Smoking‐Induced M2‐TAMs, via circEML4 in EVs, Promote the Progression of NSCLC through ALKBH5‐Regulated m6A Modification of SOCS2 in NSCLC Cells

Advanced Science, Journal Year: 2023, Volume and Issue: 10(22)

Published: May 28, 2023

Abstract Lung cancer is a commonly diagnosed disease worldwide, with non‐small cell lung cancers (NSCLCs) accounting for ≈ 85% of cases. Cigarette smoke an environmental exposure promoting progression NSCLC, but its role poorly understood. This study reports that smoking‐induced accumulation M2‐type tumor‐associated macrophages (M2‐TAMs) surrounding NSCLC tissues promotes malignancy. Specifically, extracellular vesicles (EVs) from cigarette extract (CSE)‐induced M2 promoted malignancy cells in vitro and vivo. circEML4 EVs CSE‐induced transported to cells, where it reduced the distribution ALKBH5 nucleus by interacting Human AlkB homolog H5 (ALKBH5), resulting elevated N6‐methyladenosine (m6A) modifications. m6A‐seq RNA‐seq revealed suppressor cytokine signaling 2 (SOCS2)‐mediated activation Janus kinase‐signal transducer activator transcription (JAK‐STAT) pathway regulating m6A modification SOCS2 via ALKBH5. Down‐regulation reversed EVs‐enhanced tumorigenicity metastasis cells. Furthermore, this found smoking patients showed increase circEML4‐positive M2‐TAMs. These results indicate M2‐TAMs promote through ALKBH5‐regulated SOCS2. also reveals TAMs acts as diagnostic biomarker especially history.

Language: Английский

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Multi-stage mechanisms of tumor metastasis and therapeutic strategies

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

Published: Oct. 11, 2024

The cascade of metastasis in tumor cells, exhibiting organ-specific tendencies, may occur at numerous phases the disease and progress under intense evolutionary pressures. Organ-specific relies on formation pre-metastatic niche (PMN), with diverse cell types complex interactions contributing to this concept, adding a new dimension traditional cascade. Prior metastatic dissemination, as orchestrators PMN formation, primary tumor-derived extracellular vesicles prepare fertile microenvironment for settlement colonization circulating cells distant secondary sites, significantly impacting cancer progression outcomes. Obviously, solely intervening sites passively after macrometastasis is often insufficient. Early prediction holistic, macro-level control represent future directions therapy. This review emphasizes dynamic intricate systematic alterations that progresses, illustrates immunological landscape creation, deepens understanding treatment modalities pertinent metastasis, thereby identifying some prognostic predictive biomarkers favorable early predict occurrence design appropriate combinations.

Language: Английский

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The potential role of circular RNAs -regulated PI3K signaling in non-small cell lung cancer: Molecular insights and clinical perspective

Pathology - Research and Practice, Journal Year: 2024, Volume and Issue: 257, P. 155316 - 155316

Published: April 16, 2024

Language: Английский

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SIRT5‐Mediated Desuccinylation of RAB7A Protects Against Cadmium‐Induced Alzheimer's Disease‐Like Pathology by Restoring Autophagic Flux

Advanced Science, Journal Year: 2024, Volume and Issue: 11(30)

Published: June 5, 2024

Cadmium (Cd) is a neurotoxic contaminant that induces cognitive decline similar to observed in Alzheimer's disease (AD). Autophagic flux dysfunction attributed the pathogenesis of AD, and this study aimed investigate effect autophagy on environmental Cd-induced AD progression underlying mechanism. Here, Cd exposure inhibited autophagosome-lysosome fusion impaired lysosomal function, leading defects autophagic clearance then APP accumulation nerve cell death. Proteomic analysis coupled with Ingenuity Pathway Analysis (IPA) identified SIRT5 as an essential molecular target Cd-impaired flux. Mechanistically, hampered expression SIRT5, thus increasing succinylation RAB7A at lysine 31 inhibiting activity, which contributed blockade. Importantly, overexpression led restoration blockade, alleviation Aβ deposition memory deficits, desuccinylation Cd-exposed FAD

Language: Английский

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ALKBH5 acts a tumor-suppressive biomarker and is associated with immunotherapy response in hepatocellular carcinoma

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

Published: Jan. 2, 2025

As immune-checkpoint inhibitors (ICIs) therapy has made great strides in hepatocellular carcinoma (HCC) treatment, improving patient response to this strategy become the main focus of research. Accumulating evidence shown that m6A methylation plays a crucial role tumorigenesis and progression HCC, while precise impact demethylase ALKBH5 on tumor immune microenvironment (TIME) HCC remains poorly defined. The clinical significance TIM3 were evaluated human tissues. biological function was analyzed vitro vivo. molecular subtypes identified based key ALKBH5-regulated methylation-related genes (MRGs). differences survival, features, TIME immunotherapy between these two then evaluated. regulation detected by qPCR, western blotting MeRIP. downregulated associated with worse prognosis. inhibited proliferation migration activities cells subtype high expression MRGs characterized immunosuppression phenotypes ICIs. Moreover, as target ALKBH5. Upregulated level negatively correlated survival HCC. results study suggest is an important regulator progression. exerts its influence targeting This work provides new insight into correlation modification ICI response, which may help provide therapeutic benefits patients.

Language: Английский

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m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia

Advanced Science, Journal Year: 2023, Volume and Issue: 10(34)

Published: Oct. 11, 2023

Abstract Chronic lymphocytic leukemia (CLL) is a hematological malignancy with high metabolic heterogeneity. N6‐methyladenosine (m6A) modification plays an important role in metabolism through regulating circular RNAs (circRNAs). However, the underlying mechanism not yet fully understood CLL. Herein, m6A scoring system and m6A‐related circRNA prognostic signature are established, circTET2 as potential biomarker for CLL identified. The level of found to affect transport out nucleus. By interacting RNA‐binding protein (RBP) heterogeneous nuclear ribonucleoprotein C (HNRNPC), regulates stability CPT1A participates lipid proliferation cells mTORC1 signaling pathway. mTOR inhibitor dactolisib FAO perhexiline exert synergistic effect on cells. In addition, biogenesis can be affected by splicing process RBPs RBMX YTHDC1. CP028, inhibitor, modulates expression shows pronounced inhibitory effects. summary, modulation cell This study demonstrates clinical value indicator well provides novel insights targeting treatment

Language: Английский

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Mechanistic studies of tumor-associated macrophage immunotherapy

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

Published: Sept. 30, 2024

Tumor-associated macrophages (TAMs) are present in the tumor microenvironment and can polarize into subtypes with different functions characteristics response to stimuli, classifying them anti-tumorigenic M1-type pro-tumorigenic M2-type. The inhibit growth through release of pro-inflammatory cytokines, whereas M2-type contribute progression promotion proliferation, angiogenesis metastasis. Due duality macrophage effects on tumors, TAMs have been a hot topic research. In this paper, heterogeneity plasticity TAMs, interactions between other immune cells, tumors reviewed, therapeutic strategies for summarized discussed. These encompass methods approaches recruitment deplete modulate polarization TAMs. studies help deeply understand mechanism TAMs-tumor interaction provide reference combination therapy tumors.

Language: Английский

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Insights into the m6A demethylases FTO and ALKBH5 : structural, biological function, and inhibitor development

Cell & Bioscience, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 27, 2024

Abstract N6-methyladenosine (m 6 A) is dynamically regulated by methyltransferases (termed “writers”) and demethylases (referred to as “erasers”), facilitating a reversible modulation. Changes in m A levels significantly influence cellular functions, such RNA export from the nucleus, mRNA metabolism, protein synthesis, splicing. They are intricately associated with spectrum of pathologies. Moreover, dysregulation modulation has emerged promising therapeutic target across many diseases. plays pivotal role controlling vital downstream molecules critical biological pathways, contributing pathogenesis evolution numerous conditions. This review provides an overview demethylases, explicitly detailing structural functional characteristics FTO ALKBH5. Additionally, we explore their distinct involvement various diseases, examine factors regulating expression, discuss progress inhibitor development.

Language: Английский

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Targeting MS4A4A: A novel pathway to improve immunotherapy responses in glioblastoma

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(7)

Published: July 1, 2024

Abstract Introduction Glioblastoma (GBM) remains a challenging brain tumor to treat, with limited response PD‐1 immunotherapy due tumor‐associated macrophages (TAMs), specifically the M2 phenotype. This study explores potential of MS4A4A (membrane spanning four domains, subfamily A, member 4A) inhibition in driving macrophage polarization toward M1 phenotype via ferroptosis pathway enhance effectiveness GBM. Methods Single‐cell RNA sequencing and spatial transcriptomic analyses were employed characterize expression In vitro studies utilizing TAM cultures, flow cytometry, western blot validations conducted assess impact on immune microenvironment polarization. vivo models, including subcutaneous orthotopic transplantation mice, utilized evaluate effects knockout combined checkpoint blockade (ICB) therapy growth immunotherapy. Results Distinct subsets GBM‐associated identified, distribution tissue elucidated. experiments demonstrated that inhibiting combining ICB effectively inhibited growth, reshaped by reducing infiltration enhancing CD8 + T‐cell infiltration, ultimately leading complete eradication. Conclusion shows promise converting ferroptosis, decreasing M2‐TAM GBM These findings offer novel approach developing more effective immunotherapeutic strategies for

Language: Английский

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M6A Demethylase ALKBH5 in Human Diseases: From Structure to Mechanisms

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 157 - 157

Published: Jan. 21, 2025

N6-methyladenosine (m6A) is the most abundant, dynamically reversible, and evolutionarily conserved internal chemical modification in eukaryotic RNA. It emerging as critical for regulating gene expression at post-transcriptional level by affecting RNA metabolism through, example, pre-mRNA processing, mRNA decay, translation. ALKBH5 has recently been identified an endogenous m6A demethylase implicated a multitude of biological processes. This review provides overview structural functional characteristics involvement diverse human diseases, including metabolic, immune, reproductive, nervous system disorders, well development inhibitors. In summation, this highlights current understanding structure, functions, detailed mechanisms various physiological pathological processes valuable insights clinical applications foundational research within related fields.

Language: Английский

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