Dysregulation of transposable elements and PIWI-interacting RNAs in myelodysplastic neoplasms

Biomarker Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 23, 2025

Abstract Background Myelodysplastic neoplasms (MDS) are heterogeneous hematopoietic disorders characterized by ineffective hematopoiesis and genome instability. Mobilization of transposable elements (TEs) is an important source instability leading to oncogenesis, whereas small PIWI-interacting RNAs (piRNAs) act as cellular suppressors TEs. However, the roles TEs piRNAs in MDS remain unclear. Methods In this study, we examined TE piRNA expression through parallel RNA sequencing CD34+ stem cells from patients. Results Comparative analysis between control samples revealed several significantly dysregulated molecules. significant differences were observed lower-risk (LR-MDS) higher-risk (HR-MDS) samples. HR-MDS, found inverse correlation decreased levels increased these associated with patient outcomes. Importantly, upregulation PIWIL2 , which encodes a key factor pathway, independently predicted poor prognosis patients, underscoring its potential valuable disease marker. Furthermore, pathway data that dysregulation TE‒piRNA axis linked suppression processes related energy metabolism, cell cycle, immune response, suggesting disruptions affect activity. Conclusions Our findings demonstrate HR-MDS highlighting their role progression indicating level promising molecular marker for prognosis. Graphical

Language: Английский

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HCV 5-Methylcytosine Enhances Viral RNA Replication through Interaction with m5C Reader YBX1

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(7), P. 1648 - 1660

Published: July 2, 2024

Hepatitis C virus (HCV) is a positive-stranded RNA that mainly causes chronic hepatitis, cirrhosis and hepatocellular carcinoma. Recently we confirmed m5C modifications within NS5A gene of HCV genome. However, the roles modification its interaction with host proteins in regulating HCV's life cycle, remain unexplored. Here, demonstrate infection enhances expression reader YBX1 through transcription factor MAX. acts as an reader, recognizing m5C-modified C7525 site genome significantly enhancing stability. This m5C-modification also required for colocalization lipid droplets Core protein. Moreover, facilitates replication, well viral assembly/budding. The tryptophan residue at position 65 (W65) critical these functions. Knockout or application inhibitor SU056 suppresses replication protein translation. To our knowledge, this first report demonstrating between methylation replication. Therefore, hepatic-YBX1 knockdown holds promise potential host-directed strategy therapy.

Language: Английский

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SENP1-mediated deSUMOylation of YBX1 promotes colorectal cancer development through the SENP1-YBX1-AKT signaling axis

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

Published: Feb. 23, 2025

Language: Английский

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CircPRKCA facilitates esophageal squamous cell carcinoma metastasis via m5C-dependent CSF2 mRNA stabilization

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

Published: April 1, 2025

Esophageal squamous cell carcinoma (ESCC) is a serious invasive malignancy with an ambiguous etiology. Evidence indicates that circular RNA (circRNA) significantly involved in the regulatory processes associated cancer development. Nevertheless, specific molecular mechanisms through which circRNA facilitates progression of ESCC are still largely undefined. Here, we identified expression hsa_circ_0007580 (designated circPRKCA) was markedly elevated ESCC. Fluorescence situ hybridization (FISH) conducted to verify expression, intracellular localization, and potential prognostic value circPRKCA based on tissue microarray. Gain- loss-of-function assays were employed investigate effects both vitro vivo. pull-down mass spectrometry (MS) performed identify proteins bound circPRKCA. mRNA sequencing screen downstream target genes Furthermore, immunoprecipitation methylated (MeRIP) analysis used explore mechanisms. We found exhibited significant upregulation tissues correlated unfavorable outcomes. Biological function experiments further confirmed enhances capabilities migration, invasion, angiogenesis Mechanistically, engages interaction Y-box binding protein 1 (YBX1) within cytoplasmic milieu, consequently preventing ubiquitination-mediated degradation YBX1. Increased concentrations YBX1 increase stability granulocyte–macrophage colony-stimulating factor (CSF2) 5-methylcytosine (m5C)-dependent manner. This process metastasis In this research, correlation between prognoses patients It instrumental metastatic via YBX1/CSF2 signaling pathway. Consequently, targeting may represent promising therapeutic strategy for

Language: Английский

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o8G-modified circKIAA1797 promotes lung cancer development by inhibiting cuproptosis

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

Published: April 2, 2025

Abstract Background Lung cancer is a serious threat to human life and health, but effective screening treatment methods are lacking. Circular RNAs (circRNAs) have important biological functions closely related tumour development. Some studies shown that the 8-oxo-7,8-dihydroguanosine (o8G) modification plays key role in disease process, effect of o8G on circRNAs has not been elucidated. Moreover, cuproptosis novel mode cell death which copper ions directly promote protein aggregation disruption cellular metabolic pathways. The present study revealed circKIAA1797 occurs promotes lung development by inhibiting cuproptosis, provides new perspectives for epitranscriptomic therapeutic approaches cancer. Methods circRNA differential expression profiles were via RNA high-throughput sequencing, lines tissues was detected using qPCR. Experiments such as immunoprecipitation (o8G RIP) crosslinking (CLIP) performed explore presence circKIAA1797. regulation reader Y-box binding 1 (YBX1) explored nuclear–cytoplasmic fractionation, actinomycin D (Act D) stability experiments other experiments. silencing overexpression systems constructed vivo vitro Tagged affinity purification (TRAP), (RIP), coimmunoprecipitation (Co-IP), immunofluorescence (IF) staining subsequently conducted reveal molecular mechanism regulates Results This first YBX1 recognises ROS-induced modifications increases cytoplasmic circKIAA1797, associated with stage prognosis, significantly function both vitro. inhibits intracellular ferredoxin (FDX1) mRNA, decreasing FDX1 mRNA stability, expression, signal transducer activator transcription (STAT1) lipoyltransferase (LIPT1) transcription; moreover, closure mitochondrial permeability transition pore (mPTP), ultimately Conclusions an can inhibit proteins promoting mPTP closure, only theoretical basis in-depth understanding mechanisms also potential target treatment.

Language: Английский

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KPNA2 promotes osteosarcoma progression by regulating the alternative splicing of DDX3X mediated by YBX1

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

Published: April 12, 2025

Osteosarcoma (OS) is a rapidly progressive primary malignant bone tumor that occurs in children and adolescents aged between 15 19 years adults over 60 years. As alternative splicing (AS) changes caused by abnormal factors contribute to progression, gene expression AS analyses were performed on 44 osteosarcoma patients create genome-wide co-expression network of RNA-binding proteins (RBPs), events, genes. A gain- or loss-of-function cell model was established, an interactive analysis enrichment performed. Karyopherin Subunit Alpha 2 (KPNA2) negatively correlated with patient survival. KPNA2 transports factor Y-box Binding Protein 1 (YBX1) into the nucleus YBX1 accelerates degradation ATP-dependent RNA helicase DDX3X (DDX3X) through nonsense-mediated decay (NMD) pathway promote intron retention gene, thus reducing protein levels. KPNA2/YBX1 axis regulates stability mRNA cycle progression. KPNA2/YBX1/DDX3X might be potential targets for inhibiting disease progression improving OS It integrates control represents prognostic biomarker therapeutic target therapy.

Language: Английский

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LINC02167 stabilizes KSR1 mRNA in an m5C-dependent manner to regulate the ERK/MAPK signaling pathway and promotes colorectal cancer metastasis

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

Published: April 15, 2025

Abstract Background Metastasis is a leading cause of colorectal cancer (CRC)-related mortality, yet its molecular mechanisms remain poorly understood. Long noncoding RNAs (lncRNAs) have emerged as critical regulators CRC metastasis, but their specific roles are not fully elucidated. This study identifies and characterizes novel lncRNA LINC02167 regulator metastasis. Methods expression was analyzed in tissues via real-time quantitative polymerase chain reaction fluorescence situ hybridization. Functional assays evaluated role cell migration, invasion, metastasis vitro vivo. Mechanistic exploration involves combination techniques, including RNA sequencing, mass spectrometry, pull-down, immunoprecipitation, chromatin luciferase reporter assays, stability bioinformatics analysis, to uncover the interactions pathways regulated by LINC02167. Results markedly upregulated strongly correlates with advanced clinical features poor prognosis. analyses reveal that enhances migration invasion promotes Mechanistically, serves scaffold, forming complex YBX1 ILF3 facilitate binding NSUN2-mediated m 5 C modification sites on KSR1 mRNA, thereby stabilizing mRNA activating ERK/MAPK signaling pathway drive Additionally, MYC-driven transcriptional activation leads upregulation CRC. Conclusions uncovers mechanism through which modification, underscoring potential promising therapeutic target for metastatic treatment.

Language: Английский

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New Vaccine Therapy for Triple-Negative Breast Cancer

Current Breast Cancer Reports, Journal Year: 2024, Volume and Issue: 16(3), P. 288 - 301

Published: May 8, 2024

Abstract Purpose of the review The objective this is to provide an analysis early-phase clinical trials investigating vaccine therapies for triple-negative breast cancer (TNBC). Specifically, focus on ongoing that are actively recruiting or in progress, while excluding vaccines target neoantigens those have already completed trials. Recent findings Over past decade, notable transformations occurred strategy design. Traditional approaches identifying tumor antigens, such as SEREX, been replaced with modern techniques, RNA sequencing, HLA typing, and immunoinformatics. These new methods enable identification characterization antigens. Notably, current investigations into targets extend beyond mutated self-proteins proteins overexpressed following neoplastic transformation. Clinical researchers currently examining protein associated stem cells non-malignant immune regulatory cell types within microenvironment. However, application up-to-date antigen delivery certain still lags behind. Another significant transformation comparison previous emphasis stimulating robust T-cell responses against cells, independent any B-cell response directed at tumor. Summary In conclusion, we critically assessed antigens targeted by immunotherapies these trials, used conclude discussing potential future directions development TNBC therapies.

Language: Английский

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The role of m5C RNA modification in cancer development and therapy

Heliyon, Journal Year: 2024, Volume and Issue: 10(19), P. e38660 - e38660

Published: Sept. 27, 2024

Language: Английский

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Loss of Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Tumor Microenvironment and Response to BCG Immunotherapy in a Murine Orthotopic Model of Bladder Cancer

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13296 - 13296

Published: Dec. 11, 2024

Loss of the glutathione-S-transferases Theta 2 (Gstt2) expression is associated with an improved response to intravesical Mycobacterium bovis, Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC) patients who receive fewer BCG instillations. To delineate cause, Gstt2 knockout (KO) and wildtype (WT) C57Bl/6J mice were implanted tumors before treatment or saline. RNA was analyzed via single-cell sequencing (scRNA-seq) real-time polymerase chain reaction (RT-PCR). induced PD-L1 in WT bladders, while pro-inflammatory TNF-α upregulated KO bladders. ScRNA-seq analysis showed that bladders had a higher proportion matrix remodeling fibroblasts, M2 macrophages, neuronal cells. In mice, distinct tumor cell types, activated M1 macrophages enriched genes expressed supported tumorigenesis immunosuppressive expression. contrast, involved inflammation, immune activation, suppression. An 11-gene signature (Hmga2, Peak 1, Kras, Slc2a1, Ankfn1, Ahnak, Cmss1, Fmo5, Gphn, Plec, Gstt2), derived from scRNA-seq predicted NMIBC (The Cancer Genome Atlas (TCGA) database). conclusion, our results indicate may benefit anti-PD-L1 checkpoint inhibition therapy.

Language: Английский

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