pre-mRNAs and defines substrate specificity of U7 snRNP. Among proteins that bind U7 snRNA, we also identified hnRNP A1. We show that hnRNP A1 interacts with the SMN protein of the SMN complex, a likely prerequisite for the protein that substitutes for Gemin5 in the assembly of U7-specific Sm ring. Our results also suggest a mechanism that explains why Gemin5 does not bind the Sm site of U7 snRNA.

RNA, Small Nuclear↗

PubMed2026

Development of m6A-related prognostic models for survival in lung squamous cell carcinoma with different PD-L1 expression levels.

BACKGROUND: Programmed death-ligand 1 (PD-L1) is widely used in the clinical context of immune checkpoint inhibitor therapy, but its relationship with N6-methyladenosine (m6A) RNA methylation in lung squamous cell carcinoma (LUSC) has not been well defined. This study aimed to investigate the association between PD-L1 messenger RNA (mRNA) expression and m6A regulator expression patterns and to develop exploratory m6A-based prognostic models in LUSC. METHODS: Transcriptome data from 502 patients with LUSC were obtained from The Cancer Genome Atlas (TCGA). Patients were divided into PD-L1 high-expression (PHE) and PD-L1 low-expression (PLE) groups according to the median PD-L1 mRNA level. Differential expression and correlation analyses were performed for 30 m6A regulators. Transcriptome sequencing data from surgical specimens from 28 Asian patients with LUSC were used for expression-pattern comparison. Principal component analysis (PCA), univariate Cox regression, and least absolute shrinkage and selection operator (LASSO)-Cox regression were used to construct prognostic models in the TCGA cohort. RESULTS: In the TCGA cohort, the main differentially expressed m6A regulators between the two PD-L1 groups were YTHDF2 (P<0.001), IGF2BP3 (P<0.001), and YTHDC2 (P<0.001). In the Asian cohort, ALKBH5 (P=0.008) and ZC3H13 (P=0.03) showed significant differences. LASSO-Cox models were constructed for the overall LUSC cohort and for the PHE and PLE subgroups. The overall model included METTL3, HNRNPC, and CBLL1, with a 5-year time-dependent area under the receiver operating characteristic curve (AUC) of 0.579. The 5-year AUCs were 0.742 in the PHE subgroup and 0.652 in the PLE subgroup. The risk score remained independently associated with prognosis in multivariate Cox analysis. CONCLUSIONS: In LUSC, PD-L1 mRNA status was associated with distinct m6A regulator expression profiles. In the TCGA cohort, the PHE subgroup showed higher expression of CBLL1, G3BP1, IGF2BP3, FMR1, and YTHDC2, but lower expression of VIRMA, YTHDF2, and PRRC2A compared with the PLE subgroup. In the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (CICAMS) cohort, ALKBH5 and ZC3H13 were more highly expressed in the PHE subgroup. Moreover, m6A-based risk models were associated with survival outcomes, with significant prognostic separation in the overall TCGA cohort and the PHE subgroup, whereas the PLE subgroup showed a weaker survival separation.

Lung squamous cell carcinoma (LUSC)↗

PubMed2026

Programmed ribosomal frameshifting triggers translational stress to promote viral replication.

Programmed ribosomal frameshifting (PRF) is a conserved viral strategy for expressing polyproteins from compact genomes. Although PRF is traditionally viewed as a structural mechanism, here we show that it functions as a regulatory signal that rewires host translation in favor of viral replication. A minimal SARS-CoV-2 PRF element is sufficient to activate the GCN2 arm of the integrated stress response (ISR) independently of the canonical ISR sensor ZAKα. This activation serves as a temporal switch during early infection to shut off host translation and is required for viral propagation in cells and human airway organoids. Proteomic and genetic screens identify DRG1 and IGF2BP3 as key mediators of PRF-induced GCN2 activation. We further show that this PRF-GCN2 axis is conserved in human immunodeficiency virus (HIV)-1 and West Nile virus, highlighting its broad relevance across RNA viruses. These findings reveal a sophisticated mechanism of viral translational control, highlighting PRF as a stress-inducing module that enhances viral replication.

RNA virus↗

PubMed2026

Genetic variants in IGF2BP family genes are associated with glioma risk in Chinese children.

BACKGROUND: Glioma is a highly prevalent malignant tumor of the central nervous system in children and is driven by complex genetic and environmental factors. IGF2BP family genes (IGF2BP1, IGF2BP2, and IGF2BP3) encode critical RNA epigenetic "readers" that participate in posttranscriptional gene regulation and modulate various cellular processes. However, the contributions of these gene variants to glioma risk remain unclear. METHODS: A multicenter case-control study was conducted, enrolling 360 patients with glioma and 547 cancer-free controls. Genotyping of 11 potentially functional polymorphisms within IGF2BP family genes was performed using the TaqMan assay. Unconditional logistic regression models were employed to estimate odds ratios and 95% confidence intervals. Furthermore, expression quantitative trait loci (eQTL) and The Cancer Genome Atlas (TCGA) clinical database analyses were conducted to investigate the potential regulatory mechanisms and clinical significance of the identified variants. RESULTS: We found that the IGF2BP1 rs2270575 polymorphism was significantly associated with a decreased risk of glioma. Conversely, the IGF2BP2 rs17289925 and rs7646419 polymorphisms were linked to increased glioma risk. Stratification and cumulative effect analyses revealed that harboring multiple risk genotypes of IGF2BP1 or IGF2BP2 substantially increased glioma susceptibility. This cumulative risk was especially notable among males, younger children (< 60 months), and patients diagnosed with early-stage (I + II) tumors. Additionally, eQTL and TCGA analyses revealed that the rs2270575 and rs7646419 alleles correlated significantly with altered mRNA expression levels of CALCOCO2 and AC099661.1 (ENSG00000286086), respectively, which further correlated with favorable molecular subtypes (IDH mutation status) and WHO tumor grades. CONCLUSION: Genetic polymorphisms within IGF2BP family genes significantly modulate pediatric glioma susceptibility and have cumulative, subtype-specific, and age-dependent effects; thus, these genes may serve as promising noninvasive biomarkers for early risk stratification of childhood glioma.

Adolescent↗