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R3HDM4 influences kidney renal clear cell carcinoma progression, immune modulation, and potential links to the IGSF8 immune checkpoint.
BACKGROUND: R3HDM4, or R3H domain containing 4, is a gene with uncertain functions but is frequently investigated for its potential cellular roles and associations with various diseases. Kidney renal clear cell carcinoma (KIRC ), a prevalent and aggressive form of kidney cancer, currently lacks effective treatment options. This study aimed to clarify the involvement of R3HDM4 in KIRC pathogenesis. METHODS AND RESULTS: An integrated pan-cancer approach was employed to analyze data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), ArrayExpress, and the International Cancer Genome Consortium (ICGC ), systematically assessing the prognostic relevance, clinical associations, signaling pathways, DNA methylation patterns, immune infiltration profiles, and chemotherapeutic sensitivity linked to R3HDM4 expression. Bioinformatics analyses, supported by immunohistochemistry, Western blotting (WB), and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), revealed significant upregulation of R3HDM4 in KIRC tissues compared to normal controls. Kaplan-Meier (KM) survival analysis indicated that elevated R3HDM4 expression correlated with poor clinical outcomes. Single-cell RNA sequencing identified cancer cells and dendritic cells as the primary sources of R3HDM4 within the KIRC tumor microenvironment. Functional assays using R3HDM4-targeting siRNA demonstrated that its depletion suppressed the proliferative, migratory, and invasive capabilities of KIRC cells. At the molecular level, R3HDM4 knockdown attenuated epithelial-mesenchymal transition (EMT), as evidenced by increased E-cadherin expression and reduced levels of vimentin and matrix metalloproteinases MMP-2 and MMP-9. Comprehensive immune profiling revealed significant correlations between R3HDM4 expression and several immunological parameters, including immune cell infiltration, immune checkpoint expression, tumor mutational burden (TMB), and microsatellite instability (MSI). Notably, silencing of R3HDM4 led to increased expression of Immunoglobulin Superfamily Member 8 (IGSF8). CONCLUSIONS: These analyses identify R3HDM4 as a critical oncogenic driver in KIRC, potentially acting through two mechanisms: promoting tumor growth and metastasis while also exerting immunomodulatory effects, possibly mediated by IGSF8. This suggests a potential role for IGSF8 in regulating immune checkpoints, though this remains speculative. These findings highlight R3HDM4's potential as both a prognostic biomarker and a therapeutic target in KIRC.
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Development and validation of an m6A and autophagy related lncRNAs signature for predicting survival and modulating the immune microenvironment in esophageal squamous cell carcinoma.
OBJECTIVE: This research is designed to establish a prognostic framework derived from m6A- and autophagy-related lncRNAs (m6aARLncs) to enhance survival prediction in esophageal squamous cell carcinoma (ESCC). Concurrently, it endeavors to elucidate the role of prognostic framework in modulating the tumor immune microenvironment. METHODS: Transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were employed as the training and independent validation cohorts, respectively. m6A-related genes (m6aRGs) and autophagy-related genes (ARGs) were curated from published literature and the Human Autophagy Database (HADb), respectively. Subsequently, differentially expressed m6aARLncs (DE-m6aARLncs) were identified by integrating co-expression analysis with differential expression profiling. A prognostic risk signature was constructed using univariate Cox and LASSO regression analyses. The model's predictive efficacy was rigorously validated through risk heatmap, survival analysis, ROC curves, differential analysis and independent prognostic analysis. Furthermore, the association between riskScores and clinical features was assessed. To elucidate the model's biological relevance, Gene Set Enrichment Analysis (GSEA) was performed. The impact of the risk signature on the tumor immune microenvironment was comprehensively evaluated via tumor microenvironment analysis, immune cell correlation analysis, single-sample gene set enrichment analysis (ssGSEA), and immune checkpoint profiling. Single-cell sequencing data analysis was carried out. Drug sensitivity profiling was conducted to identify putative therapeutic agents tailored to distinct risk subgroups. The putative m6A-autophagy-lncRNA regulatory axis may implicated in ESCC pathogenesis was proposed. Finally, the mRNA expression levels of m6aARLncs were validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS: We established a robust risk prognostic model based on five m6aARLncs (LINC00847, UBL7-AS1, LINC01554, LINC00601, and FAM222A-AS1), which demonstrated significant efficacy in predicting overall survival in ESCC patients. Comprehensive immune profiling delineated the unique immune phenotype of the prognostic model, characterized by the infiltration of mast cells, B cells, neutrophils, plasmacytoid dendritic cells (pDCs), helper T cells, and tumor-infiltrating lymphocytes (TILs), as well as human leukocyte antigens (HLA), etc. The B cells, neutrophils and dendritic cells identified by immune microenvironment analysis results may have been verified to some extent through single-cell sequencing analysis. Furthermore, the expression of two immune checkpoint molecules, TNFRSF18 and LAIR1, was significantly correlated with risk stratification, suggesting their potential therapeutic relevance. Pharmacogenomic analysis identified nine compounds (Shikonin, Bicalutamide, Bryostatin-1, Epothilone-B, JNK-9L, LFM-A13, QS11, VX-680, and Z-LLNle-CHO) exhibiting differential sensitivity between the dichotomous risk strata. We propose novel m6A-autophagy-lncRNA regulatory axis implicating the 5 m6aARLncs, 5 m6aRGs and 21 ARGs, which may play a pivotal role in ESCC pathogenesis. Finally, the results of RT-qPCR verification indicated that the expressions of FAM222A-AS1, LINC00601, LINC00847, LINC01554 and UBL7-AS1 were upregulated. CONCLUSION: This study yields findings that hold significant clinical implications for refining prognostic stratification and deciphering the immune landscape in ESCC. Moreover, they offer novel perspectives that may pave the way for more precise prognostic assessment and the formulation of targeted therapeutic interventions.
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Integrated bioinformatic analysis identifies GADD45B as an immune-related prognostic biomarker in skin cutaneous melanoma.
Skin cutaneous melanoma (SKCM) arises from melanocytes and is an aggressive form of skin cancer. If left untreated, most melanomas will metastasize, posing a major health risk. GADD45B, a member of the GADD45 family, is known to be involved in DNA damage repair; however, its specific role in SKCM remains largely unclear. In this study, we comprehensively investigated the function of GADD45B in SKCM. By integrating 26 SKCM-related datasets from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), cBioPortal for Cancer Genomics (cBioPortal), Gene Expression Omnibus (GEO), and other databases, we conducted functional enrichment, immune infiltration, and single-cell analyses using R. Additionally, transcriptome sequencing of 30 human SKCM cell lines, phenotype characterization of 29 SKCM lines in vitro, and macrophage polarization analysis were performed. We found that GADD45B expression was significantly downregulated in SKCM patients compared to normal controls (p < 0.001), and higher GADD45B levels correlated with better prognosis (p < 0.05). GADD45B also showed high diagnostic accuracy, with an area under the curve (AUC) of 0.986. GO and KEGG analyses revealed a strong association between GADD45B and immune-related pathways. Gene Set Variation Analysis (GSVA) and single-cell sequencing suggested that GADD45B may serve as a novel immune checkpoint, predominantly expressed in macrophages and promoting M1 polarization. In vitro, overexpression of GADD45B significantly inhibited SKCM cell proliferation, potentially via suppression of the PI3K/Akt signaling pathway, and also reduced chemotherapy resistance. Furthermore, in vivo experiments using a xenograft mouse model demonstrated that GADD45B overexpression significantly suppressed tumor growth. Mice injected with GADD45B-overexpressing tumor cells exhibited smaller tumor volumes from day 15 onwards compared to controls, with markedly reduced tumor volume and weight at the endpoint. These results underscore the potential of GADD45B as an effective tumor suppressor in SKCM. In conclusion, our findings highlight GADD45B as a key regulator in SKCM progression, capable of restraining tumor cell proliferation and enhancing apoptosis. GADD45B holds promise as a novel diagnostic and prognostic biomarker and a potential target for SKCM immunotherapy.
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Macrophage-derived exosome promotes regulatory T cell differentiation in malignant pleural effusion.
INTRODUCTION: Tumor-associated macrophages are one of the key components of the tumor microenvironment. The immunomodulatory activity and function of macrophages in malignant pleural effusion (MPE), a special tumor metastasis microenvironment, have not been clearly defined. METHODS: MPE-based single-cell RNA sequencing data was used to characterize macrophages. Subsequently, the regulatory effect of macrophages and their secreted exosomes on T cells was verified by experiments. Next, miRNA microarray was used to analyze differentially expressed miRNAs in MPE and benign pleural effusion, and data from The Cancer Genome Atlas (TCGA) was used to evaluate the correlation between miRNAs and patient survival. RESULTS: Single-cell RNA sequencing data showed macrophages were mainly M2 polarized in MPE and had higher exosome secretion function compared with those in blood. We found that exosomes released from macrophages could promote the differentiation of naïve T cells into Treg cells in MPE. We detected differential expression miRNAs in macrophage-derived exosomes between MPE and benign pleural effusion by miRNA microarray and found that miR-4443 was significantly overexpressed in MPE exosomes. Gene functional enrichment analysis showed that the target genes of miR-4443 were involved in the regulation of protein kinase B signaling and lipid biosynthetic process. CONCLUSIONS: Taken together, these results reveal that exosomes mediate the intercellular communication between macrophages and T cells, yielding an immunosuppressive environment for MPE. miR-4443 expressed by macrophages, but not total miR-4443, might serve as a prognostic marker in patients with metastatic lung cancer.
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Single-Cell Transcriptomic Atlas of Chicken Ovarian Aging and Cancer Drives Prognostic Model Development.
Background: Ovarian cancer remains the deadliest gynecologic malignancy, with its progression closely tied to age-associated remodeling of the tumor immune microenvironment. The laying hen serves as a valuable spontaneous model for human ovarian cancer. Its single-cell analyses may provide valuable insights into the immune-related axis linking ovarian aging to carcinogenesis. Methods: This study applied single-cell RNA sequencing to profile ovaries from three laying hen groups, including 35-week-old normal ovaries (A35w), 110-week-old normal ovaries (B110w), and 110-week-old ovarian cancer tissues (C110w). Key analyses had UCell-based scoring of senescence-related pathways and cancer hallmarks, differential expression analysis for overlapping dysregulated genes, LASSO regression-based prognostic model construction, and assessment of chemotherapy sensitivity and immune infiltration. Results: A comprehensive cellular landscape of chicken ovaries was established, identifying major immune populations including B cells, CD4+ T cells, CD8+ T cells, macrophages, and plasma cells. Senescence-related pathways and cancer hallmarks showed progressive activation in immune cells from A35w to B110w to C110w. A total of 216 genes commonly dysregulated in aging and carcinogenesis, reveal core links between immune dysfunction and malignant transformation. The 20-gene prognostic model derived from these genes stratified human ovarian cancer patients into high-risk and low-risk groups with significant overall survival differences, exhibited robust predictive performance across TCGA, GSE32063, and GSE140082. The model also predicted the differential chemotherapy sensitivity in high-risk and low-risk patients and correlated with specific immune infiltration patterns in the tumor microenvironment. Conclusions: Notably, this is the first single-cell RNA sequencing study of chicken ovarian cancer, and we constructed the 20-gene prognostic model for human ovarian cancer using 216 genes that change significantly in immune cells during both ovarian aging and carcinogenesis. This work provides support to establish the hen as a potential preclinical animal model and a translational tool to guide personalized therapy.
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Changes in subcutaneous white adipose tissue cellular composition and molecular programs underlie glucose intolerance in persons with HIV.
INTRODUCTION: Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population. METHODS: We generated a comprehensive single-cell multi-omic SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH across a spectrum of metabolic health. RESULTS: Glucose intolerance was associated with increased lipid-associated macrophages, CD4+ and CD8+ T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program which enriched for genes related to inflammation and lipid-processing across multiple cell types as glucose intolerance increased. Increased CD4+ effector memory tissue-resident cells most strongly associated with altered expression of adipocyte genes critical for lipid metabolism and cellular regulation. Intercellular communication analysis demonstrated enhanced pro-inflammatory and pro-fibrotic signaling between immune cells and stromal cells in PWH with glucose intolerance compared with non-diabetic PWH. Lastly, while cell type-specific gene expression among PWH with diabetes was globally similar to HIV-negative individuals with diabetes, we observed substantially divergent intercellular communication pathways. DISCUSSION: These findings suggest a central role of tissue-resident immune cells in regulating SAT inflammation among PWH with metabolic disease, and underscore unique mechanisms that may converge to promote metabolic disease.
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Dissection of tumor antigens and immune landscape in clear cell renal cell carcinoma: Preconditions for development and precision medicine of mRNA vaccine.
Accumulating evidence reveals that mRNA-type cancer vaccines could be exploited as cancer immunotherapies in various solid tumors. However, the use of mRNA-type cancer vaccines in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to identify potential tumor antigens for the development of an anti-ccRCC mRNA vaccine. In addition, this study aimed to determine immune subtypes of ccRCC to guide the selection of patients to receive the vaccine. Raw sequencing and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Further, the cBioPortal website was used to visualize and compare genetic alterations. GEPIA2 was employed to evaluate the prognostic value of preliminary tumor antigens. Moreover, the TIMER web server was used to evaluate correlations between the expression of specific antigens and the abundance of infiltrated antigen-presenting cells (APCs). Single-cell RNA sequencing data of ccRCC was used to explore the expression of potential tumor antigens at single-cell resolution. The immune subtypes of patients were analyzed by the consensus clustering algorithm. Furthermore, the clinical and molecular discrepancies were further explored for a deep understanding of the immune subtypes. Weighted gene co-expression network analysis (WGCNA) was used to cluster the genes according to the immune subtypes. Finally, the sensitivity of drugs commonly used in ccRCC with diverse immune subtypes was investigated. The results revealed that the tumor antigen, LRP2, was associated with a good prognosis and enhanced the infiltration of APCs. ccRCC could be divided into two immune subtypes (IS1 and IS2) with distinct clinical and molecular characteristics. The IS1 group showed a poorer overall survival with an immune-suppressive phenotype than the IS2 group. Additionally, a large spectrum of differences in the expression of immune checkpoints and immunogenic cell death modulators were observed between the two subtypes. Lastly, the genes correlated with the immune subtypes were involved in multiple immune-related processes. Therefore, LRP2 is a potential tumor antigen that could be used to develop an mRNA-type cancer vaccine in ccRCC. Furthermore, patients in the IS2 group were more suitable for vaccination than those in the IS1 group.
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A risk score model based on glycosylation-related genes for predicting radioresistance and prognosis of lung adenocarcinoma.
BACKGROUND: Radiotherapy resistance (RR) is the main cause of radiotherapy failure in lung cancer patients, and its mechanisms are still unrevealed. Glycosylation, as a type of post-translational modification of proteins, plays a key role in tumor progression. Some studies have shown a strong link between glycosylation and RR. However, the absence of a systematic glycosylation-related genes (GRGs) model to predict radiotherapy efficacy in lung adenocarcinoma (LUAD) patients highlights a significant clinical and research gap. The aim of the research was to investigate the prognostic characteristics of GRGs in LUAD treated with radiotherapy. METHODS: RNA sequencing data of LUAD were obtained from The Cancer Genome Atlas (TCGA) database. The expression and prognostic significance of GRGs in patients who underwent radiotherapy were analyzed with bioinformatics tools, and the Gene Expression Omnibus (GEO) database was used for verification. Gene set enrichment analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), etc. were used to analyze the potential mechanism of risk model constructed by GRGs in LUAD. The predictive significance of risk model was investigated by immune infiltration analysis, somatic mutations, and drug susceptibility analysis, etc. Single-cell sequencing and molecular docking were used to find new potential targets for LUAD patients. Finally, our bioinformatics analysis results were verified by wet experiments. RESULTS: GO and KEGG analyses found that glycosylation played a pivotal role in LUAD RR. Forty-four differentially expressed radiotherapy-related glycosylation genes (DERRGGs) were identified in LUAD. KREMEN2, NRARP, QSOX2, GOLGA3, CELSR2, and SRI were screened out by least absolute shrinkage and selection operator (LASSO) analysis. A new risk model was constructed by these six DERRGGs, which showed good predictive power. Multivariate regression found that RiskScore was an independent prognostic factor. Immune infiltration analysis suggested that patients in the high-risk group were more susceptible to suffer from immunosuppression. Single-cell sequencing analysis showed the six genes were mainly distributed in malignant tumors. Drug sensitivity analysis found that the patients in the high-risk group were more sensitive to the clinical drugs, such as afatinib, cytarabine, gemcitabine and so on. Molecular docking demonstrated that tretinoin showed good binding affinity with NRARP, KREMEN2 and QSOX2. Our wet experiment results not only demonstrated that NRARP, KREMEN2 and QSOX2 were more abundant in LUAD irradiation-resistance cells and NRARP protein was significantly up-regulated in radiation-resistant samples, but also showed that tretinoin inhibited the survival of the irradiation-resistance cell obviously. CONCLUSIONS: This study constructed glycosylation related RiskScore to predict the prognosis of LUAD patients, specifically in the context of radiotherapy. We explored the relationship between radiotherapy efficacy, glycosylation and prognosis of LUAD patients, which provides new ideas for personalized treatment of LUAD patients. And we suggested that tretinoin may be a potential radiotherapy sensitizer for LUAD, providing a foundation for future investigations.
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Genetic and genomic insights into male reproductive tract development.
Genetic and genomic analysis continues to drive important insights into male reproductive tract (MRT) development. Here, we briefly review normal MRT development, highlighting recent discoveries of cell types and cellular processes delivered by single-cell sequencing. We report a systematic review of phenotype terms and genes linked to MRT development, identifying 35 terms from the Human Phenotype Ontology associated with 269 unique genes. A parallel review of mouse data revealed differences in the phenotype terms available and the number and identity of genes linked to MRT defects, indicating opportunities for harmonization of knowledge. We used a published single-cell atlas of the developing testis to characterize the regulation of MRT genes across cell types and stages of fetal testis development. Single-cell RNA sequencing data support the conclusion that Leydig cells and Sertoli cells are the primary testicular cell types expressing MRT genes. Furthermore, we find post-conception weeks 6, 8, and 16 to be the key points of upregulation of testicular MRT genes. New advances, especially in imaging and spatially resolved molecular measurements, provide exciting prospects for MRT research and diagnosis, and we expect rapid progress in the coming years. Continued investigation in this space is essential to understand the genetic basis of MRT development and how MRT defects are related to medical outcomes in adult life.
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Identification of mitochondrial-related subtypes and development of a prognostic model for pancreatic ductal adenocarcinoma.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a poor prognosis. Mitochondrial dysfunction, including alterations in metabolism, dynamics, and DNA, is increasingly recognized as a critical factor in the initiation and progression of pancreatic cancer. This study aimed to systematically investigate the role of mitochondrial dysfunction in PDAC to identify mitochondria-related genes (MitoRGs) of prognostic significance, explore associated molecular subtypes, and examine their effects on the tumor immune microenvironment. METHODS: We integrated transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify a set of MitoRGs with significant prognostic value for PDAC. Their expression was further validated in PDAC cells and using single-cell RNA-sequencing data. Unsupervised clustering was employed to classify PDAC patients into distinct subtypes based on MitoRG expression patterns. A robust prognostic model was subsequently constructed using least absolute shrinkage and selection operator-Cox regression analysis. The predictive accuracy of the model for 1-, 3-, and 5-year overall survival (OS) was assessed. The immune cell infiltration and genomic features of the risk groups defined by the model were also analyzed. Finally, a clinically applicable nomogram was developed to facilitate prognostic prediction. RESULTS: Based on MitoRG expression, PDAC patients were classified into two distinct subtypes (clusters A and B). Patients in cluster A exhibited significantly better OS than those in cluster B. A prognostic model based on a seven-MitoRG signature was established, which demonstrated high predictive accuracy. The high-risk group, as defined by the model, was characterized by an immunosuppressive tumor microenvironment, featuring reduced cytotoxic T-cell activity and increased stromal components. This group also showed significant enrichment of driver mutations such as KRAS and TP53. CONCLUSIONS: This study established a significant link between mitochondrial dysfunction and PDAC molecular subtypes, immune microenvironment remodeling, and clinical prognosis. The developed seven-MitoRG signature and nomogram could serve as reliable prognostic tools. These findings provide insights into the role of mitochondria in the pathogenesis of PDAC and offer potential targets for developing personalized therapeutic strategies.