Exploration of the Prognostic and Immunotherapeutic Value of B and T Lymphocyte Attenuator in Skin Cutaneous Melanoma.
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ABSTRACT:
SUBMITTER: Dong X
PROVIDER: S-EPMC7953043 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: The functional significance of the proteasome activator subunit (PSME) gene family in the pathogenesis of skin cutaneous melanoma (SKCM) remains to be elucidated. Materials and methods: Clinical data for patients with SKCM, including expression levels of PSME genes, were extracted from TCGA. GO term and KEGG pathway enrichment analyses were performed. Correlations between the expression levels of PSME genes in SKCM were evaluated with the Pearson correlation coefficient. Functional and enrichment analyses were conducted using DAVID. Univariate and multivariate survival analyses adjusted by Cox regression were used to construct a prognostic signature. The mechanisms underlying the association between PSME gene expression and overall survival (OS) were explored with gene set enrichment analysis. Joint-effects survival analysis was performed to evaluate the clinical value of the prognostic signature. Results: The median expression levels of PSME1, PSME2 and PSME3 were significantly higher in SKCM than in normal skin. PSME1, PSME2, and PSME3 were significantly enriched in several biological processes and pathways including cell adhesion, adherens junction organization, regulation of autophagy, cellular protein localization, the cell cycle, apoptosis, and the Wnt and NF-κB pathways. High expression levels of PSME1 and PSME2 combined with a low expression level of PSME3 was associated with favorable OS. Conclusion: Knowledge of the expression levels of the PSME gene family could provide a sensitive strategy for predicting prognosis in SKCM.
| S-EPMC6584401 | biostudies-literature
Project description:BackgroundMeasures of the adaptive immune response have prognostic and predictive associations in melanoma and other cancer types. Specifically, intratumoral T cell density and function have considerable prognostic and predictive value in skin cutaneous melanoma (SKCM). Less is known about the significance of tumor-infiltrating B cells in SKCM. Our goal was to understand the prognostic and predictive value of B cell phenotypic subsets in SKCM using RNA sequencing.MethodsWe used our previously published algorithm, V'DJer, to assemble B cell receptor (BCR) repertoires and estimate diversity from short-read RNA sequencing (RNA-seq). We applied machine learning-based cellular phenotype classifiers to measure relative similarity of bulk tumor sample gene expression profiles and different B cell phenotypes. We assessed these aspects of B cell biology in 473 SKCM from the Cancer Genome Atlas Project (TCGA) as well as in RNA-seq data corresponding to tumor samples procured from patients who received CTLA-4 and PD-1 inhibitors for metastatic SKCM.ResultsWe found that the BCR repertoire was associated with different clinical factors, such as tumor tissue site and sex. However, increased clonality of the BCR repertoire was favorably prognostic in SKCM and was prognostic even after first conditioning on various clinical factors. Mutation burden was not correlated with any BCR measurement, and no specific mutation had an altered BCR repertoire. Lack of an assembled BCR in pre-treatment tumor tissues was associated with a lack of anti-tumor response to a CTLA-4 inhibitor in metastatic SKCM.ConclusionsThese findings suggest an important prognostic and predictive role for B cell characteristics in SKCM. This has implications for melanoma immunobiology and potential development of immunogenomics features to predict survival and response to immunotherapy.
| S-EPMC6540526 | biostudies-literature
Project description:Background: Skin cutaneous melanoma (SKCM) is a common malignancy that is associated with increased morbidity and mortality. Complement C1Q is composed of C1QA, C1QB, and C1QC and is involved in the occurrence and development of many malignant tumours. However, the effect of C1QA, C1QB, and C1QC expression on tumour immunity and prognosis of cutaneous melanoma remains unclear. Methods: First, we analysed C1QA, C1QB, and C1QC expression levels and prognostic values using Gene Expression Profiling Interactive Analysis (GEPIA) and Tumour Immune Estimation Resource (TIMER) analysis, and further validation was performed using RT-qPCR, The Human Protein Atlas, The Cancer Genome Atlas (TCGA) dataset, and Gene Expression Omnibus dataset. We then performed univariate/multivariate Cox proportional hazard model, clinicopathological correlation, and receiver operating characteristic curve analysis using TCGA dataset and established a nomogram model. Differentially expressed genes associated with C1QA, C1QB, and C1QC in SKCM were identified and analysed using LinkedOmics, TIMER, the Search Tool for the Retrieval of Interacting Genes database, and Metascape and Cytoscape software platforms. We used TIMER, GEPIA, and single-sample gene set enrichment analysis (ssGSEA) to analyse the relationship between the three genes and the level of immune cell infiltration, biomarkers, and checkpoint expression in SKCM. Finally, GSEA was utilized to study the functional pathways of C1QA, C1QB, and C1QC enrichment in SKCM. Results: The overexpression of C1QA, C1QB, and C1QC provided significant value in the diagnosis of SKCM and has been associated with better overall survival (OS). Multivariate Cox regression analysis indicated that C1QA, C1QB, and C1QC are independent prognostic biomarkers for patients with SKCM. Immune cell infiltration, biomarkers, and checkpoints were positively correlated with the expression of C1QA, C1QB, and C1QC. Furthermore, the results of functional and pathway enrichment analysis showed that immune-related and apoptotic pathways were significantly enriched in the high-expression group of C1QA, C1QB, and C1QC. Conclusion: We found that C1QA, C1QB, and C1QC can be used as biomarkers for the diagnosis and prognosis of SKCM patients. The upregulated expression levels of these three complement components benefit patients from OS and may increase the effect of immunotherapy. This result may be due to the dual effects of anti-tumour immunity and apoptosis.
| S-EPMC9468976 | biostudies-literature
Project description: Not available
| S-EPMC11337913 | biostudies-literature
Project description:Tissue Transglutaminases (TGs) are crosslinking enzymes with pleiotropic functions that have been linked to the development and progression of numerous cancers, with a recent focus on their ability to remodel the tumor microenvironment. Although several pieces of evidence demonstrated their importance in the regulation of the major signaling pathways that control oncogenesis, the correlation between TGs with clinical and pathological features remains controversial and to be further explored. Moreover, an assessment of the TGs alterations together with a functional analysis associated with clinical features and prognostic values are still lacking and would help to understand these intricacies, particularly in human cancers. In the present study, we processed data from numerous public datasets to investigate TGs distribution and prognostic signature in cancer patients. Here, we found that skin cutaneous melanoma (SKCM) shows the highest abundance of TGs mutations among the other human cancers. Interestingly, among all the TGs, TG2 is the only member whose expression is associated with a better overall survival in SKCM, although its expression increases with the worsening of the tumor phenotype. Our analysis revealed a strong positive association between TG2 expression and anti-tumoral immune response, which would explain the relationship between high mRNA levels and better overall survival. Our data suggest that TG2 may be presented as a new promising immune biomarker of prognosis in SKCM, which may contribute to identifying patients who would benefit the most from adjuvant immunotherapy.
| S-EPMC9209462 | biostudies-literature
Project description:Skin cutaneous melanoma (SKCM) is a highly malignant tumor that is prone to immune escape and distant metastasis. Immunotherapy is considered to be the best treatment for patients with SKCM. However, not all patients benefit from it. We observed a significant differential expression of the lncRNA CYTOR in patients with SKCM based on single-cell and bulk RNA sequencing data mining results. The results showed that compared to normal tissue lncRNA CYTOR expression was significantly upregulated in SKCM tissue. Subsequently, we validated this finding in clinical samples, and we also found that the expression of lncRNA CYTOR in SKCM was higher as it progressed. lncRNA CYTOR was differentially expressed in patients who responded to immunotherapy, suggesting that it may serve as a biomarker to predict the efficacy of SKCM immunotherapy. In-depth analysis revealed that lncRNA CYTOR expression was strongly correlated with immune cell infiltration, immune response, and immune checkpoint expression. Meanwhile, our experiments revealed that CYTOR affects SKCM cell invasion and clone formation and is associated with the activation of the EMT pathway. In summary, our findings illustrate, for the first time, the value of CYTOR as a potential prognostic and immunotherapeutic response marker in SKCM.
| S-EPMC11190755 | biostudies-literature
Project description:Skin cutaneous melanoma (SKCM) is a highly aggressive tumor. The mortality and drug resistance among it are high. Thus, exploring predictive biomarkers for prognosis has become a priority. We aimed to find immune cell-based biomarkers for survival prediction. Here 321 genes were differentially expressed in immune-related groups after ESTIMATE analysis and differential analysis. Two hundred nineteen of them were associated with the metastasis of SKCM via weighted gene co-expression network analysis. Twenty-six genes in this module were hub genes. Twelve of the 26 genes were related to overall survival in SKCM patients. After a multivariable Cox regression analysis, we obtained six of these genes (PLA2G2D, IKZF3, MS4A1, ZC3H12D, FCRL3, and P2RY10) that were independent prognostic signatures, and a survival model of them performed excellent predictive efficacy. The results revealed several essential genes that may act as significant prognostic factors of SKCM, which could deepen our understanding of the metastatic mechanisms and improve cancer treatment.
| S-EPMC8337057 | biostudies-literature
Project description:Skin cutaneous melanoma (SKCM) is a type of highly invasive cancer originated from melanocytes. It is reported that aberrant alternative splicing (AS) plays an important role in the neoplasia and metastasis of many types of cancer. Therefore, we investigated whether ASEs of pre-RNA have such an influence on the prognosis of SKCM and the related mechanism of ASEs in SKCM. The RNA-seq data and ASEs data for SKCM patients were obtained from the TCGA and TCGASpliceSeq database. The univariate Cox regression revealed 1265 overall survival-related splicing events (OS-SEs). Screened by Lasso regression, 4 OS-SEs were identified and used to construct an effective prediction model (AUC: .904), whose risk score was proved to be an independent prognostic factor. Furthermore, Kruskal-Wallis test and Mann-Whitney-Wilcoxon test showed that an aberrant splicing type of aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) regulated by CDC-like kinase 1 (CLK1) was associated with the metastasis and stage of SKCM. Besides, the overlapped signal pathway for AIMP2 was galactose metabolism identified by the co-expression analysis. External database validation also confirmed that AIMP2, CLK1, and the galactose metabolism were associated with the metastasis and stage of SKCM patients. ChIP-seq and ATAC-seq methods further confirmed the transcription regulation of CLK1, AIMP2, and other key genes, whose cellular expression was detected by Single Cell Sequencing. In conclusion, we proposed that CLK1-regulated AIMP2-78704-ES might play a critical role in the tumorigenesis and metastasis of SKCM via galactose metabolism. Besides, we established an effective model with MTMR14-63114-ES, URI1-48867-ES, BATF2-16724-AP, and MED22-88025-AP to predict the metastasis and prognosis of SKCM patients.
| S-EPMC8743934 | biostudies-literature
Project description:Skin cutaneous melanoma (SKCM) is one of the most aggressive and life-threatening cancers with high incidence rate, metastasis rate and mortality. Early detection and stratification of risk assessment are essential to treat SKCM and to improve survival rate. The aim of this study is to construct an immune-related lncRNAs (immlncRNAs) prognosis risk model to identify immune biomarkers for early diagnosis, prognosis assessment and target immunotherapy of SKCM. For this purpose, we identified 46 immlncRNAs significantly correlated with SKCM prognosis to construct the prognostic risk model and patients were stratified into the high- and low-risk subgroups according to the developed model. The predictive efficiency of this model has been proved by K-M survival analysis and receiver operating characteristic curve. Moreover, CIBERSORT algorithms confirmed that there were differences in immune cell infiltration between the high- and low-risk groups. Functional enrichment analysis further indicated that immlncRNAs were related to a variety of immune response process signaling pathways, suggesting that relevant immlncRNAs could play an important role in the immune regulation of SKCM. Finally, subgroup analysis and multiple Cox regression analysis further proved the stability of the model. In summary, we successfully constructed a 46 immlncRNA-related prognostic risk score model with excellent predictive efficacy and provided more possibilities to investigate the immune regulation mechanisms and to develop immunotherapy of SKCM.
| S-EPMC9037265 | biostudies-literature
Project description:BackgroundThe like-Smith (LSM) family is a group of RNA-binding proteins involved in RNA metabolism. However, their involvement in tumors, particularly skin cutaneous melanoma (SKCM), is not fully understood. In this study, we focused on the expression profiles and prognostic values of the LSM family in SKCM.MethodsRaw data were downloaded from The Cancer Genome Atlas. The expression profile and prognostic value of LSM genes in SKCM were explored using the GEPIA, cBioPortal, and HPA databases. Protein-protein and gene-gene interaction analyses were performed using STRING and GeneMANIA. Enrichment and Cox regression analysis were conducted using R software. The TISIDB database was used to explore the relationship between LSMs and immunomodulators. Receiver operating characteristic curves and nomogram models were constructed to validate prognostic values.ResultsmRNA and protein expression levels of LSM2, LSM4, and LSM12 were significantly elevated in SKCM. The upregulated mRNA expression of LSM2 (p = 0.0013) and LSM4 (p = 0.0043) was significantly correlated with poor overall survival in patients with SKCM, whereas only LSM2 (p = 0.049) overexpression was markedly associated with worse disease-free survival. LSM2 overexpression was an independent risk factor (p = 0.013) and was confirmed to have a high prognostic value in SKCM using the receiver operating characteristic curve (AUC = 0.942) and nomogram models. All LSM genes were identified as genomic mutations, whereas alteration of LSM2 (p = 0.0153) significantly affected the overall survival in patients with SKCM. Significant correlations were observed between LSM family expression, immune cell infiltration, and immunomodulator. Furthermore, function and pathway enrichment analysis showed that the LSM family was mainly RNA binding proteins and involved in RNA splicing and degradation.ConclusionExpression profiles and prognostic values of LSM in SKCM were inconsistent. Among the LSM family, only LSM2 may serve as a potential poor prognosticator and immunotherapeutic target of SKCM.
| S-EPMC9656080 | biostudies-literature