Dataset Information

A novel cuproptosis-related prognostic gene signature in adrenocortical carcinoma.

ABSTRACT:

Background

Adrenocortical carcinoma (ACC) is an aggressive and rare malignant tumor associated with poor outcomes. Cuproptosis, a new pattern of cell death, relies on mitochondrial respiration and is associated with protein lipoylation. Increasing evidence has demonstrated the potential roles of cuproptosis in several tumor entities. However, the relationship between cuproptosis and ACC remains unclear.

Methods

In total, 10 cuproptosis-related genes (CRGs) of patients with ACC were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and differential expression analysis of CRGs was analyzed. Functional enrichment of the CRGs was performed and protein-protein interaction analysis was utilized to explore the association between the CRGs. Cuproptosis-related risk score (CRRS) was constructed by Lasso Cox regression and validated.

Results

In the current study, the alteration and expression patterns of 10 CRGs in TCGA-ACC datasets were analyzed. We identified different expression patterns of CRGs in ACCs, discovered strong associations between CRGs and ACCs, and found that the CRGs were associated with immune infiltration in ACCs. A CRRS was created thereafter to predict overall survival (OS). CRRS = (0.083103718) *FDX1 + (-0.278423862) *LIAS+(0.090985682) *DLAT+(-0.018784047) *PDHA1 + (0.297218951) *MTF1 + (0.310197964) *CDKN2A. Patients were divided into high- and low-risk groups based on their CRRS, and independent prognostic factors were investigated. Finally, CDKN2A and FDX1 were found to be independent prognostic predictors of patients with ACC.

Conclusions

CDKN2A and FDX1 are independent prognostic predictors of patients with ACC. Cuproptosis may play a role in the development of ACC, providing a new perspective on therapeutic strategies related to CRGs for cancer prevention and treatment.

SUBMITTER: Gao W

PROVIDER: S-EPMC10749488 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

A novel cuproptosis-related prognostic gene signature in adrenocortical carcinoma.

Gao Wenjun W He Xiaoyan X Huangfu Qi Q Xie Yanqi Y Chen Keliang K Sun Chengfang C Wei Jingchao J Wang Bohan B

Journal of clinical laboratory analysis 20231123 21-22

<h4>Background</h4>Adrenocortical carcinoma (ACC) is an aggressive and rare malignant tumor associated with poor outcomes. Cuproptosis, a new pattern of cell death, relies on mitochondrial respiration and is associated with protein lipoylation. Increasing evidence has demonstrated the potential roles of cuproptosis in several tumor entities. However, the relationship between cuproptosis and ACC remains unclear.<h4>Methods</h4>In total, 10 cuproptosis-related genes (CRGs) of patients with ACC wer ...[more]

PMID: 37997497

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Project description:Background: Cuproptosis is a newly discovered form of programmed cell death, which is characterized by accumulation of intra-cellular copper ion leading to the aggregation of lipoproteins and destabilization of Fe-S cluster proteins in mitochondrial metabolism, thereby affecting the prognosis of patients with cancer. However, the role of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) remains elusive. Methods: Mutation signature, copy number variation and the expression of 10 CRGs were assessed in HCC from TCGA-LIHC dataset. ICGC-LIRI-JP dataset was used as further validation cohort. The least absolute shrinkage and selection operator (LASSO) was used to construct the prognostic model. Kaplan Meier curves, time-ROC curves, nomogram, univariate and multivariate Cox regression were utilized to evaluate the predictive efficacy of CRGs-score. Immune infiltration was analyzed by CIBERSOFT, ssGSEA algorithm, and TIMER database. The expression of prognostic CRGs was validated by qPCR both in-vitro and in-vivo. Drug sensitivity analysis was performed by pRRophetic. Results: All of the CRGs were differentially expressed in HCC and 5 out of them (CDKN2A, DLAT, GLS, LIPT1, MTF1) correlated with patient survival. These signature genes were selected by LASSO analysis to establish a prognosis model to stratify HCC patients into high and low CRGs-score subgroups. High CRGs-score was associated with a worse prognosis. Subsequently, univariate and multivariate Cox regression verified that CRGs-score was an independent cancer risk factor that correlated with clinical factors including stage and grade. Nomogram integrating the CRGs-score and clinical risk factors performed well to predict patient survival. Immune infiltration analysis further revealed that the expression of immune checkpoint genes was significantly enhanced in high CRGs-score group, especially PD-1 and PD-L1. An independent validation cohort (ICGC) confirmed that CRGs-score as a stable and universally applicable indicator in predicting HCC patient survival. Concordantly, the expression of five confirmed signature genes were also differentially expressed in human HCC cell lines and mouse HCC model. In addition, we also analyzed the sensitivity of 10 clinical targeted therapies between high and low CRGs-score groups. Conclusion: This study elucidated the role of dysregulated CRGs in HCC cohort, with validation with in-vitro and in-vivo models. The CRGs-score might be applied as a novel prognostic factor in HCC.

Project description:Adrenocortical carcinoma (ACC) has a low incidence but a poor prognosis. And ACC has complex clinical manifestations and limited treatment. Pyroptosis has a dual character and has both positive and negative effects on cancer. However, the role of pyroptosis-related genes (PRGs) in ACC and the impact on ACC progression remains unelucidated. This study performed systematic bioinformatics analysis and basic experimental validation to enable the establishment of prognostic models and demonstrate levels of immune infiltration. Pearson’s correlation analysis was used to assess the association of PRGs with tumor immune infiltration, tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoints. There 4 PRGs were upregulated, and 25 PRGs were downregulated in ACC. At the same time, we analyzed and reviewed the genetic mutation variation landscape of PRGs. Functional enrichment analysis was also performed to clarify the function of PRGs. Pyroptosis, the inflammatory response, the Toll-like receptor signaling pathway, and the NOD-like receptor signaling pathway are the functions and pathways mainly involved and exerted effects by these 33 PRGs. The results of the prognosis analysis revealed high expression of CASP3, CASP9, GSDMB, GSDMD, NLRC4, PRKACA, and SCAF11 caused a poor survival rate for ACC patients. The above seven PRGs were screened by the optimal λ value of LASSO Cox analysis, and the five selected genes (CASP3, CASP9, GSDMB, GSDMD, NLRC4) were involved in constructing a prognostic PRGs model which enables the overall survival in ACC patients can be predicted with moderate to high accuracy. Prognostic PRGs, especially CASP9, which is the independent factor of ACC prognosis, may be closely correlated with immune-cell infiltration, tumor mutation burden, microsatellite instability, and immune checkpoints. Quantitative Real-Time PCR (qRT-PCR), Western blot and immunohistochemical were performed to validate the mRNA expression levels of CASP9 in adjacent normal tissues and ACC tissues. According to the result of immune checkpoints analysis, NLRC4 and GSDMB may be identified as potential therapeutic targets. In conclusion, we established a prognostic model of PRG characteristics in ACC and analyzed the relationship between PRGs and immune infiltration. Through our study, it may be helpful to find the mechanism of pyroptosis in ACC.

Project description:Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, which is characterized by metabolic reprogramming. Cuproptosis, a novel form of cell death, is highly linked to mitochondrial metabolism and mediated by protein lipoylation. However, the clinical impacts of cuproptosis-related genes (CRGs) in ccRCC largely remain unclear. In the current study, we systematically evaluated the genetic alterations of cuproptosis-related genes in ccRCC. Our results revealed that CDKN2A, DLAT, DLD, FDX1, GLS, PDHA1 and PDHB exhibited differential expression between ccRCC and normal tissues (|log2(fold change)| > 2/3 and p < 0.05). Utilizing an iterative sure independence screening (SIS) method, we separately constructed the prognostic signature of CRGs for predicting the overall survival (OS) and progression-free survival (PFS) in ccRCC patients. The prognostic score of CRGs yielded an area under the curve (AUC) of 0.658 and 0.682 for the prediction of 5-year OS and PFS, respectively. In the Kaplan−Meier survival analysis of OS, a higher risk score of cuproptosis-related gene signature was significantly correlated with worse overall survival (HR = 2.72 (2.01−3.68), log-rank p = 1.76 × 10−7). Patients with a higher risk had a significantly shorter PFS (HR = 2.83 (2.08−3.85), log-rank p = 3.66 × 10−7). Two independent validation datasets (GSE40435 (N = 101), GSE53757 (N = 72)) were collected for meta-analysis, suggesting that CDKN2A (log2(fold change) = 1.46, 95%CI: 1.75−2.35) showed significantly higher expression in ccRCC tissues while DLAT (log2(fold change) = −0.54, 95%CI: −0.93−−0.15) and FDX1 (log2(fold change) = −1.01, 95%CI: −1.61−−0.42) were lowly expressed. The expression of CDKN2A and FDX1 in ccRCC was also significantly associated with immune infiltration levels and programmed cell death protein 1 (PD-1) expression (CDKN2A: r = 0.24, p = 2.14 × 10−8; FDX1: r = −0.17, p = 1.37 × 10−4). In conclusion, the cuproptosis-related gene signature could serve as a potential prognostic predictor for ccRCC patients and may offer novel insights into the cancer treatment.

Project description:Bladder Urothelial Carcinoma (BLCA) remains the most common urinary system tumor, and its prognosis is poor. Cuproptosis is a recently discovered novel cell death involved in the development of tumor cells. However, the use of cuproptosis to predict the prognosis and immunity of Bladder Urothelial Carcinoma remains largely unclear, and this study was designed to verify cuproptosis-related long non-coding RNAs (lncRNAs) to estimate the prognosis and immunity of Bladder Urothelial Carcinoma. In our study, we first defined the expression of cuproptosis-related genes (CRGs) in BLCA, and 10 CRGs were up- or downregulated. We then constructed a co-expression network of cuproptosis-related mRNA and long non-coding RNAs using RNA sequence data from The Cancer Genome Atlas Bladder Urothelial Carcinoma (TCGA-BLCA), clinical features and mutation data from BLCA patients to obtain long non-coding RNAs by Pearson analysis. Afterward, univariate and multivariate COX analysis identified 21 long non-coding RNAs as independent prognostic factors and used these long non-coding RNAs to construct a prognostic model. Then, survival analysis, principal component analysis (PCA), immunoassay, and comparison of tumor mutation frequencies were performed to verify the accuracy of the constructed model, and GO and KEGG functional enrichment analysis was used to verify further whether cuproptosis-related long non-coding RNAs were associated with biological pathways. The results showed that the model constructed with cuproptosis-related long non-coding RNAs could effectively evaluate the prognosis of BLCA, and these long non-coding RNAs were involved in numerous biological pathways. Finally, we performed immune infiltration, immune checkpoint and drug sensitivity analyses on four genes (TTN, ARID1A, KDM6A, RB1) that were highly mutated in the high-risk group to evaluate the immune association of risk genes with BLCA. In conclusion, the cuproptosis-related lncRNA markers constructed in this study have evaluation value for prognosis and immunity in BLCA, which can provide a certain reference for the treatment and immunity of BLCA.

Project description:BackgroundCuproptosis is a new type of copper-induced cell death that is characterized by the aggregation of lipoylated tricarboxylic acid (TCA) cycle proteins. However, its role in hepatocellular carcinoma (HCC) remains unclear. The goal of this research is to develop a cuproptosis-related signature predicting the prognosis of HCC.MethodsThe cuproptosis-related genes were defined using Pearson correlation coefficients. LASSO-Cox regression analysis was used to evaluate the prognostic values of cuproptosis-related genes to construct a cuproptosis-related prognostic model. The immune microenvironment analysis was performed by "ssGSEA" to reveal the associated immune cell infiltration patterns with the cuproptosis-related genes signature. The expression levels of one of the prognostic genes PDXK were then verified in HCC samples by Western Blot and immunohistochemistry. The potential roles of target genes in cuproptosis were further explored during in-vitro experiments.ResultsA total of 136 cuproptosis-related genes were discovered using Pearson correlation analysis in HCC. A cuproptosis-related signature that included 5 cuproptosis-related genes (PDXK, HPN, SLC25A28, RNFT1, CLEC3B) was established in the TCGA-LIHC training cohort. TCGA validation cohort and another two external validation cohorts confirmed the robustness of the signature's predictive value. Moreover, a nomogram using the risk score was created to best predict the survival of HCC patients. The immune microenvironment analysis revealed distinct immune infiltrations patterns between different risk groups based on the signature model. Furthermore, the upregulation of PDXK was confirmed in HCC tumor tissues in 30 clinical HCC specimens. The knockdown of PDXK reduced the proliferation, migration and invasion of HCC cells. Besides, the expression of PDXK was upregulated after the induction of cuproptosis by elesclomol-CuCL2, which could be suppressed when pretreated with a copper ion chelator. And PDXK deficiency increased the sensitivity of HCC cells to cuproptosis inducer.ConclusionOur study identified a new cuproptosis-related gene signature that could predict the prognosis of HCC patient. Besides, the upregulated PDXK could promote the proliferation and metastasis of HCC. And PDXK deficiency facilities cuproptosis in HCC. Therefore, these fundings highlighted that PDXK might serve as a potential diagnostic and therapeutic target for HCC.

Dataset Information

A novel cuproptosis-related prognostic gene signature in adrenocortical carcinoma.

Background

Methods

Results

Conclusions

Publications

A novel cuproptosis-related prognostic gene signature in adrenocortical carcinoma.

Similar Datasets

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