Your browser does not allow saving data (e.g. private mode): bookmarks will be lost when the tab closes.
Search PubMed
Keywords, author, journal, years — results from PubMed, abstracts with Russian translation, bookmarks in your browser.
Found: 4 942
Page 438 of 495-
Pan-cancer analysis reveals BAF complexes as immune-related biomarkers and validation in triple-negative breast cancer.
AIMS: BAF complexes (BAFs), ATP-dependent regulators of chromatin structure, play a significant role in cancer progression. This pan-cancer study aimed to decode the potential of specific BAFs in the pathology, immunity, and therapy of targeted cancers. MATERIALS AND METHODS: Data were retrieved from The Cancer Genome Atlas, Gene Expression Omnibus, and IMvigor210 databases and were analyzed for expression patterns, prognostic value, mutational signatures, biological pathways, tumor immune microenvironment (TIME) remodeling, and therapeutic resistance of BAFs. Experimental validation was also conducted. KEY FINDINGS: BAFs exhibit abnormal expression in various human cancers. The BAFs model and nomogram (based on multiple variables) were developed as prognostic tools. BAFs regulate the TIME and influence the response to anti-PD-L1 therapy, particularly through ACTL6A, as observed in RNA sequencing and single-cell RNA sequencing datasets (high-resolution gene expression data at the single-cell level). ACTLA6 is a major adverse gene in the prognostic model. Patients with high ACTL6A expression showed significantly worse overall survival (hazard ratio = 1.32, 95 % CI: 1.26-1.39, p < 0.001). ACTL6A expression escalates with breast cancer (BRCA) malignancy, particularly in triple-negative BRCA (TNBC), and correlates with immune checkpoint expression while playing a crucial role in promoting cancer metastasis in TNBC. SIGNIFICANCE: Our findings first emphasize the significance of a novel BAFs model for patient prognosis and corroborate the considerable role of BAFs as immune-related biomarkers in pan-cancer progression. ACTL6A has a dual role as an immune-related biomarker and potential therapeutic target in TNBC, deepening our comprehension of its function as an oncogene.
-
BZW2 is a potential regulator of non-small cell lung cancer progression.
BACKGROUND: Personalized targeted therapy has become an important strategy for cancer treatment owing to its remarkable therapeutic efficacy and safety. However, drug resistance remains the primary cause of treatment failure. Basic leucine zipper and W2 domain 2 (BZW2), which is aberrantly expressed in cancer, has been implicated in tumor progression and may serve as a new therapeutic target. Therefore, the role of BZW2 in non-small cell lung cancer (NSCLC) requires further investigation. METHODS: The expression and genetic alterations of BZW2 in pan-cancers were explored using The Cancer Genome Atlas (TCGA) PanCancer databases. The mRNA and protein levels of BZW2 in patients with NSCLC were verified in our cohort. Functional experiments including CCK8, colony formation, and transwell assays were performed to evaluate the impact of BZW2 on the proliferative, migratory, and invasive capacities of SK-MES-1 cells. Gene Set Enrichment Analysis was used to identify underlying biological processes and pathways. Single-cell RNA (scRNA) sequencing data were employed to investigate the tumor microenvironment of NSCLC and the co-expression of BZW2 and stemness-related genes. RESULTS: Dysregulated BZW2 expression was observed in various malignant tumors. BZW2 expression was found to be significantly elevated in NSCLC. BZW2 depletion inhibited the growth, mobility, and invasive abilities of lung squamous cell carcinoma SK-MES-1 cells. BZW2 may be related to signaling pathways such as nucleotide excision repair, ubiquitin-mediated proteolysis, and the P53 signaling pathway. Biological processes, including translational initiation, tRNA processing, and RNA methylation, were observed to be enriched in the high-BZW2 group. Furthermore, there was a positive correlation between BZW2 and the m6A- and m5C-related genes. scRNA analysis revealed a co-expression relationship between BZW2 and stemness-related genes such as CD44, SOX9, and CD133. CONCLUSIONS: Elevated BZW2 expression is associated with the proliferation, migration, and invasion of NSCLC, and BZW2 may be a potential therapeutic target for NSCLC.
-
Clinical characterization and immunosuppressive regulation of CD161 (KLRB1) in glioma through 916 samples.
BACKGROUND: Glioblastoma is a paradigm of cancer-associated immunosuppression, limiting the effects of immunotherapeutic strategies. Thus, identifying the molecular mechanisms underlying immune surveillance evasion is critical. Recently, the preferential expression of inhibitory natural killer (NK) cell receptor CD161 on glioma-infiltrating cytotoxic T cells was identified. Focusing on the molecularly annotated, large-scale clinical samples from different ethnic origins, the data presented here provide evidence of this immune modulator's essential roles in brain tumor biology. METHODS: Retrospective RNA-seq data analysis was conducted in a cohort of 313 patients with glioma in the Chinese Glioma Genome Atlas (CGGA) database and 603 patients in The Cancer Genome Atlas (TCGA) database. In addition, single-cell sequencing data from seven surgical specimens of glioblastoma patients and a model in which patient-derived glioma stem cells were cocultured with peripheral lymphocytes, were used to analyze the molecular evolution process during gliomagenesis. RESULTS: CD161 was enriched in high-grade gliomas and isocitrate dehydrogenase (IDH)-wildtype glioma. CD161 acted as a potential biomarker for the mesenchymal subtype of glioma and an independent prognostic factor for the overall survival (OS) of patients with glioma. In addition, CD161 played an essential role in inhibiting the cytotoxicity of T cells in glioma patients. During the process of gliomagenesis, the expression of CD161 on different lymphocytes dynamically evolved. CONCLUSION: The expression of CD161 was closely related to the pathology and molecular pathology of glioma. Meanwhile, CD161 promoted the progression and evolution of gliomas through its unique effect on T cell dysfunction. Thus, CD161 is a promising novel target for immunotherapeutic strategies in glioma treatment.
-
Identification of tryptophan metabolism- and immune-related genes signature and prediction of immune infiltration landscape in bladder urothelial carcinoma.
INTRODUCTION: Tryptophan metabolism is indirectly involved in immune tolerance and promotes response to anticancer drugs. However, the mechanisms underlying tryptophan metabolism and immune landscape in bladder urothelial carcinoma (BLCA) are not fully understood. METHODS: A BLCA dataset containing 406 tumor samples with clinical survival information and 19 normal samples were obtained from the Cancer Genome Atlas database. The validation set, GSE32894, contained 223 BLCA tumor samples with survival information, and the single-cell dataset, GSE135337, included seven BLCA tumor samples; both were obtained from the gene expression omnibus database. Univariate and multivariate Cox regression analyses were conducted to evaluate clinical parameters and risk scores. Immune infiltration and checkpoint analyses were performed to explore the immune landscape of BLCA. Single-cell analysis was conducted to further identify the roles of model genes in BLCA. Finally, NAMPT expression in BLCA and adjacent tissues was detected using RT-qPCR, CCK-8 and Transwell assays were conducted to determine the role of NAMPT in BLCA cells. RESULTS: Six crossover genes (TDO2, ACAT1, IDO1, KMO, KYNU, and NAMPT) were identified by overlap analysis of tryptophan metabolism-related genes, immune-related genes, and differentially expressed genes (DEGs). Three biomarkers, NAMPT, IDO1, and ACAT1, were identified using Cox regression analysis. Accordingly, a tryptophan metabolism- and immune-related gene risk model was constructed, and the patients were divided into high- and low-risk groups. There were significant differences in the clinical parameters, prognosis, immune infiltration, and immunotherapy response between the risk groups. RT-qPCR revealed that NAMPT was upregulated in BLCA samples. Knocking down NAMPT significantly inhibited BLCA cell proliferation, migration, and invasion. DISCUSSION: In our study, we constructed a tryptophan metabolism- and immune-related gene risk model based on three biomarkers, namely NAMPT, IDO1, and ACAT1, that were significantly associated with the progression and immune landscape of BLCA. The risk model could effectively predict patient prognosis and immunotherapy response and can guide individualized immunotherapy.
-
A single-cell atlas of bone marrow B cells reveals defective central B-cell tolerance in immune thrombocytopenia.
Immune thrombocytopenia (ITP) is characterized by the overproduction of antiplatelet autoantibodies. Although B-cell depletion therapies show promise in ITP, their high relapse rates suggest a potential de novo breakdown of tolerance during an early stage of B-cell development. Here, we investigated how central B-cell tolerance mechanisms affect autoantibody production in ITP. Paired single-cell RNA/B-cell receptor (BCR) sequencing and bulk BCR sequencing revealed reduced V-J genomic distances in immunoglobulin kappa-chain (IGK) genes within bone marrow and peripheral B cells from patients with ITP, along with decreased expression of recombination-activating gene in the immature B cells, suggesting insufficient receptor editing. Single-cell antibody cloning demonstrated increased autoreactive and polyreactive naïve B cells in ITP, indicating defective central B-cell tolerance. Through an in vivo study, we established a causal link between receptor editing defects and antiplatelet antibody production, validating the immature B-cell stage as the key phase of dysregulation. These findings suggest that insufficient receptor editing of immature B cells triggers central B-cell tolerance deficiency and autoantibody accumulation in ITP.
-
Treatment resistance to melanoma therapeutics on a single cell level.
Therapy targeting the BRAF-MEK cascade created a treatment revolution for patients with BRAF mutant advanced melanoma. Unfortunately, 80% patients treated will progress by 5 years follow-up. Thus, it is imperative we study mechanisms of melanoma progression and therapeutic resistance. We created a scRNA (single cell RNA) atlas of 128,230 cells from 18 tumors across the treatment spectrum, discovering melanoma cells clustered strongly by transcriptome profiles of patients of origins. Our cell-level investigation revealed gains of 1q and 7q as likely early clonal events in metastatic melanomas. By comparing patient tumors and their derivative cell lines, we observed that PD1 responsive tumor fraction disappears when cells are propagated in vitro. We further established three anti-BRAF-MEK treatment resistant cell lines using three BRAF mutant tumors. ALDOA and PGK1 were found to be highly expressed in treatment resistant cell populations and metformin was effective in targeting the resistant cells. Our study suggests that the investigation of patient tumors and their derivative lines is essential for understanding disease progression, treatment response and resistance.
-
Single-cell multi-omics of human preimplantation embryos shows susceptibility to glucocorticoids.
The preconceptual, intrauterine, and early life environments can have a profound and long-lasting impact on the developmental trajectories and health outcomes of the offspring. Given the relatively low success rates of assisted reproductive technologies (ART; ∼25%), additives and adjuvants, such as glucocorticoids, are used to improve the success rate. Considering the dynamic developmental events that occur during this window, these exposures may alter blastocyst formation at a molecular level, and as such, affect not only the viability of the embryo and the ability of the blastocyst to implant, but also the developmental trajectory of the first three cell lineages, ultimately influencing the physiology of the embryo. In this study, we present a comprehensive single-cell transcriptome, methylome, and small RNA atlas in the day 7 human embryo. We show that, despite no change in morphology and developmental features, preimplantation glucocorticoid exposure reprograms the molecular profile of the trophectoderm (TE) lineage, and these changes are associated with an altered metabolic and inflammatory response. Our data also suggest that glucocorticoids can precociously mature the TE sublineages, supported by the presence of extravillous trophoblast markers in the polar sublineage and presence of X Chromosome dosage compensation. Further, we have elucidated that epigenetic regulation-DNA methylation and microRNAs (miRNAs)-likely underlies the transcriptional changes observed. This study suggests that exposures to exogenous compounds during preimplantation may unintentionally reprogram the human embryo, possibly leading to suboptimal development and longer-term health outcomes.
-
Identifying and validating the roles of the cuproptosis-related gene DKC1 in cancer with a focus on esophageal carcinoma.
BACKGROUND: Esophageal cancer is a common malignancy of the digestive tract. Despite remarkable advancements in its treatment, the overall prognosis for patients remains poor. Cuproptosis is a form of programmed cell death that affects the malignant progression of tumors. This study aimed to examine the impact of the cuproptosis-associated gene DKC1 on the malignant progression of esophageal cancer. METHODS: Clinical and RNA sequencing data of patients with esophageal cancer were extracted from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis was used to identify the differentially expressed genes related to cuproptosis that are associated with prognosis. We then validated the difference in the expression of DKC1 between tumor and normal tissues via three-dimensional multiomics difference analysis. Subsequently, we investigated the association between DKC1 expression and the tumor microenvironment by employing the TIMER2.0 algorithm, which was further validated in 96 single-cell datasets obtained from the TISCH database. Additionally, the functional role of DKC1 in pancarcinoma was assessed through GSEA. Furthermore, a comprehensive pancancer survival map was constructed, and the expression of DKC1 was verified in various molecular subtypes. By utilizing the CellMiner, GDSC, and CTRP databases, we successfully established a connection between DKC1 and drug sensitivity. Finally, the involvement of DKC1 in the progression of esophageal cancer was investigated through in vivo and in vitro experiments. RESULTS: In this study, we identified a copper death-related gene, DKC1, in esophageal cancer. Furthermore, we observed varying levels of DKC1 expression across different tumor types. Additionally, we conducted an analysis to determine the correlation between DKC1 expression and clinical features, revealing its association with common cell cycle pathways and multiple metabolic pathways. Notably, high DKC1 expression was found to indicate poor prognosis in patients with various tumors and to influence drug sensitivity. Moreover, our investigation revealed significant associations between DKC1 expression and the expression of molecules involved in immune regulation and infiltration of lymphocyte subtypes. Ultimately, the increased expression of DKC1 in esophageal cancer tissues was verified using clinical tissue samples. Furthermore, DKC1-mediated promotion of esophageal cancer cell proliferation and migration was confirmed through both in vitro and in vivo experiments. Additionally, it is plausible that DKC1 may play a role in the regulation of cuproptosis. CONCLUSION: In this study, we conducted a systematic analysis of DKC1 and its regulatory factors and experimentally validated its excellent diagnostic and prognostic abilities in various cancers. Further research indicated that DKC1 may reshape the tumor microenvironment (TME), highlighting the potential of DKC1-based cancer treatment and its usefulness in predicting the response to chemotherapy.
-
Single-cell RNA sequencing reveals the mechanism of PI3K/AKT/mTOR signaling pathway activation in lung adenocarcinoma by KRAS mutation.
BACKGROUND: Aberrant activation of the phosphatidlinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway has been shown to play an important role in lung adenocarcinoma (LUAD). The effect of KRAS mutations, one of the important signatures of LUAD, on the PI3K/AKT/mTOR pathway in LUAD remains unclear. METHODS: The Seurat package and principal component analysis were used for cell categorization of single-cell RNA sequencing data of LUAD. The AUCell score was used to assess the activity of the PI3K/AKT/mTOR pathway. Meanwhile, using the gene expression profiles and mutation profiles in the The Cancer Genome Atlas dataset, LUAD patients were categorized into KRAS-mutant (KRAS-MT) and KRAS-wild-types (KRAS-WT), and the corresponding enrichment scores were calculated using gene set enrichment analysis analysis. Finally, the subpopulation of cells with the highest pathway activity was identified, the copy number variation profile of this subpopulation was inscribed using the inferCNV package and the CMap database was utilized to make predictions for drugs targeting this subpopulation. RESULTS: There is higher PI3K/AKT/mTOR pathway activity in LUAD epithelial cells with KRAS mutations, and high expression of KRAS, PIK3CA, AKT1 and PDPK1. In particular, we found significantly higher levels of pathway activity and associated gene expression in KRAS-MT than in KRAS-WT. We identified the highest pathway activity on a subpopulation of GRB2+ epithelial cells and the presence of amplified genes within its pathway. Finally, drugs were able to target GRB2+ epithelial cell subpopulations, such as wortmannin, palbociclib and angiogenesis inhibitor. CONCLUSIONS: The present study provides a basic theory for the activation of the PI3K/AKT/mTOR signaling pathway as a result of KRAS mutations.
-
Comprehensively analysis of IL33 in hepatocellular carcinoma prognosis, immune microenvironment and biological role.
IL33 plays an important role in cancer. However, the role of liver cancer remains unclear. Open-accessed data was obtained from the Cancer Genome Atlas, Xena, and TISCH databases. Different algorithms and R packages are used to perform various analyses. Here, in our comprehensive study on IL33 in HCC, we observed its differential expression across cancers, implicating its role in cancer development. The single-cell analysis highlighted its primary expression in endothelial cells, unveiling correlations within the HCC microenvironment. Also, the expression level of IL33 was correlated with patients survival, emphasizing its potential prognostic value. Biological enrichment analyses revealed associations with stem cell division, angiogenesis, and inflammatory response. IL33's impact on the immune microenvironment showcased correlations with diverse immune cells. Genomic features and drug sensitivity analyses provided insights into IL33's broader implications. In a pan-cancer context, IL33 emerged as a potential tumour-inhibitor, influencing immune-related molecules. This study significantly advances our understanding of IL33 in cancer biology. IL33 exhibited differential expression across cancers, particularly in endothelial cells within the HCC microenvironment. IL33 is correlated with the survival of HCC patients, indicating potential prognostic value and highlighting its broader implications in cancer biology.