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Targeting HVEM-GPT2 axis: a novel approach to T cell activation and metabolic reprogramming in non-small cell lung cancer therapy.
BACKGROUND: The modulation of tumor microenvironments through immune checkpoint pathways is pivotal for the development of effective cancer immunotherapies. This study aims to explore the role of HVEM in non-small cell lung cancer (NSCLC) microenvironment. METHODS: The lung cancer datasets for this study were directly downloaded from The Cancer Genome Atlas (TCGA). Single-cell data were sourced from the Tumor Immune Single-cell Hub (TISCH). Multiplex immunohistochemistry (mIHC) was used to explore the cellular composition and spatial distribution of HVEM in lung cancer immune microenvironment. The immune microenvironment of HVEM KO mice bearing mouse lung cancer cell was also evaluated. Co-cultured system and phenotype assays facilitated the examination of Jurkat T cells' effect on A549 and H1299 lung cancer cells. Quantitative PCR and Western blotting determined gene and protein expression, respectively, cellular respiration was measured through oxygen consumption rate (OCR) assays. Lung cancer cells co-cultured with Jurkat T cells were xenografted into nude mice to evaluate tumor growth and metastatic potential. Next, RNA-seq, COIP, Dual-luciferase reporter experiment, and CHIP-seq were used to explore the potential underlying mechanism. RESULTS: In our study, we investigated the role of HVEM in the microenvironment of NSCLC and its implications in immunotherapy. Crucially, HVEM, part of the tumor necrosis factor receptor superfamily, influences T cell activation, potentially impacting immunotherapeutic outcomes. Using the TIDE algorithm, our results showcased a link between HVEM levels and immune dysfunction in NSCLC patients. Delving deeper into the NSCLC microenvironment, we found HVEM predominantly expressed in T cell subpopulations. CD8 + HVEM + and CD4 + HVEM + indicated better prognosis in lung adenocarcinoma tissue microarray using multiplex immunohistochemistry. Activated T cells, particularly from the Jurkat cell line, significantly inhibited NSCLC progression, reducing both proliferation and invasion capabilities of A549 and H1299 lung cancer cell lines. In vivo models reinforced these observations. Manipulating HVEM expression revealed its essential role in T cell survival and activation. In addition, animal experiments revealed the importance of HVEM in maintaining activated peripheral immunity and inflamed local tumor microenvironment. Furthermore, our data suggest that HVEM is pivotal in T cell metabolic reprogramming, transitioning from oxidative phosphorylation to aerobic glycolysis. RNA sequencing illuminated a potential relationship between HVEM and GPT2, an enzyme tied to amino acid metabolism and cellular energetics. Subsequent experiments confirmed that HVEM's influence on T cell activation and metabolism is potentially mediated through its regulation of GPT2. In addition, GATA1 was validated to regulate HVEM expression in activated Jurkat T cells. CONCLUSIONS: Our study establishes that HVEM significantly influences T cell functionality and NSCLC cell dynamics, pinpointing the HVEM-GPT2 axis as a promising target for NSCLC therapy.
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Heterogeneity of fibroblasts is a hallmark of age-associated erectile dysfunction.
BACKGROUND: The prevalence of age-associated erectile dysfunction (ED) increases pronouncedly with age. However, the cellular composition and transcriptomic changes of aging penile corpus cavernosum remain largely unclear. METHODS: Herein, we performed single cell sequencing penile corpus cavernosum from five young with normal erectile response and five old rats with ED. RESULTS: Clustering analysis identified 19 cell types, such as fibroblasts, myofibroblasts and immune cells. We next revealed their transcriptomic alterations and investigated novel subpopulations of major cell types. Among them, fibroblasts possessed the largest cell number and showed apparent heterogeneity. By performing single-cell entropy analysis on fibroblasts, we observed the age-associated decrease of entropy, and aged fibroblasts were found to adopt senescent secretory phenotype, as evidenced by the high expression of genes associated with the senescence-associated secretory phenotype (SASP). Finally, we constructed a comprehensive intercellular communication network and highlighted key mediators of crosstalk between fibroblasts and other cell types. CONCLUSIONS: We plotted a cellular atlas of aging cells within penile corpus cavernosum, especially fibroblasts. Our work will deepen the understanding of the heterogeneity among certain cell types within aged penile corpus cavernosum, which will generate positive effects on the future treatment of age-associated ED.
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Low NT5DC2 expression predicts favorable prognosis and suppresses soft tissue sarcoma progression via ECM-receptor interaction pathway.
BACKGROUND: Soft tissue sarcoma, a malignant tumor arising from mesenchymal tissues with poor prognosis. 5'-Nucleotidase Domain Containing 2 (NT5DC2) is a novel oncogene, and the precise involvement of NT5DC2 in soft tissue sarcoma were still undefined. Hence, our study aims to investigate NT5DC2 functions in soft tissue sarcoma progression. METHODS: The tumor immune single-cell hub 2 (TISCH2) website, The Cancer Genome Atlas (TCGA) pan-cancer or sarcoma and Gene Expression Omnibus (GEO, GSE21122) databases were applied to visualize the NT5DC2 status in the sarcoma databases. The NT5DC2 protein expression in sarcoma tissues in our hospital was detected by using immunohistochemistry (IHC) and analyzed the associations between NT5DC2 expression and clinicopathological parameters. Real-time quantitative polymerase chain reaction (RT-qPCR), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) assay, wound healing, transwell, flow cytometry and xenograft model were used to elucidate the effects of NT5DC2 downregulated by lentivirus in sarcoma cell. RESULTS: The TISCH2 website detection found that NT5DC2 expression is enriched in malignant cells in sarcoma single-cell database. Furthermore, the TCGA-sarcoma database indicated that NT5DC2 expression correlates with metastasis, positive margin status, prognosis, and diagnostic value. Additionally, IHC staining showed that 40 % of soft tissue sarcoma patients present high expression of NT5DC2, and NT5DC2 upregulation is closely associated with poor prognosis. Functional verification analysis further revealed that downregulating NT5DC2 expression can suppress sarcoma progression through the ECM-receptor interaction pathway. CONCLUSION: Low expression of NT5DC2 predicts a favorable prognosis in soft tissue sarcoma, and downregulated NT5DC2 expression can suppress sarcoma cell progression through the ECM-receptor interaction pathway.
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Low-grade glioma risk SNP rs11706832 is associated with type I interferon response pathway genes in cell lines.
Genome-wide association studies (GWAS) have contributed to our understanding of glioma susceptibility. To date, 25 risk loci for development of any of the glioma subtypes are known. However, GWAS studies reveal little about the molecular processes that lead to increased risk, especially for non-coding single nucleotide polymorphisms (SNP). A particular SNP in intron 2 of LRIG1, rs11706832, has been shown to increase the susceptibility for IDH1 mutated low-grade gliomas (LGG). Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is important in cancer development as it negatively regulates the epidermal growth factor receptor (EGFR); however, the mechanism responsible for this particular risk SNP and its potential effect on LRIG1 are not known. Using CRISPR-CAS9, we edited rs11706832 in HEK293T cells. Four HEK293T clones with the risk allele were compared to four clones with the non-risk allele for LRIG1 and SLC25A26 gene expression using RT-qPCR, for global gene expression using RNA-seq, and for metabolites using gas chromatography-mass spectrometry (GC-MS). The experiment did not reveal any significant effect of the SNP on the expression levels or splicing patterns of LRIG1 or SLC25A26. The global gene expression analysis revealed that the risk allele C was associated with upregulation of several mitochondrial genes. Gene enrichment analysis of 74 differentially expressed genes in the genome revealed a significant enrichment of type I interferon response genes, where many genes were downregulated for the risk allele C. Gene expression data of IDH1 mutated LGGs from the cancer genome atlas (TCGA) revealed a similar under expression of type I interferon genes associated with the risk allele. This study found the expression levels and splicing patterns of LRIG1 and SLC25A26 were not affected by the SNP in HEK293T cells. However, the risk allele was associated with a downregulation of genes involved in the innate immune response both in the HEK293T cells and in the LGG data from TCGA.
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POSTN+ cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma.
OBJECTIVE: Hepatocellular carcinoma (HCC) poses a significant clinical challenge because the long-term benefits of immune checkpoint blockade therapy are limited. A comprehensive understanding of the mechanisms underlying immunotherapy resistance in HCC is imperative for improving patient prognosis. DESIGN: In this study, to systematically investigate the characteristics of cancer-associated fibroblast (CAF) subsets and the dynamic communication among the tumor microenvironment (TME) components regulated by CAF subsets, we generated an HCC atlas by compiling single-cell RNA sequencing (scRNA-seq) datasets on 220 samples from six datasets. We combined spatial transcriptomics with scRNA-seq and multiplexed immunofluorescence to identify the specific CAF subsets in the TME that determine the efficacy of immunotherapy in HCC patients. RESULTS: Our findings highlight the pivotal role of POSTN+ CAFs as potent immune response barriers at specific tumor locations, as they hinder effective T-cell infiltration and decrease the efficacy of immunotherapy. Additionally, we elucidated the interplay between POSTN+ CAFs and SPP1+ macrophages, whereby the former recruits the latter and triggers increased SPP1 expression via the IL-6/STAT3 signaling pathway. Moreover, we demonstrated a spatial correlation between POSTN+ CAFs and SPP1+ macrophages, revealing an immunosuppressive microenvironment that limits the immunotherapy response. Notably, we found that patients with elevated expression levels of both POSTN+ CAFs and SPP1+ macrophages achieved less therapeutic benefit in an immunotherapy cohort. CONCLUSION: Our research elucidates light on the role of a particular subset of CAFs in immunotherapy resistance, emphasizing the potential benefits of targeting specific CAF subpopulations to improve clinical responses to immunotherapy.
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The prognostic impact of pathogenic stromal cell-associated genes in lung adenocarcinoma.
BACKGROUND: Lung adenocarcinoma (LUAD) stands as the most prevalent subtype among lung cancers. Interactions between stromal and cancer cells influence tumor growth, invasion, and metastasis. However, the regulatory mechanisms of stromal cells in the lung adenocarcinoma tumor microenvironment remain unclear. This study seeks to elucidate the regulatory connections among critical pathogenic genes and their associated expression variations within distinct stromal cell subtypes. METHOD: Analysis and investigation were conducted on a total of 114,019 single-cell RNA data and 346 The Cancer Genome Atlas (TCGA) LUAD-related samples using bioinformatics and statistical algorithms. Differential gene expression analysis was performed for tumor samples and controls, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Differential genes between stromal cells and other cell clusters were identified and intersected with the differential genes from TCGA. We employed a combination of LASSO regression and multivariable Cox regression to identify the ultimate set of pathogenic gene. Survival models were trained to predict the relationship between patient survival and these pathogenic genes. Analysis of transcription factor (TF) cell specificity and pseudotime trajectories within stromal cell subpopulations revealed that vascular endothelial cells (ECs) and matrix cancer-associated fibroblasts (CAFs) are key in regulation of the prognosis-associated genes CAV2, COL1A1, TIMP1, ETS2, AKAP12, ID1 and COL1A2. RESULTS: Seven pathogenic genes associated with LUAD in stromal cells were identified and used to develop a survival model. High expression of these genes is linked to a greater risk of poor survival. Stromal cells were categorized into eight subtypes and one unannotated cluster. Mesothelial cells, vascular endothelial cells (ECs), and matrix cancer-associated fibroblasts (CAFs) showed cell-specific regulation of the pathogenic genes. CONCLUSIONS: The seven disease-causing genes in vascular ECs and matrix CAFs can be used to detect the survival status of LUAD patients, providing new directions for future targeted drug design.
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Upregulation of HCFC1 expression promoted hepatocellular carcinoma progression through inhibiting cell cycle arrest and correlated with immune infiltration.
Background: Host cell factor 1 (HCFC1) was reported associated with the progression of a variety of cancers. However, its role in the prognosis and immunological characteristics of hepatocellular carcinoma (HCC) patients has not been revealed. Methods: The expression and prognostic value of HCFC1 in HCC were investigated from the Cancer Genome Atlas (TCGA) dataset and a cohort of 150 HCC patients. The associations between HCFC1 expression with somatic mutational signature, tumor mutational burden (TMB), and microsatellite instability (MSI) were investigated. Next, the correlation of HCFC1 expression with immune cell infiltration was investigated. In vitro, cytological experiments were conducted to verify the role of HCFC1 in HCC. Results: HCFC1 mRNA and protein upregulated in HCC tissues and correlated to poor prognosis. Multivariate regression analysis based on a cohort of 150 HCC patients revealed that high HCFC1 protein expression was an independent risk factor for prognosis. Upregulation of HCFC1 expression was associated with TMB, MSI, and tumor purity. HCFC1 expression showed a significant positive association with B cell memory, T cell CD4 memory, macrophage M0, and a significant positive association with immune checkpoint-related gene expression in the tumor microenvironment. HCFC1 expression negatively correlated to ImmuneScore, EstimateScore, and StromalScore. The single-cell RNA sequencing analysis demonstrated that the malignant cells and immune cells (B cells, T cells, and macrophages) represented high HCFC1 expression in HCC tissues. Functional analysis revealed that HCFC1 was remarkably correlated with cell cycle signaling. HCFC1 knockdown inhibited the proliferation, migration, and invasion capacity while promoting the apoptosis of HCC cells. At the same time, the cell-cycle-related proteins such as Cyclin D1 (CCND1), Cyclin A2 (CCNA2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) were downregulated. Conclusion: Upregulation of HCFC1 predicted undesirable prognosis of HCC patients and promoted tumor progression through inhibiting cell cycle arrest.
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Comprehensive pan-cancer investigation: unraveling the oncogenic, prognostic, and immunological significance of Abelson interactor family member 3 gene in human malignancies.
Background: Abelson interactor Family Member 3 (ABI3) encodes protein that not only suppresses the ectopic metastasis of tumor cells but also hinders their migration. Although ABI3 had been found to modulate the advancement of diverse neoplasms, there is no comprehensive pan-cancer analysis of its effects. Methods: The transcriptomics data of neoplasm and normal tissues were retrieved from the Genomic Data Commons (GDC) data portal, and UCSC XENA database. To gather protein information for ABI3, Human Protein Atlas (HPA) and GeneMANIA websites were utilized. Additionally, Tumor Immune Single-cell Hub (TISCH) database was consulted to determine the primary cell types expressing ABI3 in cancer microenvironments. Univariate Cox regression approach was leveraged to evaluate ABI3's prognostic role across cancers. The Cbioportal and Gene Set Cancer Analysis (GSCA) website were leveraged to scrutinize the genomic landscape information across cancers. TIMER2.0 was leveraged to probe the immune cell infiltrations associated with ABI3 across cancers. The associations of ABI3 with immune-related genes were analyzed through Spearman correlation method. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were utilized to search associated biological pathways. The CellMiner database and molecular docking were implemented to identify potential interactions between the ABI3 protein and specific anticarcinogen. Findings: ABI3 expression and its ability to predict prognosis varied distinct tumor, with particularly high expression observed in Tprolif cells and monocytes/macrophages. Copy number variation (CNV) and methylation negatively correlated with ABI3 expression in the majority of malignancies. Corresponding mutation survival analysis indicated that the mutation status of ABI3 was strongly connected to the prognosis of LGG patients. ABI3 expression was linked to immunotherapeutic biomarkers and response in cancers. ESTIMATE and immune infiltrations analyses presented ABI3 association with immunosuppression. ABI3 was significantly correlated with immunoregulators and immune-related pathways. Lastly, prospective ABI3-targeted drugs were filtered and docked to ABI3 protein. Interpretation: Our study reveals that ABI3 acts as a robust tumor biomarker. Its functions are vital that could inhibit ectopic metastasis of tumor cells and modulate cellular adhesion and migration. The discoveries presented here may have noteworthy consequences for the creation of fresh anticancer suppressors, especially those targeting BRCA.
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C1ORF112 drives lung adenocarcinoma progression through e2f8-mediated transcriptional activation.
BACKGROUND: Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality, with poor prognosis driven by metastasis and therapeutic resistance. Chromosome 1 open reading frame 112 (C1ORF112) encodes a nuclear protein involved in DNA replication and repair, but its role in LUAD is unclear. To systematically investigate the clinical relevance, functional impact, and transcriptional regulation of C1ORF112 in LUAD through integrative bioinformatic and experimental approaches. METHODS: C1ORF112 expression and prognostic significance were analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Single-cell RNA sequencing defined cellular localization and communication patterns. Functional enrichment, protein-protein interaction (PPI), and transcription factor prediction analyses were performed. In vitro assays and xenograft models assessed biological functions and transcriptional regulation by E2F8. RESULTS: C1ORF112 was significantly upregulated in LUAD and correlated with poor overall survival (OS). Single-cell analysis showed elevated expression in malignant cells, fibroblasts, endothelial cells, and mast cells, accompanied by increased communication with M2 macrophages and exhausted CD8+ T cells. Overexpression of C1ORF112 inhibited apoptosis and promoted proliferation in LUAD cells, while xenografts exhibited accelerated tumor growth and increased Ki67 expression. Mechanistically, E2F8 directly bound the C1ORF112 promoter, enhancing its transcription and inhibiting downstream p53 signaling. CONCLUSIONS: Our integrative analysis suggests that C1ORF112 exhibits oncogenic properties in LUAD by promoting tumor survival, proliferation, and potentially remodeling the tumor microenvironment. The transcriptional activation by E2F8 highlights the E2F8-C1ORF112 axis as a candidate prognostic biomarker and therapeutic vulnerability, though prospective clinical validation and drug sensitivity studies are warranted.
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Deciphering the transcriptional regulatory network driving lung adenocarcinoma progression.
Normal type II alveolar epithelial cells transform into lung adenocarcinoma through intermediate stages of adenocarcinoma in situ and minimally invasive adenocarcinoma, eventually becoming invasive adenocarcinoma. Transcription factors (TFs) are pivotal in tumorigenesis and development, etc. In this study, we modeled the malignant transformation of AT2 cells into lung adenocarcinoma using single-cell profiling, focusing on TF-mediated transcriptional repression or activation as a key mechanism. We analyzed data from 29 motifs database, including Jaspar, Bergman, Transfac and cisBP, compiling a collection of 18,422 motifs. By integrating Motif analysis to deduce the target genes regulated by transcription factors exhibiting activity alterations across various progression stages of lung adenocarcinoma, and subsequently determining the intersection between these target genes and the differentially expressed genes at each stage, we can pinpoint the target genes that are both differentially expressed and under the regulation of key transcription factors at each stage. Consequently, the regulatory mechanism of TFs on target genes in lung adenocarcinoma was speculated. Furthermore, the transcriptional regulatory network reveals that TFs modulate signaling pathways, cellular metabolism, and biological processes during the transformation process. In addition, leveraging six transcription factors (REBF2, CEBPB, TFCP2, IRF6, ETV4, and BHLHE40) that exhibit progressively increasing activity during the progression of lung adenocarcinoma, we developed a pivotal progression model score, termed the "Lung Adenocarcinoma Transformation TFs Upregulation" (LUAD-TTFs-UP) score, to predict both the progression and prognosis of this disease.