Oncometabolite D-2HG drives tumor metastasis and protumoral macrophage polarization by targeting FTO/m6A/ANGPTL4/integrin axis in triple-negative breast cancer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: Feb. 6, 2025

Abstract Background D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported diverse effects of D-2HG in pathophysiological processes, yet its role breast cancer remains largely unexplored. Methods We applied advanced biosensor approach to detect levels samples. then investigated biological functions through multiple vitro and vivo assays. A joint MeRIP-seq RNA-seq strategy was used identify target genes regulated by D-2HG-mediated N6-methyladenosine (m 6 A) modification. RNA pull-down assays were further reader that could specifically recognize m modification on angiopoietin like 4 (ANGPTL4) mRNA immunoprecipitation confirm findings. Results found accumulated triple-negative (TNBC), exerting oncogenic both promoting TNBC cell growth metastasis. Mechanistically, enhanced global modifications cells, notably upregulating ANGPTL4 mRNA, which mediated inhibition Fat-mass obesity-associated protein (FTO), resulting increased recognition A-modified YTH binding F1 (YTHDF1), thereby translation ANGPTL4. As a secretory protein, subsequently activated integrin-mediated JAK2/STAT3 signaling cascade cells autocrine signaling. Notably, knockdown or treatment with GLPG1087 (an integrin antagonist) significantly reduced D-2HG-induced proliferation metastasis cells. Additionally, promote macrophage M2 polarization within tumor microenvironment via paracrine signaling, driving progression. The association poor prognosis patients underscores clinical relevance. Conclusions Our study unveils previously unrecognized for progression targeting D-2HG/FTO/m A/ANGPTL4/integrin axis can serve as promising therapeutic patients.

Language: Английский

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LRPPRC promotes glycolysis by stabilising LDHA mRNA and its knockdown plus glutamine inhibitor induces synthetic lethality via m⁶A modification in triple‐negative breast cancer

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(2)

Published: Feb. 1, 2024

Targeted therapy for triple-negative breast cancer (TNBC) remains a challenge. N6-methyladenosine (m

Language: Английский

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Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: June 8, 2024

Abstract Background Breast cancer is the most common malignant tumor, and metastasis remains major cause of poor prognosis. Glucose metabolic reprogramming one prominent hallmarks in cancer, providing nutrients energy to support dramatically elevated tumor growth metastasis. Nevertheless, potential mechanistic links between glycolysis breast progression have not been thoroughly elucidated. Methods RNA-seq analysis was used identify glucose metabolism-related circRNAs. The expression circSIPA1L3 tissues serum examined by qRT-PCR, further assessed its diagnostic value. We also evaluated prognostic analyzing a cohort 238 patients. Gain- loss-of-function experiments, transcriptomic analysis, molecular biology experiments were conducted explore biological function regulatory mechanism circSIPA1L3. Results Using identified as critical mediator responsible for adaption upon stress. revealed that exerted stimulative effect on glycolysis, which could be transported exosomes facilitated behaviors among cells. Significantly, lactate secretion caused circSIPA1L3-mediated enhancement promoted recruitment associated macrophage their tumor-promoting roles. Mechanistically, EIF4A3 induced cyclization cytoplasmic export circSIPA1L3, inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing UPS7-IGF2BP3 interaction. Furthermore, increased mRNA stability carrier SLC16A1 intake enhancer RAB11A either strengthening interaction with or sponging miR-665, leading enhanced glycolytic metabolism. Clinically, indicated unfavorable prognosis base Moreover, highly expressed patients exhibited high value Conclusions Our study highlights oncogenic role mediating metabolism, might serve promising biomarker therapeutic target cancer.

Language: Английский

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miR-9-5p/HMMR regulates the tumorigenesis and progression of clear cell renal cell carcinoma through EMT and JAK1/STAT1 signaling pathway

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 9, 2025

The most common malignant type of kidney cancer is clear cell renal carcinoma (ccRCC). expression levels hyaluronan-mediated motility receptor (HMMR) in many tumor types are significantly elevated. HMMR closely associated with tumor-related progression, treatment resistance, and poor prognosis, has yet to be fully investigated terms its patterns molecular mechanisms action ccRCC. Further research imperative elucidate these aspects. We used Cancer Genome Atlas (TCGA) database preliminarily investigate function ccRCC the data for 19 samples from NCBI GEO (GSE207493) single-cell analysis. assessed differential level between cancerous tissues their matched non-tumor tissues. Subsequently, a series vivo vitro experiments were designed biological ccRCC, including Transwell assays, CCK-8 clone formation assays subcutaneous xenograft nude mice. Through bioinformatics analysis, we identified potential microRNAs (miRNAs) that may regulate HMMR, as well possible signaling pathways involved. Finally, conducted cellular functional validate our hypotheses regarding axis. was up-regulated patients, elevated showed strong correlation progression adverse prognoses patients. Knocking down inhibited proliferative migratory abilities cells, while overexpression amplified oncogenic properties. In mice model, reduced proliferation vivo. Furthermore, an upstream transcriptional regulator, miR-9-5p, effectively downregulated thus impeded cells migration. might influence growth via Epithelial-Mesenchymal Transition (EMT) pathway Janus Kinase 1/Signal Transducer Activator Transcription 1 (JAK1/STAT1) pathway. overexpressed there significant link high patient prognosis. Specifically, could targeted by miR-9-5p modulate tumorigenesis through both EMT JAK1/STAT1

Language: Английский

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Crosstalk between lncRNAs and Wnt/β-catenin signaling pathways in lung cancers: From cancer progression to therapeutic response

Non-coding RNA Research, Journal Year: 2024, Volume and Issue: 9(3), P. 667 - 677

Published: March 14, 2024

Lung cancer (LC) is considered to have the highest mortality rate around world. Because there are no early diagnostic signs or efficient clinical alternatives, distal metastasis and increasing numbers of recurrences a challenge in management LC. Long non-coding RNAs (lncRNAs) recently been recognized as critical regulator involved progression treatment response The Wnt/β-catenin pathway has shown influence LC occurrence progress. Therefore, discovering connections between Wnt signaling lncRNAs may offer new therapeutic targets for improving management. In this review, purpose article present possible approaches by reviewing particular relationships, key processes, molecules associated beginning development

Language: Английский

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CCAAT enhancer binding protein delta activates vesicle associated membrane protein 3 transcription to enhance chemoresistance and extracellular PD-L1 expression in triple-negative breast cancer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: April 16, 2024

Abstract Background Chemoresistance and immunosuppression are two major obstacles in the current anti-cancer treatments. This study investigates involvements of a CCAAT enhancer binding protein delta (CEBPD)/vesicle associated membrane 3 (VAMP3) axis paclitaxel (PTX) resistance immune evasion triple-negative breast cancer (TNBC). Methods PTX resistance-related genes were screened by bioinformatics. CEBPD VAMP3 expression clinical TNBC samples was examined immunohistochemistry. Three PTX-resistant cell lines (MDA-MB-231/PTX, MDA-MB-468/PTX MDA-MB-453/PTX) generated, their drug analyzed. Autophagy cells analyzed immunofluorescence staining. Interaction between promoter identified immunoprecipitation luciferase assays. The extracellular programmed death-ligand 1 (PD-L1) detected. Extracellular vesicles (EVs) from isolated to examine effects on CD8 + T exhaustion. Results upregulated chemo-resistant tissue cells. downregulation enhanced sensitivity However, further upregulation restored resistance, which likely due activation autophagy, as autophagy antagonist chloroquine found bind activate its transcription. CEBPD/VAMP3 also increased PD-L1 conditioned medium cell-derived EVs exhaustion co-cultured Conclusion provides novel evidence that plays key role enhancing across various subtypes through VAMP3-mediated activation. Additionally, increases level, delivered EVs, suppress cell-mediated anti-tumor response. These significant observations may provide new insights into treatment TNBC, suggesting promising targets overcome resistance.

Language: Английский

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Single‐cell transcriptome sequencing reveals SPP1‐CD44‐mediated macrophage–tumor cell interactions drive chemoresistance in TNBC

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(13)

Published: July 1, 2024

Abstract Triple‐negative breast cancer (TNBC) is often considered one of the most aggressive subtypes cancer, characterized by a high recurrence rate and low overall survival (OS). It notorious for posing challenges related to drug resistance. While there has been progress in TNBC research, mechanisms underlying chemotherapy resistance remain largely elusive. We collect single‐cell RNA sequencing (scRNA‐seq) data from five patients susceptible resistant cases. Comprehensive analyses involving copy number variation (CNV), pseudotime trajectory, cell–cell interactions, pseudospace analysis, as well transcription factor functional enrichment are conducted specifically on macrophages malignant cells. Furthermore, we performed validation experiments clinical samples using multiplex immunofluorescence. identified subset SPP1 + that secrete signals interacting with CD44 cell surfaces, potentially activating PDE3B pathway within cells via integrin pathway, leading The abnormally enhanced signal between may serve promoting patients. Therefore, could therapeutic target reduce

Language: Английский

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Exercise-downregulated CD300E acted as a negative prognostic implication and tumor-promoted role in pan-cancer

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

Published: July 31, 2024

Breast cancer ranks as one of the most prevalent malignancies among women globally, with increasing incidence rates. Physical activity, particularly exercise, has emerged a potentially significant modifier prognosis, influencing tumor biology and patient outcomes.

Language: Английский

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MiR-3682-3p promotes esophageal cancer progression by targeting FHL1 and activating the Wnt/β-catenin signaling pathway

Cellular Signalling, Journal Year: 2024, Volume and Issue: 119, P. 111155 - 111155

Published: March 31, 2024

Language: Английский

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Autophagy‐related CMTM6 promotes glioblastoma progression by activating Wnt/β‐catenin pathway and acts as an onco‐immunological biomarker

The Journal of Gene Medicine, Journal Year: 2024, Volume and Issue: 26(5)

Published: April 30, 2024

Abstract Background Glioblastoma multiforme (GBM) is identified as one of the most prevalent and malignant brain tumors, characterized by poor treatment outcomes a limited prognosis. CMTM6, membrane protein, has been found to upregulate expression programmed cell death 1 ligand protein (PD‐L1) acts an immune checkpoint inhibitor inhibiting protein/PD‐L1 signaling pathway. Recent research demonstrated high CMTM6 in GBM, suggesting its potential role influencing pathogenesis progression well association with infiltration tumor microenvironment. However, underlying mechanism GBM requires further investigation. Methods Data from cancer patients The Cancer Genome Atlas, Gene Expression Omnibus Chinese Glioma Atlas cohorts were consolidated for current study. Through multi‐omics analysis, study systematically examined profile epigenetic modifications, prognostic significance, biological functions, mechanisms action alterations Additionally, investigated lines normal cells using reverse transcription PCR western blot analysis. impact on proliferation, migration invasion was evaluated combination counting kit‐8 assay, clone formation 5‐ethynyl‐2′‐deoxyuridine incorporation wound healing assay Transwell assay. In order explore Wnt/ β ‐catenin pathway autophagy‐related genes verified through Results highly expressed multiple particularly GBM. shown be valuable diagnostic biomarker various bioinformatics approaches. plays pivotal cancer, specifically modulating processes such DNA methyltransferase expression, RNA modification, copy number variation, genomic heterogeneity, stemness methylation. findings experiment indicate significant correlation between elevated invasion, autophagy cells, key roles mediated Furthermore, implicated closely linked inhibitors modulators, within context High levels also enhance responsiveness radiotherapy chemotherapy, thereby offering insights guiding strategies Conclusions Autophagy‐related types especially it can regulate capable being used target diagnosis, selection prognosis

Language: Английский

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