Project description:Skin cutaneous melanoma (SKCM, hereafter referred to as melanoma) is the most lethal skin cancer with increasing incidence. Regulated cell death plays an important role in tumorigenesis and serves as an important target for almost all treatment strategies. Cuproptosis is the most recently identified copper-dependent regulated cell death form that relies on mitochondria respiration. However, its role in tumorigenesis remains unknown. The correlation of cuproptosis-related genes with tumor prognosis is far to be understood, either. In the present study, we explored the correlation between cuproptosis-related genes with the prognosis of melanoma by accessing and analyzing a public database and found 11 out 12 genes were upregulated in melanoma tissues and three genes (LIPT1, PDHA1, and SLC31A1) have predictive value for the prognosis. The subgroup of melanoma patients with higher cuproptosis-related gene expression showed longer overall survival than those with lower gene expression. We chose LIPT1 for further exploration. LIPT1 expression was increased in melanoma biopsies and was an independent favorable prognostic indicator for melanoma patients. Moreover, LIPT1 expression was positively correlated with PD-L1 expression and negatively associated with Treg cell infiltration. The melanoma patients with higher LIPT1 expression showed longer overall survival than those with lower LIPT1 expression after receiving immunotherapy, indicating the prognostic predictive value of LIPT1. Finally, a pan-cancer analysis indicated that LIPT1 was differentially expressed in diverse cancers as compared to normal tissues and correlated with the expression of multiple immune checkpoints, especially PD-L1. It could serve as a favorable prognosis indicator in some cancer types. In conclusion, our study demonstrated the prognostic value of cuproptosis-related genes, especially LIPT1, in melanoma, and revealed the correlation between LIPT1 expression and immune infiltration in melanoma, thus providing new clues on the prognostic assessment of melanoma patients and providing a new target for the immunotherapy of melanoma.

Project description:BackgroundBeing among the most common malignancies worldwide, hepatocellular carcinoma (HCC) accounting for the third cause of cancer mortality. The regulation of cell death is the most crucial step in tumor progression and has become a crucial target for nearly all therapeutic options. Cuproptosis, a copper-induced cell death, was recently reported in Science. However, its primary function in carcinogenesis is still unclear.MethodsCuproptosis-related lncRNAs significantly associated with overall survival (OS) were screened by stepwise univariate Cox regression. The signature of cuproptosis-related lncRNAs for HCC prognosis was constructed by the LASSO algorithm and multivariate Cox regression. Further Kaplan-Meier analysis, proportional hazards model, and ROC analysis were performed. Functional annotation was performed using gene set enrichment analysis (GSEA). The relationship between prognostic cuproptosis-related lncRNAs and HCC prognosis was further explored by GEPIA( http://gepia.cancer-pku.cn/ ) online analysis tool. Finally, we used the ESTIMATE and XCELL algorithms to estimate stromal and immune cells in tumor tissue and cast each sample to infer the underlying mechanism of cuproptosis-related lncRNAs in the tumor immune microenvironment (TIME) of HCC patients.ResultsFour cuproptosis-related lncRNAs were used to construct a prognostic lncRNA signature, which was an independent factor in predicting OS in HCC patients. Kaplan-Meier curves showed significant differences in survival rates between risk subgroups (p = 0.002). At the same time, we found that the expression levels of most immune checkpoint genes increased with increasing risk scores. Tumorigenesis and immunological-related pathways were primarily enhanced in the high-risk group, as determined by GSEA. The results of drug sensitivity analysis showed that compared with patients in the high-risk group, the IC50 values of erlotinib and lapatinib were lower in patients in the low-risk group, while the opposite was true for sunitinib, paclitaxel, gemcitabine, and imatinib. We also found that elevated AL133243.2 expression was significantly associated with worse OS and disease-free survival (DFS), more advanced T stage and higher tumor grade, and reduced immune cell infiltration, suggesting that HCC patients with low AL133243.2 expression in tumor tissues may have a better response to immunotherapy.ConclusionCollectively, the cuproptosis-associated lncRNA signature can serve as an independent predictor to guide individual treatment strategies. Furthermore, AL133243.2 is a promising marker for predicting immunotherapy response in HCC patients. This data may facilitate further exploration of more effective immunotherapy strategies for HCC.

Project description:BackgroundImmune infiltration plays an important role in the course of ischemic stroke (IS) progression. Cuproptosis is a newly discovered form of programmed cell death. To date, no studies on the mechanisms by which cuproptosis-related genes regulate immune infiltration in IS have been reported.MethodsIS-related microarray datasets were retrieved from the Gene Expression Omnibus (GEO) database and standardized. Immune infiltration was extracted and quantified based on the processed gene expression matrix. The differences between the IS group and the normal group as well as the correlation between the infiltrating immune cells and their functions were analyzed. The cuproptosis-related DEGs most related to immunity were screened out, and the risk model was constructed. Finally, Gene Ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and drug target were performed using the Enrichr website database. miRNAs were predicted using FunRich software. Finally, cuproptosis-related differentially expressed genes (DEGs) in IS samples were typed, and Gene Set Variation Analysis (GSVA) was used to analyze the differences in biological functions among the different types.ResultsSeven Cuproptosis-related DEGs were obtained by merging the GSE16561 and GSE37587 datasets. Correlation analysis of the immune cells showed that NLRP3, NFE2L2, ATP7A, LIPT1, GLS, and MTF1 were significantly correlated with immune cells. Subsequently, these six genes were included in the risk study, and the risk prediction model was constructed to calculate the total score to analyze the risk probability of the IS group. KEGG analysis showed that the genes were mainly enriched in the following two pathways: D-glutamine and D-glutamate metabolism; and lipids and atherosclerosis. Drug target prediction found that DMBA CTD 00007046 and Lithocholate TTD 00009000 were predicted to have potential therapeutic effects of candidate molecules. GSVA showed that the TGF-β signaling pathway and autophagy regulation pathways were upregulated in the subgroup with high expression of cuproptosis-related DEGs.ConclusionsNLRP3, NFE2L2, ATP7A, LIPT1, GLS and MTF1 may serve as predictors of cuproptosis and play an important role in the pathogenesis of immune infiltration in IS.

Project description:Osteosarcoma (OS) is one of the most prevalent primary bone tumors at all ages of human development. The objective of our study was to develop a model of Cuproptosis-Related Genes (CRGs) for predicting prognosis in OS patients. All datasets of OS patients were obtained from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database and Gene Expression Omnibus (GEO) database. We obtained the gene set (81 CRGs) related to cuproptosis by accessing the database and previous literature. All the CRGs were analyzed by univariate COX regression, least absolute shrinkage and selection operator (LASSO) COX regression analysis to screen for CRGs associated with prognosis in OS patients. Then these CRGs were used to construct a prognostic signature, which was further verified by independent cohort (GSE21257) and clinical correlation analysis. Afterward, to identify underlying mechanisms, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used for the high-risk group by using the GSEA method. The association between the prognostic signature and 28 types of immune infiltrating cells in the tumor microenvironment was assessed. Ultimately, Lipoic Acid Synthetase (LIAS) (HR=0.632, P=0.004), Lipoyltransferase 1 (LIPT1) (HR=0.524, P=0.011), BCL2 Like 1 (BCL2L1/BCL-XL) (HR=0.593, P=0.022), and Pyruvate Dehydrogenase Kinase 1 (PDK1) (HR=0.662, P=0.025) were identified. Subsequently, they were used to calculate the risk score and build a prognostic model. In the training cohort, risk score (HR=1.878, P=0.003) could be considered as an independent prognostic factor, and OS patients with high-risk scores showed lower survival rates. Biological pathways related to substance metabolism and transport were enriched. There were significant differences in immune infiltrating cells in the tumor microenvironment. All in all, The CRGs signature is related to the tumor immune microenvironment and could be used as a credible predictor of the prognostic status in OS patients.

Project description:Background: Cuproptosis is a novel form of cell death discovered in recent. A great quantity of researches has confirmed the close relationships and crucial roles between long non-coding RNAs (lncRNAs) with the progression of colorectal cancer (CRC). However, the relationship between cuproptosis and lncRNAs remains unclear in CRC. Methods: 1,111 co-expressed lncRNAs with 16 cuproptosis regulators were retrieved from CRC samples of The Cancer Genome Atlas (TCGA) database. Through univariate Cox and least absolute shrinkage and selection operator regression analysis, a prognosis model was constructed with 15 lncRNAs. The Kaplan-Meier, receiver operating characteristic curve, C-index and principal component analysis identified the prognostic power. Furthermore, a cuproptosis-related cluster was generated based on the 15 lncRNAs by unsupervised methods. The correlations between the cuproptosis-related signatures with immune cell infiltration and anti-tumor therapy were explored by multiple algorithms. Results: A risk score and nomogram with great prediction ability were constructed for CRC prognosis evaluation. The immune activate pathways, immune infiltration cells, immune functions, immune score and immune activation genes were remarkably enriched in the high risk group. The cuproptosis-related cluster was generated, of which the cluster 2 showed longer overall survival. The immune cell infiltration analysis indicated the similar results of cluster 2 with the high risk group, implying a significant marker for "hot tumor." The cluster 2 also presented high expression of immune checkpoint molecules, MSI-H status and higher susceptibility to multiple immunotherapy drugs. Conclusion: We appraised a novel cuproptosis-related prognosis model and molecular signature associated with prognosis, immune infiltration and immunotherapy. The identification of cuproptosis-related lncRNAs improved our understanding of immune infiltration and provided a significant marker for prognosis and immunotherapy in CRC.

Project description:Adrenocortical carcinoma (ACC) is a rare malignant tumor with poor prognosis. Ferroptosis, a new form of cell death, differs from other forms of cell death and plays a vital role in tumor progress. Our study aimed to establish a ferroptosis-related signature with prognostic value in ACC. RNA-seq data and corresponding clinical characteristics for ACC were downloaded from TCGA and GEO databases. Genes included in ferroptosis risk signature were assessed by univariable and multivariable Cox regression analysis as well as lasso regression analysis. The prognostic value of the ferroptosis risk signature was assessed using K-M and ROC curves. Furthermore, we performed GSEA to discover the enriched gene sets in high-risk group. Additionally, TIMER website was applied to detect a possible connection between the signature and immune cells infiltration. ssGSEA was performed to evaluate scores of immune cells and immune-related pathways in two groups. A ferroptosis signature comprised of six genes (SLC7A11, TP53, HELLS, ACSL4, PCBP2, and HMGB1) was constructed to predict prognosis and reflect the immune infiltration in ACC. Patients in high-risk group were inclined to have worse prognosis. The ferroptosis model performed well in predicting prognosis and could be served as an independent indicator in ACC. GSEA revealed that gene sets correlated with biological processes including cell cycle, DNA replication, base excision repair, and P53 signaling pathway were highly enriched in high-risk group. In addition, we discovered that the expressional levels of hub genes were linked to six immune cells' infiltration in ACC tumor. ssGSEA revealed that contents of most immune cells significantly decreased in the high-risk group. In conclusion, the novel ferroptosis risk signature could be useful in predicting prognosis and reflecting immune infiltration in ACC. It also brings us new insights into the possible value of targeting ferroptosis during the therapy of ACC.

Project description:BackgroundColorectal cancer (CRC) is a common malignancy, with high incidence and high mortality rates. Cuproptosis, a novel form of copper-induced programmed cell death, contributes to tumor progression. However, whether cuproptosis-related genes (CRGs) play a role in CRC remains unclear. This study aims to elucidate the role of CRGs in CRC development, patient prognosis, and immune response.MethodsWe performed bioinformatics analysis of the differential expression of CRGs between CRC and normal tissues. Least absolute shrinkage and selection operator (LASSO), and univariate and multivariate Cox analyses were employed to identify risk factors, which were used to construct a risk score model. Patients with CRC were categorized into high- and low-risk groups based on their median risk scores. Receiver operating characteristic curve analysis was used to verify the predictive accuracy of the risk model. A nomogram was developed for CRC through univariate and multivariate Cox regression analyses. The chemotherapeutic drug sensitivity was compared between patients with high and low CDKN2A/DLAT expression using the Wilcoxon rank-sum test. Spearman's correlation and TISIDB database analyses were conducted to determine relationships between CDKN2A or DLAT and immune cell infiltration.ResultsEight of ten identified CRGs exhibited significant differential expression between CRC and normal tissues. Among the eight significant differential expression CRGs, CDKN2A and DLAT were identified as independent risk factors for predicting overall survival (OS) in CRC. Patients with CRC in the low-risk group had longer OS than those in the high-risk group. The risk score model had good predictive accuracy for OS. Based on CDKN2A, DLAT and some clinical characteristics, a prognostic nomogram was developed to predict OS for CRC patients and showed good predictive ability. CDKN2A and DLAT expressions were significantly associated with chemotherapeutic drug sensitivity and immune cell infiltration in CRC, and the molecular subtypes and immune subtypes differed between CDKN2A and DLAT.ConclusionsOur research revealed the prognostic value of CRGs, particularly CDKN2A and DLAT, in CRC and demonstrated the relationship between CDKN2A/DLAT and immune infiltration in CRC, thereby contributing to the outcome evaluation of patients with CRC and identifying novel targets for CRC immunotherapy.

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Comprehensive analysis of the role of cuproptosis-related genes in the prognosis and immune infiltration of adrenocortical Carcinoma

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