Ferroptosis Associates With Diagnosis and Prognosis by Promoting Antitumor Immune Response in Melanoma.
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ABSTRACT:
SUBMITTER: Qian B
PROVIDER: S-EPMC9304890 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCutaneous melanoma is a common but aggressive tumor. Ferroptosis is a recently discovered cell death with important roles in tumor biology. Nevertheless, the prognostic power of ferroptosis-linked genes remained unclear in cutaneous melanoma.MethodsCutaneous melanoma patients of TCGA (The Cancer Genome Atlas) were taken as the training cohort while GSE65904 and GSE22153 as the validation cohorts. Multifactor Cox regression model was used to build a prognostic model, and the performance of the model was assessed. Functional enrichment and immune infiltration analysis were used to clarify the mechanisms.ResultsA five ferroptosis-linked gene predictive model was developed. ALOX5 and GCH1 were illustrated as independent predictive factors. Functional assessment showed enriched immune-linked cascades. Immune infiltrating analysis exhibited the distinct immune microenvironment.ConclusionHerein, a novel ferroptosis-related gene prognostic model was built in cutaneous melanoma. This model could be used for prognostic prediction, and maybe helpful for the targeted and immunotherapies.
| S-EPMC8384470 | biostudies-literature
Project description:Skin cutaneous melanoma (SKCM) is the skin cancer that causes the highest number of deaths worldwide. There is growing evidence that the tumour immune microenvironment is associated with cancer prognosis, however, there is little research on the role of immune status in melanoma prognosis. In this study, data on patients with Skin cutaneous melanoma were downloaded from the GEO, TCGA, and GTEx databases. Genes associated with the immune pathway were screened from published papers and lncRNAs associated with them were identified. We performed immune microenvironment and functional enrichment analyses. The analysis was followed by applying univariate/multivariate Cox regression algorithms to finally identify three lncRNAs associated with the immune pathway for the construction of prognostic prediction models (CXCL10, RXRG, and SCG2). This stepwise downscaling method, which finally screens out prognostic factors and key genes and then uses them to build a risk model, has excellent predictive power. According to analyses of the model's reliability, it was able to differentiate the prognostic value and continued existence of Skin cutaneous melanoma patient populations more effectively. This study is an analysis of the immune pathway that leads lncRNAs in Skin cutaneous melanoma in an effort to open up new treatment avenues for Skin cutaneous melanoma.
| S-EPMC9845246 | biostudies-literature
Project description:Ferroptosis is a non-apoptotic regulated cell death process, and much research has indicated that ferroptosis can induce the non-apoptotic death of tumor cells. Ferroptosis-related genes are expected to become a biological target for cancer treatment. However, the regulation of ferroptosis-related genes in skin cutaneous melanoma (SKCM) has not been well studied. In the present study, we conducted a systematic analysis of SKCM based on RNA sequencing data and clinical data obtained from The Cancer Genome Atlas (TCGA) database and the FerrD database. SKCM patients from the GSE78220 and MSKCC cohorts were used for external validation. Applying consensus clustering on RNA sequencing data from TCGA the generated ferroptosis subclasses of SKCM, which were analyzed based on the set of differentially expressed ferroptosis-related genes. Then, a least absolute shrinkage and selection operator (LASSO)-Cox regression was used to construct an eight gene survival-related linear signature. The median cut-off risk score was used to divide patients into high- and low-risk groups. The time-dependent receiver operating characteristic curve was used to examine the predictive power of the model. The areas under the curve of the signature at 1, 3, and 5 years were 0.673, 0.716, and 0.746, respectively. Kaplan-Meier survival analysis showed that the prognosis of high-risk patients was worse than that of low-risk patients. Univariate and multivariate Cox regression analyses showed that the risk signature was a robust independent prognostic indicator. By incorporating risk scores with tumor staging, a nomogram was constructed to predict prognostic outcomes for SKCM patients. In addition, the immunological analysis showed different immune cell infiltration patterns. Programmed-death-1 (PD-1) immunotherapy showed more significant benefits in the low-risk group than in the high-risk group. In summary, a model based on ferroptosis-related genes can predict the prognosis of SKCM and could have a potential role in guiding targeted therapy of SKCM.
| S-EPMC8595480 | biostudies-literature
Project description:BackgroundIn this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC.MethodsIntegrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes.ResultsFour genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The diagnostic models successfully distinguished HCC from normal samples and proliferative nodule samples. Compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression, and it was showed to affect Th17 cell differentiation and IL-17 signaling pathway through bioinformatics analysis, indicating it a potential agent of cancer immunotherapy.ConclusionsThe prognostic and diagnostic models based on the four genes indicated superior diagnostic and predictive performance, indicating new possibilities for individualized treatment of HCC patients. Video Abstract.
| S-EPMC7592541 | biostudies-literature
Project description:Ferroptosis is a newly discovered form of non-apoptotic cell death that relies on iron-mediated oxidative damage, playing a crucial role in the progression and therapy resistance of melanoma. Hence, the potential value of ferroptosis-related genes (FRGs) as a prognostic model and therapeutic target in melanoma requires further investigation. In this study, the relationship between FRGs and melanoma was revealed by analyzing the mRNA expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Synthesis (GEO). A 6-FRGs signature was constructed by Univariate, multivariate, and lasso Cox regression analyses in the TCGA cohort. The GEO database was used to validate the efficacy of the signature. The protein and mRNA expression level of the signature genes were examined in real-world melanoma tissues via immunohistochemical and quantificational real-time polymerase chain reaction (qRT-PCR). Functional enrichment analysis and immune-related analysis were conducted to identify the potential biological functions and pathways of the signature. Ten putative small molecule drugs were predicted by Connectivity Map (CMAP). As a result, a 6-FRGs signature was constructed to stratify melanoma patients into two risk groups. Compared with the low-risk group, patients in the high-risk group had a worse prognosis and a lower ImmuneScore. Immune-related pathways were enriched in the low-risk group. Immune Function and immune cell infiltration of the low-risk group were significantly higher than that of the high-risk group. The differential expression of these six FRGs in melanoma and adjacent normal tissues was confirmed. Moreover, higher expression of immune checkpoint molecules and a greater sensitivity to immunotherapy were observed in the low-risk group. Some small molecular drugs in the CMAP database hold the potential to treat melanoma. Overall, we identified a novel FRGs signature for prognostic prediction in melanoma. Based on the signature-related immune infiltration landscape found in our study, targeting the FRGs might be a therapeutic alternative for melanoma.
| S-EPMC9174666 | biostudies-literature
Project description:PurposeMost patients with metastatic melanoma show variable responses to radiation therapy and do not benefit from immune checkpoint inhibitors. Improved strategies for combination therapy that leverage potential benefits from radiation therapy and immune checkpoint inhibitors are critical.Methods and materialsWe analyzed metastatic melanoma tumors in the TCGA cohort for expression of genes coding for subunits of type A γ-aminobutyric acid (GABA) receptor (GABAAR), a chloride ion channel and major inhibitory neurotransmitter receptor. Electrophysiology was used to determine whether melanoma cells possess intrinsic GABAAR activity. Melanoma cell viability studies were conducted to test whether enhancing GABAAR mediated chloride transport using benzodiazepine-impaired viability. A syngeneic melanoma mouse model was used to assay the effect of benzodiazepine on tumor volume and its ability to potentiate radiation therapy or immunotherapy. Treated tumors were analyzed for changes in gene expression by RNA sequencing and presence of tumor-infiltrating lymphocytes by flow cytometry.ResultsGenes coding for subunits of GABAARs express functional GABAARs in melanoma cells. By enhancing GABAAR-mediated anion transport, benzodiazepines depolarize melanoma cells and impair their viability. In vivo, benzodiazepine alone reduces tumor growth and potentiates radiation therapy and α-PD-L1 antitumor activity. The combination of benzodiazepine, radiation therapy, and α-PD-L1 results in near complete regression of treated tumors and a potent abscopal effect, mediated by increased infiltration of polyfunctional CD8+ T cells. Treated tumors show expression of cytokine-cytokine receptor interactions and overrepresentation of p53 signaling.ConclusionsThis study identifies an antitumor strategy combining radiation and/or an immune checkpoint inhibitor with modulation of GABAARs in melanoma using benzodiazepine.
| S-EPMC8329598 | biostudies-literature
Project description:BackgroundCutaneous Melanoma (CM) is a malignant disease with increasing incidence and high mortality. Ferroptosis is a new kind of cell death and related to tumor blood and lymphatic metastasis. This study aims at using bioinformatics technology to construct a prognostic signature and identify ferroptosis-related biomarkers to improve the prognosis and treatment of cutaneous melanoma.MethodsWe used bioinformatics tools to analyze RNA sequencing expression data with clinical information from multiple databases, utilized varieties of statistical methods to construct a ferroptosis-related prognostic signature of cutaneous melanoma and screened out specific genes with independent prognostic ability.ResultsWe obtained 22 ferroptosis-related (P < 0.05) prognostic DEGs in the uniCox regression analysis, among which 10 high-expressed genes (ATG5, CHAC1, FANCD2, FBXL5, HMOX2, HSPB1, NQO1, PEBP1, PRNP, SLC3A2) were screened out by LASSO regression analysis to establish a predictive model. Meanwhile, the ferroptosis-related signature and the nomogram we drew performed an excellent performance based on Kaplan-Meier (K-M), Receiver operating characteristic (ROC) and calibration curves. Univariate and multivariable cox analyses displayed that our model was greater than other prognostic features. GO and KEGG analyses revealed that 10-biomarker signature was mainly related to epidermis differentiation and immunity. ssGSEA analysis indicated that the immune status between the two risk groups was highly different. Besides, we found that two genes (CP, ZEB1) had independent prognostic ability and can be applied for drug research. Both genes were highly related to immunity. GSEA illustrated that ZEB1 may be involved in cellular functions such as proliferation, apoptosis, and migration, while CP was closely connected to immune cell related functions.ConclusionThe present study suggested a 10-biomarker signature can be clinically used to predict the prognosis of cutaneous melanoma, which was better than conventional factors. CP and ZEB1 were independent prognostic genes and can be applied to guide treatment. In addition, ZEB1 mutation was highly related to overall survival in cutaneous melanoma, while CP may be associated with tumor progression. Our study comprehensively analyzed the relationship between iron metabolism, ferroptosis-related genes, and the prognosis of cutaneous melanoma, provided new insight for molecular mechanisms and treatment of ferroptosis and cutaneous melanoma.
| S-EPMC8886785 | biostudies-literature
Project description:Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.
| S-EPMC7140048 | biostudies-literature
Project description:Cutaneous melanoma (CM) is a skin cancer that is highly metastatic and aggressive, with a dismal prognosis. This is the first study to use inflammatory response-related genes to build a model and evaluate their predictive significance in CM. This study used public databases to download CM patients' mRNA expression profiles and clinical data to create multigene prognostic markers in the UCSC cohort. We compared overall survival (OS) between high- and low-risk groups using the Kaplan-Meier curve and determined independent predictors using Cox analysis. We also used enrichment analysis to assess immune cell infiltration fraction and immune pathway-related activity using KEGG enrichment analysis. Furthermore, we detected prognostic genes' mRNA and protein expression in CM and normal skin tissues using qRT-PCR and immunohistochemistry. Finally, we developed a 5-gene predictive model that showed that patients in the high-risk group had a considerably shorter OS than those in the low-risk group. The analysis of the receiver operating characteristic (ROC) curve proved the model's predictive ability. We also conducted a drug sensitivity analysis and discovered that the expression levels of prognostic genes were substantially linked with cancer cell sensitivity to antitumor medicines. The findings show that the model we developed, which consists of five inflammatory response-related genes, can be used to forecast the prognosis and immunological state of CM, giving personalized and precision medicine a new goal and direction.
| S-EPMC9389732 | biostudies-literature
Project description:Osteosarcoma has been the most common malignant bone tumor in children and adolescents, while the 5-y survival of osteosarcoma patients gained no significant improvement over the past decades. This study aimed to explore the role of ferroptosis-related genes (FRGs) in the development and prognosis of osteosarcoma. The datasets of osteosarcoma patients including RNA sequencing data and clinical information were acquired from the TRGET and Gene Expression Omnibus (GEO) databases. The identification of molecular subgroups with different FRG expression patterns was achieved through nonnegative matrix factorization (NMF) clustering. The prognostic model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analysis. The ESTIMATE algorithm was applied for determining the stromal score, immune score, ESTIMA score, and tumor purity of osteosarcoma patients. Functional analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were conducted to explore the underlying mechanisms in the development and prognosis of osteosarcoma. Two molecular subgroups with different FRGs expression patterns were identified. The molecular subgroups with higher immune score and more active immune status showed better prognostic survival. On the basis of FRGs, a prognostic model and a nomogram integrating clinical characteristics were constructed and their prediction efficiency for osteosarcoma prognosis were well validated. Gene functional enrichment analysis showed that these differentially expressed FRGs were mainly enriched in immunity-related signaling pathways, indicating that FRGs may affect the development and prognosis of osteosarcoma by regulating the immune microenvironment. The expression profiles of FRGs were closely related to the immunity status and prognostic survival of osteosarcoma patients. The interaction between ferroptosis and immunity in the development of osteosarcoma could provide a new insight into the exploration of molecular mechanisms and targeted therapies of osteosarcoma patients.
| S-EPMC8586685 | biostudies-literature