ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner

Molecular Cancer, Год журнала: 2025, Номер 24(1)

Опубликована: Янв. 15, 2025

The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role tumorigenesis and cancer progression. However, the detailed biological functions underlying mechanisms of m6A regulation gastric (GC) are poorly understood. Our research revealed that demethylase ALKBH5 was markedly downregulated GC tissues, which associated with poor patient prognosis. Functional studies demonstrated suppressing expression enhanced cell proliferation, migration, invasion. Mechanistically, removed modifications from 5' uncapped polyadenylated transcripts (UPTs) WRAP53. This demethylation decreased WRAP53 stability translation efficiency. lower level disrupts interaction between USP6 RALBP1 protein, promoting degradation thereby PI3K/Akt/mTOR signaling cascade, ultimately attenuating progression GC. These findings highlight pivotal ALKBH5-mediated inhibiting potential promising biomarker therapeutic target for intervention.

Язык: Английский

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Single‐cell RNA sequencing elucidated the landscape of breast cancer brain metastases and identified ILF2 as a potential therapeutic target

Cell Proliferation, Год журнала: 2024, Номер 57(11)

Опубликована: Июнь 29, 2024

Abstract Distant metastasis remains the primary cause of morbidity in patients with breast cancer. Hence, development more efficacious strategies and exploration potential targets for metastatic cancer are urgently needed. The data six brain metastases (BCBrM) from two centres were collected, a comprehensive landscape entire tumour ecosystem was generated through utilisation single‐cell RNA sequencing. We utilised Monocle2 CellChat algorithms to investigate interrelationships among each subcluster. In addition, multiple signatures collected evaluate key components subclusters multi‐omics methodologies. Finally, we elucidated common expression programs malignant cells, experiments conducted vitro vivo determine functions interleukin enhancer‐binding factor 2 ( ILF2 ), which is gene module, BCBrM progression. found that major cell type exhibited diverse characteristics. Besides, our study indicated specifically associated BCBrM, experimental validations further demonstrated deficiency hindered Our offers novel perspectives on heterogeneity suggests could serve as promising biomarker or therapeutic target BCBrM.

Язык: Английский

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circLIFR-007 reduces liver metastasis via promoting hnRNPA1 nuclear export and YAP phosphorylation in breast cancer

Cancer Letters, Год журнала: 2024, Номер 592, С. 216907 - 216907

Опубликована: Апрель 27, 2024

Язык: Английский

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RNA modification gene WDR4 facilitates tumor progression and immunotherapy resistance in breast cancer

Journal of Advanced Research, Год журнала: 2024, Номер unknown

Опубликована: Июль 1, 2024

Growing interest toward RNA modification in cancer has inspired the exploration of gene sets related to multiple modifications. However, a comprehensive elucidation clinical value various modifications breast is still lacking. This study aimed provide strategy based on modification-related genes for predicting therapy response and survival outcomes patients. Genes thirteen patterns were integrated establishing nine-gene-containing signature-RMscore. Alterations tumor immune microenvironment featured by different RMscore levels assessed bulk transcriptome, single-cell transcriptome genomics analyses. The biological function key RMscore-related molecules was investigated cellular experiments vitro vivo, using flow cytometry, immunohistochemistry immunofluorescence staining. raised an effective patients after well-rounded investigation genes. With great performance patient prognosis, high proposed this represented suppressive resistance, including adjuvant chemotherapy PD-L1 blockade treatment. As contributor RMscore, inhibition WDR4 impaired progression significantly as well participated regulating cell cycle mTORC1 signaling pathway via m7G modification. Briefly, developed promising tactics achieve prediction probabilities treatment

Язык: 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, Год журнала: 2024, Номер 43(1)

Опубликована: Апрель 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.

Язык: Английский

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A new peptide inhibitor of C1QBP exhibits potent anti‐tumour activity against triple negative breast cancer by impairing mitochondrial function and suppressing homologous recombination repair

Clinical and Translational Medicine, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 1, 2025

Abstract C1QBP exhibits heightened expression across a spectrum of tumours, thereby fostering their proliferation and metastasis, rendering it pivotal therapeutic target. Nevertheless, to date, no pharmacological agents capable directly targeting inducing the degradation have been identified. In this study, we unveiled new peptide, PDBAG1, derived from precursor protein GPD1, employing peptidomics‐based drug screening strategy. PDBAG1 has demonstrated substantial efficacy in suppressing triple‐negative breast cancer (TNBC) both vitro vivo. Its mechanism action involves mitochondrial impairment inhibition oxidative phosphorylation (OXPHOS), achieved through direct binding C1QBP, promoting its ubiquitin‐dependent degradation. Concomitantly, due metabolic adaptability, observed an up‐regulation glycolysis compensate for OXPHOS inhibition. We aberrant phenomenon wherein hypoxia signalling pathway tumour cells exhibited significant activation under normoxic conditions following treatment. Through size‐exclusion chromatography (SEC) isothermal titration calorimetry (ITC) assays, validated that is with K d value 334 nM. Furthermore, inhibits homologous recombination repair proteins facilitates synergism poly‐ADP‐ribose polymerase inhibitors therapy. This underscores ultimately induces insurmountable survival stress multiple mechanisms while concurrently engendering vulnerabilities specific TNBC. Key points The newly discovered peptide first small molecule substance found target degrade demonstrating inhibitory effects potential.

Язык: Английский

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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, Год журнала: 2025, Номер 44(1)

Опубликована: Фев. 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.

Язык: Английский

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ALKBH5, an m6A demethylase, attenuates tumor growth and inhibits metastasis in papillary thyroid carcinoma

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 9, 2025

Язык: Английский

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Metabolic reprogramming and synergistic cytotoxicity of genistein and chemotherapy in human breast cancer cells

Life Sciences, Год журнала: 2025, Номер unknown, С. 123562 - 123562

Опубликована: Март 1, 2025

Язык: Английский

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mRNA‐Lipid Nanoparticle‐Mediated Restoration of PTPN14 Exhibits Antitumor Effects by Overcoming Anoikis Resistance in Triple‐Negative Breast Cancer

Advanced Science, Год журнала: 2024, Номер 11(32)

Опубликована: Июнь 21, 2024

Triple-negative breast cancer (TNBC) poses a challenging prognosis due to early metastasis driven by anoikis resistance. Identifying crucial regulators overcome this resistance is vital for improving patient outcomes. In study, genome-wide CRISPR/Cas9 knockout screen in TNBC cells has identified tyrosine-protein phosphatase nonreceptor type 14 (PTPN14) as key regulator of PTPN14 expression shown progressive decrease from normal tissue metastatic tumors. Overexpressing induced and inhibited cell proliferation cells, while human are unaffected. Mechanistically, factor dephosphorylating antiestrogen 3, novel substrate, leading the subsequent inhibition PI3K/AKT ERK signaling pathways. Local delivery vitro transcribed mRNA encapsulated lipid nanoparticles mouse model effectively tumor growth metastasis, prolonging survival. The study underscores potential therapeutic target TNBC, with strategy based on demonstrating clinical application prospects alleviating burden both primary tumors disease.

Язык: Английский

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