m⁶A‐Dependent Modulation via IGF2BP3/MCM5/Notch Axis Promotes Partial EMT and LUAD Metastasis

Advanced Science, Journal Year: 2023, Volume and Issue: 10(20)

Published: May 12, 2023

The importance of mRNA N6-methyladenosine (m6 A) modification during tumor metastasis is controversial as it plays distinct roles in different biological contexts. Moreover, how cancer cell plasticity shaped by m6 A interesting but remains uncharacterized. Here, this work shows that reader insulin like growth factor 2 binding protein 3 (IGF2BP3) remarkably upregulated metastatic lung adenocarcinoma (LUAD) and indicates worse prognosis patients. Interestingly, IGF2BP3 induces partial epithelial-mesenchymal-transition (EMT) confers LUAD cells to metastasize through A-dependent overactivation Notch signaling. Mechanistically, recognized A-modified minichromosome maintenance complex component (MCM5) mRNAs prolong stability them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1-mediated deacetylation Notch1 intracellular domain (NICD1), stabilizes NICD1 contributes IGF2BP3-mediated cellular plasticity. Notably, a tight correlation the IGF2BP3/MCM5/Notch axis evidenced clinical specimens. Therefore, study elucidates critical role on fostering via above axis, providing potential targets for LUAD.

Language: Английский

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Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 14, 2024

Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the tolerant persister (DTP) cell phenotype is attracting more and attention giving a predominant non-genetic role in cancer therapy The DTP characterized by quiescent or slow-cell-cycle reversible state subpopulation inert specialization to stimuli, which tolerates exposure some extent through interaction multiple underlying recovering growth proliferation after withdrawal, ultimately leading treatment resistance recurrence. Therefore, targeting cells anticipated provide new opportunities for patients, although our current knowledge these remains limited. In this review, we comprehensive overview formation characteristics cells, investigate potential drugs (including preclinical drugs, novel use old natural products) based on different medicine models, discuss necessity feasibility anti-DTP therapy, related application forms, future issues that will need be addressed advance emerging field towards clinical applications. Nonetheless, understanding functions may enable us develop effective improve outcomes patients.

Language: Английский

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NELL2 suppresses epithelial-mesenchymal transition and induces ferroptosis via notch signaling pathway in HCC

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 25, 2025

Although various malignant tumors have been associated with the aberrant expression of Neural Epidermal Growth Factor-Like 2 (NELL2), its involvement in hepatocellular carcinoma (HCC) has not previously documented. In this study, NELL2, recognized as a crucial tumor-suppressor gene, was found to be infrequently expressed HCC. vitro experiments demonstrated that overexpression NELL2 significantly inhibited proliferation, migration, and invasion liver cancer cells, whereas suppression markedly enhanced these oncogenic properties. Further investigation revealed impedes epithelial-mesenchymal transition (EMT) via Notch signaling pathway. Inhibition pathway reversed increased tumor observed following downregulation expression. Notably, gene enrichment analysis studies indicated effectively induced ferroptosis HCC evidenced by levels cellular malondialdehyde (MDA), iron, Reactive Oxygen Species (ROS), alongside decreased glutathione (GSH) levels. The blockade substantially diminished NELL2's capacity induce ferroptosis. summary, our findings suggest modulates inhibit EMT promote Consequently, may serve novel therapeutic target, potentially functioning suppressor

Language: Английский

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Regulatory mechanisms and therapeutic implications of insulin-like growth factor 2 mRNA-binding proteins, the emerging crucial m⁶A regulators of tumors

Theranostics, Journal Year: 2023, Volume and Issue: 13(12), P. 4247 - 4265

Published: Jan. 1, 2023

Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) serve essential biological functions as post-transcriptional performers, participating in the acquisition or maintenance of tumor hallmarks due to their distinct protein structures.Emerging evidence indicates that IGF2BPs belong class III type RNA N 6 -methyladenosine (m A) modification readers, controlling stability, storage, localization, metabolism, and translation multiple vital bioprocesses, particularly tumorigenesis progression.Here, we discuss underlying regulatory mechanisms pathological which act m A readers context pathogenesis multidrug resistance.Furthermore, highlight potential drug targets clinical treatment.Hence, precise novel therapeutic approaches could be uncovered by targeting epigenetic heterogeneity.

Language: Английский

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SLC7A11 inhibits ferroptosis and downregulates PD-L1 levels in lung adenocarcinoma

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 9, 2024

Introduction Lung adenocarcinoma (LUAD) is a prevalent form of lung cancer originating from glandular cells with low survival rates despite recent therapeutic advances due to its diverse and complex nature. Recent evidence suggests link between ferroptosis the effectiveness anti-PD-L1 therapy, potential synergistic effects. Methods Our study comprehensively analyzed expression patterns regulators in LUAD their association prognosis PD-L1 expression. Furthermore, we identified two distinct subtypes through consensus clustering regulators, revealing significant tumor heterogeneity, divergent expression, varying prognoses subtypes. Results Among selected SLC7A11 emerged as an independent prognostic marker for patients exhibited negative correlation Subsequent investigations revealed high population. In vitro experiments demonstrated that overexpression led reduced inhibited A549 cells, underscoring role LUAD. Additionally, pan-cancer analyses indicated immune checkpoint genes across multiple types poor prognoses. Discussion From clinical standpoint, these findings offer foundation identifying optimizing combination strategies enhance inhibitors improve

Language: Английский

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The human 18S rRNA m6A methyltransferase METTL5 promotes tumorigenesis via DEPDC1 in lung squamous cell carcinoma

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 13, 2025

Background N6-Methyladenosine (m6A) is one of the post-transcriptional modifications and abnormal m6A critical for cancer initiation, progression, metastasis in Lung squamous cell carcinoma (LUSC). Ribosomal RNA (rRNA) accounts most total cellular RNA, however, functions molecular mechanisms underlying rRNA LUSC remained largely unclear. Methods High-throughput library screening identifies key regulator METTL5 LUSC. Cell animal experiments were used to identify that promoted tumorigenesis enhance DEP domain containing 1 (DEPDC1) translation via modification. Results We showed N6-methyladenosine methyltransferase was an independent risk factor associated with poor prognosis patients. Notedly, overexpression modification, while knockdown markedly inhibited proliferation migratory ability tumor cells vitro vivo . Mechanistically, m6a increase DEPDC1. Conclusion Our results revealed enhances DEPDC1 contribute prognosis, providing a potential prognostic biomarker therapeutic target

Language: Английский

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The m6A reader IGF2BP3 promotes HCC progression by enhancing MCM10 stability

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 10, 2025

Abnormal N6-methyladenosine (m6A) modifications were associated with the occurrence, development, and metastasis of cancer. However, functions mechanisms m6A regulators in cancer remained largely elusive should be explored. Here, we identified that insulin like growth Factor 2 mRNA binding protein 3 (IGF2BP3) was specifically overexpressed poor prognosis liver hepatocellular carcinoma (HCC). Importantly, IGF2BP3 promoted HCC cells progression an m6A-dependent manner, silencing significantly inhibited proliferation migratory ability tumor vitro vivo. Mechanistically, interacted minichromosomal maintenance complex component (MCM10) mRNAs to prolong stability m6A-modified RNA. Therefore, our findings indicated reader contributed tumorigenesis prognosis, providing a potential prognostic biomarker therapeutic target for HCC.

Language: Английский

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The N6‐methyladenosine reader IGF2BP3 promotes bladder cancer progression through enhancing HSP90AB1 expression

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

N 6 ‐methyladenosine (m A) is the most abundant RNA modification in mammalian cells, and has emerged as an important player tumour development through post‐transcriptional gene regulation. In this study, we found that m A reader protein IGF2BP3 was upregulated modifier bladder cancer proteomic analysis of 17 pairs human tissues adjacent normal tissues, for which expression also positively correlated with higher stage poorer prognosis. vitro vivo assays demonstrated powerful oncogenic function cancer. Further combined analyses RNA‐sequencing, A‐sequencing, RIP (RNA Binding Protein Immunoprecipitation)‐sequencing, well site‐directed mutagenesis RIP‐qPCR identified A‐tagged HSP90AB1 mRNA a direct target IGF2BP3. Mechanistically, assays, clinical sample analysis, modulated modification‐dependent manner, thus activating PI3K/AKT‐signaling pathway, promoting Collectively, our study highlights critical role IGF2BP3‐HSP90AB1‐signaling axis progression, may serve promising therapeutic approach

Language: Английский

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Nomograms Integrating MRI-derived Apparent Diffusion Coefficient and Clinicopathologic Features for Prediction of Axillary Lymph Node Metastasis in Breast Cancer

Radiology Imaging Cancer, Journal Year: 2025, Volume and Issue: 7(2)

Published: March 1, 2025

Three nomogram models combining apparent diffusion coefficient and clinicopathologic features showed good performance in predicting status of pretreatment axillary lymph nodes, nonsentinel the nodes after neoadjuvant chemotherapy treatment patients with breast cancer.

Language: Английский

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Multi-omics pan-cancer analysis reveals the diagnostic and prognostic value of C8orf76, with experimental validation of its impact on lung adenocarcinoma cell proliferation

Frontiers in Genetics, Journal Year: 2025, Volume and Issue: 16

Published: March 26, 2025

Background Chromosome 8 open reading frame 76 (C8orf76) is a nuclear protein-encoding gene, has received limited attention in current study. Multi-omics pan-cancer analysis focused on the diagnosis, prognosis, immune cell infiltration, methylation, and anti-cancer drug sensitivity remains an enigma. The effect of C8orf76 lung adenocarcinoma (LUAD) unknown. Methods by utilizing datasets including UALCAN, TIMER 2.0, Human Protein Atlas (HPA), Cancer Genome (TCGA), Genotype-Tissue Expression (GTEx), cBioPortal, Gene Profiling Interactive Analysis (GEPIA), OncoDB, MethSurv datasets, were conducted to analyze across 33 cancer types. Furthermore, differential R packages uesd for in-depth C8orf76. correlation between expression diagnostic, genetic alteration, mRNA modification, DNA lncRNA-miRNA-C8orf76 regulatory network, anti-tumor drugs response explored evaluate potential roles Most importantly, experiments quantitative polymerase chain reaction (qPCR), RNA interference (RNAi), Western blotting (WB), Edu staining, performed experimental verification. Results It was noted that markedly elevated multiple tumor Moreover, showed as diagnostic prognostic biomarker. Besides, it confirmed related infiltration cells. network established study LUAD. Experimental validation LUAD A549 cells demonstrated knockdown significantly inhibited proliferation Conclusion present first report multi-omics predicts promising target immunology, chemotherapy, highlighting its influence with validation.

Language: Английский

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