Integrated single-cell and bulk transcriptome analysis of R-loop score-based signature with regard to immune microenvironment, lipid metabolism and prognosis in HCC

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 9, 2025

Hepatocellular carcinoma (HCC) is one of the most prevalent causes cancer-related morbidity and mortality worldwide. Late-stage detection complex molecular mechanisms driving tumor progression contribute significantly to its poor prognosis. Dysregulated R-loops, three-stranded nucleic acid structures associated with genome instability, play a key role in malignant characteristics various tumors. However, detailed mechanism R-loops HCC remain elusive require further exploration. This study aimed construct an R-loop scoring signature centered on prognosis lipid metabolism, thereby enhancing our understanding identifying potential therapeutic targets. In this study, we utilized single-cell RNA-sequencing (scRNA-seq) data from patients (GSE149614 CRA002308) model based identified regulator genes (RLRGs) related HBV infection through WGCNA analysis. We also explored microenvironment intercellular communication score. Additionally, prognostic risk fatty metabolism-associated RLRGs was constructed using TCGA database, association immune infiltration, mutations, drug sensitivity analyzed. vitro vivo experiments were performed investigate RLRG CLTC metabolism progression. Using scRNA-seq HCC, established infection. Moreover, more suppressive stronger displayed cells high scores. The cell trajectory cellular analysis exhibited significant between RLRGs. consisting 8 which effectively evaluated value, status microenvironment, gene chemotherapeutic for patients. Notably, validation suggested that could regulate formation facilitate HCC. Collectively, proposes value. CLTC, regulator, emerges as promising biomarker target, offering new insights into treatment strategies

Язык: Английский

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Identification and Construction of a R-loop Mediated Diagnostic Model and Associated Immune Microenvironment of COPD through Machine Learning and Single-Cell Transcriptomics

Inflammation, Год журнала: 2025, Номер unknown

Опубликована: Янв. 11, 2025

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic inflammatory airway with high incidence and significant burden. R-loops, functional chromatin structure formed during transcription, are closely associated inflammation due to its aberrant formation. However, the role of R-loop regulators (RLRs) in COPD remains unclear. Utilizing both bulk transcriptome data single-cell RNA sequencing data, we assessed diverse expression patterns RLRs lung tissues patients. A lower score was found patients neutrophils. 12 machine learning algorithms (150 combinations) identified 14 hub (CBX8, EHD4, HDLBP, KDM6B, NFAT5, NLRP3, NUP214, PAFAH1B3, PINX1, PLD1, POLB, RCC2, RNF213, VIM) COPD. RiskScore based on two distinct subtypes. Patient groups at risk (low scores) had higher immune increase neutrophils their microenvironment compared low-risk groups. PD-0325901 QL-X-138 represent prospective treatments for high-risk score) (high Finally, RT-PCR experiments confirmed differences 8 (EHD4, mice tissue. R-loops significantly contribute development constructing predictive models may provide crucial insight into personalized treatment strategies

Язык: Английский

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Mechanisms underlining R-loop biology and implications for human disease

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Фев. 21, 2025

R-loops are three-stranded non-canonical nucleic acid structures composed of nascent RNA hybridized with the template DNA strand, leaving non-template strand displaced. These play crucial roles in regulating gene expression, replication, and transcription processes. However, have also been increasingly described as highly deleterious, causing genomic instability damage. To maintain at a relatively safe level, complex regulatory mechanisms exist to prevent their excessive formation. The growing understanding R-loop functions has provided valuable insights into structure potential clinical applications. Emerging research indicates that contribute pathogenesis various disorders, including neurodegenerative, immune-related, neoplastic diseases. This review summarizes metabolism its significance etiology associated disorders. By elucidating governing R-loops, we aim establish theoretical foundation for disease exploring novel therapeutic strategies targeting these hybrid structures.

Язык: Английский

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Integrative analysis of genetic variability and functional traits in lung adenocarcinoma epithelial cells via single-cell RNA sequencing, GWAS, bayesian deconvolution, and machine learning

Genes & Genomics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Abstract Background Lung adenocarcinoma remains a leading cause of cancer-related mortality worldwide, characterized by high genetic and cellular heterogeneity, especially within the tumor microenvironment. Objective This study integrates single-cell RNA sequencing (scRNA-seq) with genome-wide association studies (GWAS) using Bayesian deconvolution machine learning techniques to unravel functional complexity lung epithelial cells. Methods We performed scRNA-seq GWAS analysis identify critical cell populations affected variations. were applied investigate progression, prognosis, immune-epithelial interactions, particularly focusing on immune checkpoint markers such as PD-L1 CTLA-4. Results Our highlights importance genes like SLC2A1, which regulates glucose metabolism correlates invasiveness poor prognosis. Immune-epithelial interactions suggest suppressive microenvironment, potentially hindering responses. Additionally, models core prognostic F12, GOLM1, S100P, are significantly associated patient survival. Conclusions comprehensive approach provides novel insights into biology, emphasizing role factors in progression. The findings support development personalized therapeutic strategies targeting both cells

Язык: Английский

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Targeting the crosstalk between glutamine metabolism and tumor immune microenvironment for lung cancer immunotherapy

Deleted Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Abstract Lung cancer remains one of the deadliest cancers globally, which may be attributed in part to a limited understanding its development. Therefore, exploration fundamental processes lung and innovative therapies is imminent. Recently, immunotherapy has become crucial topic interest, it pertains metabolism tumor microenvironment. In particular, glutamine plays pivotal role immunotherapy. This review summarizes crosstalk between immune microenvironment, explores potential strategies as an enhancement It also discusses traditional Chinese medicine regulating offer valuable insights promising directions for future studies on this subject.

Язык: Английский

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Identifying PSIP1 as a critical R-loop regulator in osteosarcoma via machine-learning and multi-omics analysis

Cancer Cell International, Год журнала: 2025, Номер 25(1)

Опубликована: Апрель 22, 2025

Dysregulation of R-loops has been implicated in tumor development, progression, and the regulation immune microenvironment (TME). However, their roles osteosarcoma (OS) remain underexplored. In this study, we firstly constructed a novel R-loop Gene Prognostic Score Model (RGPSM) based on RNA-sequencing (RNA-seq) datasets evaluated relationships between RGPSM scores TME. Additionally, identified key R-loop-related genes involved OS progression using single-cell RNA sequencing (scRNA-seq) dataset, validated these findings through experiments. We found that patients with high-RGPSM exhibited poorer prognosis, lower Huvos grades more suppressive Moreover, proportion malignant cells was significantly higher group. And integrated analysis RNA-seq scRNA-seq revealed PC4 SRSF1 Interacting Protein 1 (PSIP1) highly expressed osteoblastic proliferative cells. Notably, high expression PSIP1 associated poor prognosis patients. Subsequent experiments demonstrated knockdown inhibited both vivo vitro, leading increased accumulation DNA damage. Conversely, overexpression facilitated resolution reduced damage induced by cisplatin. conclusion, developed effectively predicted outcomes across diverse cohorts as critical modulator regulating

Язык: Английский

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The miR-941/FOXN4/TGF-β feedback loop induces N2 polarization of neutrophils and enhances tumor progression of lung adenocarcinoma

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Апрель 25, 2025

Background Lung adenocarcinoma (LUAD) is a major subtype of lung cancer and one the deadliest cancers in humans. Dysregulation miRNA activity tumor-associated neutrophils (TANs) tumor microenvironment plays an important role occurrence development LUAD. Method In this study, miReact algorithm was used to analyze single-cell RNA sequencing data LUAD samples reveal profile characteristics TANs patients. The function miR-941 investigated vivo vitro . target gene underlying signaling pathway were predicted validated with qPCR, luciferase assay, WB ELISA assay. Results results indicated crucial TANs, especially N2-TANs significantly upregulated MiR-941 overexpression promoted proliferation, invasion, migration anti-apoptosis A549 H1299. xenograft mouse model confirmed that enhanced growth tumors formed by H1299 cells. Bioinformatics analysis showed targeted suppressor FOXN4, we FOXN4 could counteract malignant effects miR-941. addition, may drive progression through FOXN4/TGF-β feedback loop participate N2-TAN polarization. Conclusion summary, these findings key miR-941/FOXN4/TGF-β provide potential therapeutic targets for future interventions.

Язык: Английский

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R-loops’ m6A modification and its roles in cancers

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Окт. 18, 2024

R-loops are three-stranded nucleic acid structures composed of an RNA–DNA hybrid and a displaced DNA strand. They widespread play crucial roles in regulating gene expression, replication, histone modifications. However, their regulatory mechanisms remain unclear. As R-loop detection technology advances, changes levels have been observed cancer models, often associated with transcription-replication conflicts genomic instability. N6-methyladenosine (m6A) is RNA epigenetic modification that regulates expression by affecting localization, splicing, translation, degradation. Upon reviewing the literature, we found m6A modifications implicated tumor development progression. This article summarizes molecular methods regulation, reviews recent research on m6A-modified oncology. Our goal to provide new insights into origins instability potential strategies for targeted therapy.

Язык: Английский

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[Advancements in Single-cell RNA Sequencing Technology
in the Study of the Tumor Microenvironment in Lung Cancer].

PubMed, Год журнала: 2024, Номер 27(6), С. 441 - 450

Опубликована: Июнь 20, 2024

The immune microenvironment plays a key role in the development and progression of tumors. In recent years, with rapid advancement high-throughput sequencing technologies, researchers have gained deeper understanding composition function cells tumor microenvironment. However, traditional bulk technologies are limited resolving heterogeneity at single-cell level, constraining comprehensive complexity advent RNA technology has brought new opportunities to uncover lung cancer. Currently, T-cell-centered immunotherapy clinical settings is prone side effects affecting prognosis, such as immunogenic drug resistance or immune-related pneumonia, factor being changes interactions between Single-cell can reveal origins functions different subgroups within from perspectives intercellular pseudotime analysis, thereby discovering cell novel biomarkers, providing avenues for uncovering monitoring therapeutic efficacy. This review comprehensively discusses newest research techniques advancements unveiling after cancer immunotherapy, offering insights enhancing precision personalization immunotherapy. .

Язык: Английский

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Unraveling the complexity: Advanced methods in analyzing DNA, RNA, and protein interactions

Advances in cancer research, Год журнала: 2024, Номер unknown, С. 251 - 302

Опубликована: Янв. 1, 2024

Язык: Английский

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