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Integrated analysis identifies a palmitoylation-associated prognostic model (ACSM5/SKA3) for lung adenocarcinoma across multiple cohorts.
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer and remains associated with poor prognosis despite therapeutic advances. Protein palmitoylation, particularly reversible S-palmitoylation, modulates oncogenic signaling, membrane localization, and immune checkpoint stability, but the prognostic landscape of palmitoylation-related genes (PRGs) in LUAD and their relationship with the tumor microenvironment are not well defined. METHODS: PRGs were curated from GeneCards and integrated with transcriptomic and clinical data from The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) cohort. Differential expression and univariate Cox analyses were performed to identify prognostic PRGs, which were then used for consensus clustering to define molecular subtypes and to construct a LASSO-Cox prognostic model. Associations between the risk score and functional pathways, genomic alterations, tumor mutational burden (TMB), tumor immune dysfunction and exclusion (TIDE) scores, and immune infiltration were evaluated. Three Gene Expression Omnibus (GEO) cohorts were used for external validation. Single-cell RNA sequencing (scRNA-seq) datasets and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) of paired LUAD and adjacent tissues were used to assess cell type-associated expression and validate key genes. RESULTS: We identified 201 differentially expressed PRGs in LUAD and 15 genes significantly associated with overall survival, including the protective gene ACSM5 and the risk gene SKA3. PRG-based consensus clustering defined two molecular subtypes with distinct prognoses, differential enrichment of metabolism- versus proliferation-related pathways, and divergent immune microenvironment features. A two-gene signature comprising ACSM5 and SKA3 stratified patients into high- and low-risk groups in The Cancer Genome Atlas (TCGA) and three external cohorts, with time-dependent area under the curve (AUCs) of 0.717, 0.733, and 0.697 at 1, 3, and 5 years in TCGA and comparable performance in GEO validation cohorts (5-year AUC up to 0.778), indicating moderate discriminative performance. Low-risk patients generally showed higher stromal and immune scores and increased infiltration of multiple immune cell subsets, along with complex patterns in TMB and TIDE indices. Single-cell analyses indicated predominant expression of ACSM5 in macrophages and of SKA3 in proliferating CD8+ T cells and macrophages, and RT-qPCR confirmed downregulation of ACSM5 and upregulation of SKA3 in LUAD tissues. CONCLUSION: This integrated analysis outlines a palmitoylation-associated molecular framework in LUAD and supports an ACSM5/SKA3 two-gene signature as a candidate prognostic tool that stratifies patient outcomes and reflects distinct metabolic, proliferative, and immune microenvironmental states, potentially providing a palmitoylation-associated basis for risk stratification and for the design of future mechanistic and therapeutic studies in LUAD.
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3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) is a potential diagnostic and prognostic biomarker in colon adenocarcinoma.
Colon cancer represents a global health challenge. The 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. However, the correlation between PAPSS2 and diagnosis, prognosis, and immune cell infiltration in colon adenocarcinoma (COAD) has rarely been mentioned. We analyzed PAPSS2 expression levels in pan-cancer from The Cancer Genome Atlas (TCGA) database; and validated it in the Gene Expression Omnibus (GEO) database. RNA-seq data were analyzed using the R package to identify differentially expressed genes (DEGs) between COAD tissues with high and low PAPSS2 expression from multiple databases. The ssGSEA algorithm was used to analyze the correlation between PAPSS2 and immune cell infiltration in COAD. Tumor tissues and normal tissues were classified and assayed at the single-cell level to analyze differences in PAPSS2 expression. CCK8 and EdU assays were used to validate proliferative capacity; wound healing assays to validate migratory capacity; and Transwell assays to examine changes in invasive capacity. The PAPSS2 expression level was significantly lower in the tumor tissues and associated with worse clinical parameters and prognosis in COAD patients. And we constructed a transcriptional regulatory network involving FLI1 and hsa-miR-152-3p targeting PAPSS2 to support the role of PAPSS2.Enrichment analysis revealed that PAPSS2 is involved in O-glycan biosynthesis, TP53 pathway and extracellular matrix formation. PAPSS2 was found to be positively associated with the infiltration of numerous immune cells, immunomodulatory factors and chemokines. Cytological experiments demonstrated that PAPSS2 knockdown enhanced the proliferation, migration, and invasion of HCT116 and HT-29 cells. Our study suggests that PAPSS2 acts as a promising diagnostic and prognostic biomarker, which facilitates malignant progression in part through its regulation of the p53 signaling pathway.
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RETRACTED: Exploring the tumor microenvironment: Chemokine-related genes and immunotherapy/chemotherapy response in clear-cell renal cell carcinoma.
BACKGROUND: The treatment of clear-cell renal cell carcinoma (ccRCC) remains challenge. Chemokines laid impact on the proliferation and metastasis of cancer cells. The objective was to identify the chemokine-related genes and construct a prognostic model for ccRCC. METHODS: Bulk transcriptomic data (n = 531), single-cell RNA sequencing (scRNA-seq) dataset GSE159115, and other validation cohorts were acquired from the Cancer Genome Atlas Program (TCGA) and GEO databases. All clustering analysis was conducted by Seurat R package. Gene set enrichment analysis (GSEA), immune infiltration analysis, single nucleotide variations (SNV) analysis, and predictive response analysis of immunotherapy/chemotherapy were conducted. 786-O and A498 cell lines were cultured and applied into CCK-8, Western blot, and RT-qPCR kits. RESULTS: Univariate Cox analysis was used to screen out chemokine-related genes related to survival. ZIC2, SMIM24, COL7A1, IGF2BP3, ITPKA, ADAMTS14, CYP3A7, and AURKB were identified and applied for the construction of the prognostic model. High-risk group had a poorer prognosis than the low-risk group in each dataset. Memory CD8+ T cells, macrophages, and memory B cells were higher in the high-risk group, while the content of basophils was higher in the low-risk group. Bortezomib_1191, Dactinomycin_1911, Docetaxel_1007, and Daporinad_1248 were more sensitive to high-risk groups than low-risk groups. Moreover, we found that IGF2BP3 significantly elevated in both 786-O and A498 cell lines resistance to sunitinib. Knockdown of IGF2BP3 markedly reduced ccRCC cell migration and viability. CONCLUSION: Our study has yielded a novel prognostic model of chemokine-related genes based on comprehensive transcriptional atlas of ccRCC patients, shedding light on the significant impact of the tumor microenvironment on biology and immunotherapy response of ccRCC. We identified IGF2BP3 as a pivotal regulator in regulating ccRCC resistance to sunitinib.
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Desmoglein-1 coordinates cell proliferation and actin dynamics to promote epidermal morphogenesis.
Skin development depends on coordinated biochemical and mechanical signaling to form a multilayered epidermal barrier. Our previous work demonstrated that the stratified tissue-specific desmosomal cadherin Desmoglein-1 (Dsg1) promotes epidermal differentiation in human in vitro models. Dsg1 first appears in the developing mouse epidermis around E14, coinciding with a developmental transition in stratification and the onset of terminal differentiation, raising the question of how Dsg1 contributes to epidermal morphogenesis in vivo . We generated a wild-type (WT) single-cell RNA sequencing (scRNA-seq) atlas of murine skin and integrated scRNA-seq data from Dsg1 knockout (Dsg1 KO) embryos spanning E14.5, E15.5, E16.5, and E18.5. Six keratinocyte subpopulations were annotated, including a Transitional subpopulation co-expressing basal and suprabasal markers, positioned between basal and differentiated states. Dsg1 KO epidermis exhibited reduced thickness at E14.5-E15.5, but recovered by E16.5-E18.5, suggesting compensatory adaptation. Differential gene expression analysis revealed enrichment of cell-cycle and actin-associated programs in Dsg1 KO during late development. EdU incorporation and PCNA staining confirmed increased proliferation in superficial layers accompanied by altered actin organization and changed cell morphology. Notably, actin and the Arp2/3 actin nucleation-promoting factor N-WASP exhibited marked changes in distribution during early and late development, respectively. Mechanistically, Dsg1 associates with Nck1, an adaptor linking N-WASP to Arp2/3-dependent actin polymerization. Silencing Nck1 or N-WASP reduced Dsg1-mediated stratification significantly, while a Nck1-binding-deficient Dsg1 mutant failed to rescue stratification in Dsg1-deficient keratinocytes in vitro . Together, these findings identify a Dsg1-Nck1-N-WASP axis linking desmosomal adhesion to cytoskeletal remodeling and support a model in which Dsg1 coordinates cell-cycle, cell morphology, and actin dynamics to drive epidermal morphogenesis.
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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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Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies.
Diabetic kidney disease (DKD) occurs in ∼40% of patients with diabetes and causes kidney failure, cardiovascular disease, and premature death. We analyzed the response of a murine DKD model to five treatment regimens using single-cell RNA sequencing (scRNA-seq). Our atlas of ∼1 million cells revealed a heterogeneous response of all kidney cell types both to DKD and its treatment. Both monotherapy and combination therapies targeted differing cell types and induced distinct and non-overlapping transcriptional changes. The early effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the S1 segment of the proximal tubule suggest that this drug class induces fasting mimicry and hypoxia responses. Diabetes downregulated the spliceosome regulator serine/arginine-rich splicing factor 7 (Srsf7) in proximal tubule that was specifically rescued by SGLT2i. In vitro proximal tubule knockdown of Srsf7 induced a pro-inflammatory phenotype, implicating alternative splicing as a driver of DKD and suggesting SGLT2i regulation of proximal tubule alternative splicing as a potential mechanism of action for this drug class.
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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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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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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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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.