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Integrated genome-wide high-throughput screening and functional validation identifies Sm proteins as essential splicing regulators for gastric cancer progression.
Alternative splicing mediated by Smith antigen (Sm) proteins involving seven small nuclear ribonucleoprotein polypeptides (SNRPs), plays a critical role in cancer progression. Our previous work identified Sm protein B (SNRPB) as an essential gene in gastric cancer (GC) cells. However, the functional roles of the broader Sm proteins and their regulatory mechanisms in GC progression remain unclear. Integrating genome-wide CRISPR-Cas9 and RNA interference proliferation screening data from human GC cell lines, we identified Sm proteins as essential genes for GC growth. Analysis of RNA-seq data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas revealed elevated Sm proteins mRNA levels in GC. Further Single-cell RNA sequencing data from the GSE183904 dataset further confirmed Sm proteins overexpression in GC malignant epithelial cells. Functional validation demonstrated that knockdown of SNRPB, SNRPD1, SNRPD2, or SNRPD3 suppressed GC cell proliferation. Specifically, scRNA-seq data analysis and in vitro assays showed that SNRPB depletion modulated the expression of apoptosis-related proteins, thereby impairing cell proliferation and migration while promoting apoptosis. Consistently, SNRPB knockdown markedly inhibited tumor growth in xenograft models. Mechanistically, SNRPB depletion mediated exon skipping in CASP6 pre-mRNA, upregulating CASP6 transcript variant ENST00000352981, which restrained proliferation and induced apoptosis. Clinical analysis of four independent cohorts revealed that SNRPB overexpression in GC tissues was significantly associated with poor patient prognosis. In conclusion, our integrated approach defines the Sm proteins as essential for GC progression. Specifically, SNRPB mediated exon skipping of CASP6 facilitates tumor progression, highlighting the therapeutic potential of targeting this splicing pathway.
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Hypoxia Promotes Malignant Progression of Colorectal Cancer by Inducing POSTN+ Cancer-Associated Fibroblast Formation.
Colorectal cancer (CRC) is one of the most common malignancies. Hypoxia can promote the occurrence and development of CRC. However, how hypoxia regulates the CRC immune microenvironment needs to be further explored. The bulk RNA sequencing data and clinicopathological information of CRC patients were enrolled from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The single-cell RNA sequencing (scRNA-seq) datasets of CRC were collected from and analyzed from the GEO database and the ArrayExpress database. The score of the hypoxia gene set was estimated using the "ssGSEA" algorithm in the "GSVA" R package. The functional characteristics of CAF subtypes were studied by bioinformatics analysis and in vitro experiments, and a prognostic model was constructed based on machine learning correlation. Hypoxia is associated with poor prognosis in CRC patients. Periostin (POSTN) + Fib is a cancer-associated fibroblast (CAF) closely associated with hypoxia, and high infiltration of POSTN + Fib is associated with adverse outcomes in overall survival (OS) and relapse-free survival (RFS) in CRC patients. Hypoxia can induce POSTN expression and secretion in CAFs. Hypoxia-induced increase of POSTN expression in CAFs can significantly promote the migration and proliferation of CRC cells. Hypoxia-induced increase of POSTN expression in CAFs can significantly promote the proliferation and migration of CRC cells. The POSTN+Fib Hypoxia-Related Risk Model (PFHRM) can predict the survival and immunotherapy response of CRC patients. Our study identified a POSTN+Fib cell subpopulation closely associated with hypoxia, which promotes the malignant progression of CRC. The development of PFHRM provides a theoretical basis for improving patient survival and prognosis.
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Single-cell RNA-seq profiles of colonic intestinal mucosa in IBS-D rats to explore the mechanism of immune barrier regulation in pathogenesis.
Imbalance of intestinal mucosal immune regulation is a key mechanism in diarrhea-predominant irritable bowel syndrome (IBS-D). We aimed to characterize this dysregulation in the intestinal mucosa at single-cell resolution. Intestinal mucosal cells from control and neonatal maternal separation-induced IBS-D rats were isolated and subjected to single-cell RNA sequencing (scRNA-seq). Bioinformatics analyses included clustering, differential expression, trajectory inference, and cell-cell communication assessment. We obtained transcriptomes from 4572 high-quality cells, identifying epithelial, stromal, immune, and endothelial lineages. In IBS-D rats, we observed a significant remodeling of the immune compartment, characterized by an increase in monocytes, mast cells, and cycling immune cells, alongside a decrease in T and B lymphocyte subsets. Epithelial cells showed upregulated expression of Krt7 and Foxa3, and downregulated expression of Cst6, Elapor1, and Kcnma1. Cell-cell communication analysis revealed enhanced interactions between epithelial and innate immune cells, involving ligands such as TIGIT. Regulon activity analysis highlighted key transcription factors, including Pax5 in B cells and Mafb in monocytes. Single-cell RNA sequencing reveals that immune barrier dysregulation in the intestinal mucosa of rats with IBS-D is associated with altered immune cell composition, dysregulated expression of epithelial function-related genes, and disrupted intercellular communication, providing novel insights into the pathogenesis of IBS-D. Our high-resolution scRNA-seq atlas delineates the cellular and molecular landscape of intestinal mucosal immune barrier dysfunction in IBS-D, pinpointing novel potential therapeutic targets for this disorder.
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Landscape of adenosine-to-inosine RNA recoding across human tissues.
RNA editing by adenosine deaminases changes the information encoded in the mRNA from its genomic blueprint. Editing of protein-coding sequences can introduce novel, functionally distinct, protein isoforms and diversify the proteome. The functional importance of a few recoding sites has been appreciated for decades. However, systematic methods to uncover these sites perform poorly, and the full repertoire of recoding in human and other mammals is unknown. Here we present a new detection approach, and analyze 9125 GTEx RNA-seq samples, to produce a highly-accurate atlas of 1517 editing sites within the coding region and their editing levels across human tissues. Single-cell RNA-seq data shows protein recoding contributes to the variability across cell subpopulations. Most highly edited sites are evolutionary conserved in non-primate mammals, attesting for adaptation. This comprehensive set can facilitate understanding of the role of recoding in human physiology and diseases.
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Immunosuppression of HMOX1 contributes to metastasis and poor prognosis in glioma.
BACKGROUND: Glioma is the most prevalent form of brain cancer, characterized by immunosuppression and heterogeneity. Recently, numerous genes associated with immunosuppression have been identified in glioma. Nevertheless, the molecular mechanisms underlying this immunosuppression remain unclear. In this study, we aim to delineate the relationship between HMOX1 and cancer-related immunosuppression in glioma. METHODS: Two GEO datasets were selected for assessment the expression of HMOX1. The Chinese Glioma Genome Atlas (CGGA, 693 patients) and the Cancer Genome Atlas (TCGA, 702 patients) were analyzed using R software. Additionally, single-cell RNA sequencing (scRNA-seq) data from CGGA were also analyzed. Cell experiments and xenograft model were carried out to validate the role of HMOX1 in glioma metastasis. RESULTS: Two GEO datasets revealed a significantly increased expression of HMOX1 in glioma. This upregulation of HMOX1 was associated with WHO grade 4, IDH wild-type, 1p/19q non-codeletion, and poor survival in both CGGA and TCGA datasets. GO, KEGG, and GSVA analyses indicated that immune-related pathways were the most dysregulated processes. We observed infiltration of M2 macrophages and activation of checkpoint genes in HMOX1-upregulated glioma. ScRNA-seq analysis showed that HMOX1 was upregulated in M2 macrophages, indicating the association between HMOX1 upregulation and polarization of M2 macrophages. Knockdown HMOX1 reduced the growth and metastasis of glioma cells in vitro and in vivo. Co-cultured HMOX1-inhibited M2 macrophages with glioma cells decreased the invasive ability of glioma cells. CONCLUSION: In glioma, high expression of HMOX1 was associated with cancer-related immunosuppression through polarization of M2 macrophages. Moreover, knockdown HMOX1 reduced the growth and metastasis of tumor cells in vitro and in vivo. These findings suggested that HMOX1 could serve as a prognostic factor for glioma.
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Bioinformatics analysis identifies ULK3 as a novel prognostic and immune-related biomarker in esophageal cancer.
BACKGROUND: Esophageal cancer (EC) is a leading global malignancy, exhibiting high incidence in East Asia, especially China. Although tumor, node, metastasis (TNM) staging remains the cornerstone of clinical evaluation, molecular profiling of tumors and blood now offers complementary prognostic and therapeutic information. Yet patient survival rates remain unsatisfactory. Autophagy plays a dual role in tumor. ULK3, a kinase related to autophagy regulation, remains underexplored in EC. This study aimed to investigate the role of ULK3 in EC prognosis and tumor immunity. METHODS: ULK3 expression patterns were examined across pan-cancer and EC using The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) and Gene Expression Profiling Interactive Analysis (GEPIA2), with gene set cancer analysis (GSCA) characterizing its single nucleotide variation (SNV) and copy number variation (CNV) profiles. Gene Expression Omnibus (GEO) datasets validated these findings [GSE13898: esophageal adenocarcinoma (EAC), 15 Barrett's esophagus, 28 normal; GSE53625: 179 esophageal squamous cell carcinoma (ESCC), 179 normal; GSE77861: 7 ESCC, 7 normal; GSE92396: 12 EAC, 9 normal; GSE213565: 10 ESCC, 10 normal]. GEPIA2 and KM-Plotter assessed prognostic associations with EC and immunotherapy patients, which were subsequently validated in GSE53625, while GSCA analyzed CNV-survival correlations. The Cancer Genome Atlas (TCGA) EC cohort (96 ESCC, 88 EAC, 1 mucinous cystic neoplasm), incorporating race, tumor location, pathological grade, smoking status, alcohol consumption, gender, age, stage, molecular markers, and overall survival (OS) was used to analyze ULK3's clinical associations and prognostic value. Immune infiltration, T-cell exhaustion, and immunotherapy response were evaluated using TCGA EC, complemented by GSCA's drug sensitivity assessment. Pathway enrichment analysis was used to explore potential mechanisms, while T-cell and epithelial phenotypes across ULK3 expression groups were compared using single-cell RNA sequencing (SCRNA-seq) data (GSE196756: 3 ESCC, 3 normal). Mendelian randomization (MR) employed data from FinnGen and IEU OPEN Genome-Wide Association Study (GWAS) to investigate genetic susceptibility of ULK3 and EC. RESULTS: ULK3 expression was elevated in normal EC tissues, with pan-cancer SNV mutations primarily consisting of missense mutations and EC CNV mutations biased toward deletions. Multivariate Cox regression identified ULK3 as an independent survival factor [hazard ratio (HR): 0.417, 95% confidence interval (CI): 0.218-0.798, P=0.008]. Immunologically, ULK3 was associated with reduced macrophage infiltration, improved chemotherapy and immunotherapy responses. Enrichment analysis showed ULK3 association with epidermal growth, immune regulation, and microautophagy pathways. ScRNA-seq data revealed ULK3-mediated T-cell activation and suppression of tumor phenotype. MR analysis yielded consistent risk associations [IEU OPEN GWAS, odds ratio (OR): 0.9994, 95% CI: 0.9992-0.9996, P=7.89×10-8; FinnGen, OR: 0.9047, 95% CI: 0.8218-0.9959, P=0.04]. CONCLUSIONS: ULK3's mutation profile, expression patterns, prognostic associations, immune correlations and MR results suggest that its elevated expression may reduce EC risk and progression, supporting its potential as a prognostic biomarker. Single-cell and pathway analyses indicate that microautophagy-mediated regulation of tumor proliferation and immunity underlies these effects.
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Genome-wide identification of long non-coding RNAs in pigs and their roles in muscle development.
OBJECTIVE: Long non-coding RNAs (lncRNAs) regulates complex traits in pigs and the systematic annotation and functional roles of these genes remain poorly understood. This study aimed to construct a comprehensive porcine lncRNA atlas and explore the regulatory role of lncRNAs in muscle development. METHODS: We used 8,871 strand-specific RNA-seq datasets to identify porcine lncRNAs. Their transcriptional characteristics, tissue specificity, evolutionary conservation, and expression quantitative trait locus (eQTL)-supported regulatory relationships were esamined. Single-cell RNA-seq, Hi-C, H3K27ac ChIP-seq, and population differentiation analyses were further incorporated to investigate candidate lncRNAs involved in muscle development. RESULTS: We identified 50,203 porcine lncRNA genes with greater tissue specificity and lower expression levels than protein-coding genes. A subset of lncRNAs showed sequence conservation across mammals. Integration with pigGTEx data identified extensive eQTLsupported lncRNA-mRNA candidate regulatory pairs enriched in active promoter and enhancer chromatin states. Single-cell and multi-omics analyses highlighted PRANCR as a candidate regulator of postnatal muscle growth in Laiwu pigs. A highly distinct enhancer variation (chr5:g.34155013T>C; Sscrofa11.1) could affect SOX8 binding and regulate PRANCR expression in satellite stem cells. CONCLUSION: The current study provides the most comprehensive porcine lncRNA resource currently available and proposes a potential enhancer-lncRNA regulatory mechanism that contributes to muscle development in pigs.
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Identification of estrogen response-associated STRA6+ granulosa cells within high-grade serous ovarian carcinoma by single-cell sequencing.
BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is a pathologic subtype of ovarian cancer (OC) with a more lethal prognosis. Extensive heterogeneity results in HGSOC being more susceptible to treatment resistance and adverse treatment effects. Revealing the heterogeneity involved is crucial. METHODS: We downloaded the single-cell RNA-seq (scRNA) data from GEO database and performed a scRNA analysis for cell landscape of HGSOC by using the Seurat package. The highly expressed genes were uploaded into the DAVID and KEGG database for enrichment analysis, and the AUCell package was used to calculate cancer-associated hallmark score. The SCENIC analysis was used for key regulons, the estrogen response enrichment scores in TCGA-OV RNA-seq dataset were calculated by using the GSVA package. Besides, the expression of STRA6 and IRF1 and the cell invasion and migration in si-STRA6 OC cells were detected by using the quantitative reverse transcription (qRT)-PCR method and Transwell assay respectively. RESULTS: We successfully constructed a single-cell atlas of HGSOC and delineated the heterogeneity of epithelial cells therein. There were five epithelial cell subpopulations, GLDC + Epithelial cells, PEG3+ leydig cells, STRA6+ granulosa cells, POLE2+ Epithelial cells, and AURKA + Epithelial cells. STRA6+ granulosa cells have the potential to promote tumor growth as well as the highest estrogen response early activity through the biological pathways analysis of highly expressed genes and estrogen response score of ssGSEA. We found that IRF1 and STRA6 expression was remarkably upregulated in the OC cancer cell line HEY. Silencing of STRA6 markedly decreased the invasion and migration ability of the OC cancer cell line HEY. CONCLUSION: There is extreme heterogeneity of epithelial cells in HGSOC, and STRA6+ granulosa cells may be able to promote cancer progression. Our findings are benefit to the heterogeneity identification of HGSOC and develop targeted therapy strategy for HGSOC patients.
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Molecular subtyping and prognostic modeling of non-small cell lung cancer based on disulfidptosis-related genes.
BACKGROUND: Non-small cell lung cancer (NSCLC) shows substantial molecular and immune heterogeneity, and prognosis varies widely even among patients with similar clinicopathologic stage, highlighting the need for biologically grounded biomarkers. Disulfidptosis is a newly described form of regulated cell death triggered by disulfide stress and linked to tumor metabolic vulnerability, but its molecular patterns and prognostic relevance in NSCLC remain unclear. This study aimed to define disulfidptosis-related molecular subtypes in NSCLC, construct and externally validate a disulfidptosis-based prognostic gene signature, and investigate its associations with the tumor immune microenvironment (TIME) and potential immunotherapy response. METHODS: We analyzed NSCLC gene expression and clinical follow-up data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Initial unsupervised clustering identified disulfidptosis-related molecular subtypes. Further analysis used weighted gene co-expression network analysis (WGCNA), univariate and least absolute shrinkage and selection operator (LASSO)-COX regression, and stepwise Cox regression to identify disulfidptosis-related prognostic genes, which were then validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in surgically resected NSCLC tumor specimens in our center. A Disulfidptosis Score-based risk model was built and evaluated with Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. Single-cell RNA sequencing (RNA-seq) data characterised gene-expression patterns in the TIME. RESULTS: Two molecular subtypes (C1 and C2) based on 16 disulfidptosis genes were identified, among which subtype C2 had a lower immune infiltration score and poorer prognosis. Furthermore, eight disulfidptosis-related prognostic genes were identified and validated through our local cohort by RT-PCR. The Disulfidptosis Score-based on these eight genes effectively stratified patients into high- and low-risk categories. Kaplan-Meier analysis demonstrated that disulfidptosis-related genes were significantly associated with survival outcomes. A prognostic model based on the Disulfidptosis Score and Stage was validated using independent datasets, and the area under the curve (AUC) was 0.728, 0.763, and 0.73 at one, three and five years respectively. Single-cell analysis revealed the expression of disulfidptosis-related prognostic genes across various immune cell types, particularly in plasma cells. CONCLUSIONS: This study identified disulfidptosis-related gene characteristics and their correlation with tumor microenvironment and prognosis in NSCLC. These findings could provide new insights into NSCLC heterogeneity and offer potential biomarkers for prognosis and therapeutic strategies.
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DIAPH3 is upregulated in high-grade gliomas and linked to chromosomal instability.
ABSTRACT: BackgroundDiaphanous-related formin 3 (DIAPH3) is a member of the formin family, a group of proteins that regulate actin and microtubule dynamics. During mitosis, DIAPH3 localizes specifically to the centrosome. Its loss destabilizes microtubules and disrupts mitotic spindle polarity, leading to multipolar mitoses and abnormal chromosome segregation, which ultimately causes aneuploidy in daughter cells. METHODS: We investigated DIAPH3 expression in glioma samples-including low-grade and high-grade gliomas-using publicly available datasets (The Cancer Genome Atlas and a single-cell RNA-seq study). We also explored the impact of DIAPH3 expression on aneuploidy in cultured glioblastoma cells. RESULTS: DIAPH3 expression was specifically increased in grade 4 gliomas. However, its prognostic value did not surpass that of the WHO CNS5 glioma classification. DIAPH3 was predominantly expressed in mitotic cells and showed strong coexpression with genes involved in cell division, particularly those regulating mitotic progression and chromosome segregation. Several transcription factors known to drive proliferation and cancer progression may regulate DIAPH3 expression. In glioblastoma cell lines, we confirmed that DIAPH3 is upregulated during mitosis and that its knockdown increases aneuploidy. CONCLUSIONS: These findings confirm the role of DIAPH3 in chromosome segregation in clinical glioma samples and demonstrate its association with high-grade, poor-prognosis gliomas.