Cuproptosis in ccRCC: key player in therapeutic and prognostic targets
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ABSTRACT:
SUBMITTER: Lv Y
PROVIDER: S-EPMC10642186 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia have an ETV6/RUNX1 (E/R) gene fusion that results from a t(12;21). This genetic subgroup of leukemia is associated with near-triploidy, near-tetraploidy, and trisomy 21 as rather specific types of secondary changes. Here, we show that, unlike various controls, E/R-expressing Ba/F3 clones acquire a tetraploid karyotype on prolonged culture, corroborating the assumption that E/R may attenuate the mitotic checkpoint (MC). Consistent with this notion, E/R-expressing diploid murine and human cell lines have decreased proportions of cells with 4N DNA content and a lower mitotic index when treated with spindle toxins. Moreover, both RUNX1 and E/R regulate mitotic arrest-deficient 2 L1 (MAD2L1), an essential MC component, by binding to promoter-inherent RUNX1 sites, which results in down-regulation of MAD2L1 mRNA and protein in E/R-expressing cells. Forced expression of E/R also abolishes RUNX1-induced reporter activation, whereas E/R with a mutant DNA-binding site leads to only minor effects. Our data link for the first time E/R, MC, and MAD2L1 and provide new insights into the function of the E/R fusion gene product. Although tetraploidy is an almost exclusive feature of E/R-positive leukemias, its rarity within this particular subgroup implies that further yet unknown factors are required for its manifestation.
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Project description:Inflammation is a hallmark and potent driver of pathological vascular remodelling in atherosclerosis. However, current anti-inflammatory therapeutic strategies have shown mixed results. As an alternative perspective on the conundrum of chronic inflammation emerging evidence points towards a small subset of senescent cells as a critical player and central node driving atherosclerosis. Senescent cells belonging to various cell types are a dominant and chronic source of a large array of pro-inflammatory cytokines and various additional plaque destabilizing factors, being involved with various aspects of atherosclerosis pathogenesis. Antagonizing these key agitators of local chronic inflammation and plaque instability may provide a causative and multi-purpose therapeutic strategy to treat atherosclerosis. Anti-senescence treatment options with translational potential are currently in development. However, several questions and challenges remain to be addressed before these novel treatment approaches may enter the clinical setting.
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Project description:Renal cell carcinoma is one of the most malignant cancers, with limited prognostic prediction system. The present study aimed to determine the prognostic value of novel von Hippel-Lindau (VHL) substrate targets in predicting the outcome of clear cell renal cell carcinoma (ccRCC). A total of 97 patients with ccRCC were enrolled in the present study, and the tissue microarray that was constructed using 97 ccRCC samples was used for immunohistochemical analysis. Univariate and multivariate Cox regression analyses were performed to determine the independent prognostic factors. Reverse transcription-quantitative PCR analysis demonstrated that the mRNA expression levels of scm-like with four malignant brain tumor domains (SFMBT1) and zinc fingers and homeoboxes 2 (ZHX2) were upregulated in cancer tissues compared with adjacent normal tissues. Among the 97 patients with ccRCC, SFMBT1 expression was upregulated in 61.9% (60/97), while ZHX2 expression was upregulated in 52.6% (51/97). Overall survival (OS) and disease-free survival (DFS) analyses indicated that SFMBT1 or ZHX2 alone were of limited predictive value; however, the combined expression of these two targets (high SFMBT1 and high ZHX2 expression, SHZH group) was significantly associated with OS (P=0.0350) and DFS (P=0.0434). In addition, multivariate analysis identified SHZH as an independent prognostic factor in patients with ccRCC. Taken together, these results suggest that SFMBT1 and ZHX2 act as novel substrate targets of VHL and, to the best of our knowledge, the present study was the first to provide insight on the co-expression of these two targets in representing a promising biomarker to predict the outcome of patients with ccRCC.
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Project description:Osteosarcoma is one of the most common malignant bone tumours in children. In this study, we aimed to construct a cuproptosis-related lncRNAs signature to predict the prognosis and immune landscape of osteosarcoma patients. Databases from TARGET were used to acquire osteosarcoma patient datasets, which included clinical information and RNA sequencing data. Cuproptosis-related lncRNAs was obtained by correlation analysis. Through univariate Cox regression analysis, prognosis-related lncRNAs were obtained. We used nonnegative matrix factorization clustering to identify potential molecular subgroups with different cuproptosis-related lncRNA expression patterns. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression analysis were used to construct the prognostic signature. The ESTIMATE algorithm, Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes were applied to explore the underlying mechanisms in the immune landscape of osteosarcoma. We used gene set enrichment analysis to compare the different enrichments in the high-risk group and the low-risk group. Furthermore, we predicted the response to targeted drugs in patients with different risk groups. Using multivariable analysis, we developed a risk scoring model based on 7 long noncoding RNAs and calculated two molecular subgroups from osteosarcoma patients from the database. There is a better immune microenvironment in the low-risk group compared to the high-risk group. At the same time, the gene functional enrichment analysis based on the differently expressed genes obtained by grouping showed they were mainly related to immunity, indicating that cuproptosis-related lncRNAs may affect the prognosis of osteosarcoma by regulating immunity. Moreover, these patients in high-risk group were more susceptible to targeted drugs than the low-risk group. We identified a cuproptosis-related lncRNA prognostic signature for osteosarcoma and showed a close connection in terms of immunity. Moreover, we provided some potential targeted drugs for the treatment of osteosarcoma.
| S-EPMC11696132 | biostudies-literature
Project description:Recent studies have found that the protein encoded by the FDX1 gene is involved in mediating Cuproptosis as a regulator of protein lipoylation and related to immune response process of tumors. However, the specific biological function of FDX1 in glioma is currently unclear. To explore the potential function of FDX1, this study explored the correlation between the expression of FDX1 in cancers and survival prognosis by analyzing the public databases of GEPIA and Cbioportal. Immune infiltration was analyzed by the TIMER2.0 database in tumors. The possible biological processes and functions of FDX1-related in glioma were annotated through gene enrichment. Relationship between Cuproptosis and autophagy was explored through gene co-expression studies. Summary and conclusions of this study: (1) FDX1 is highly expressed in gliomas and associated with poor prognosis in low-grade gliomas (LGG). (2) Gene annotation indicates that FDX1 is mainly involved in the tumor protein lipoylation and cell death. (3) FDX1 expression is positively correlated with the infiltration of immune cells. (4) LIPT2 and NNAT, two other genes involved in lipoylation, may be unidentified marker gene for Cuproptosis. And the Cuproptosis genes related to FDX1 were positively correlated with the expression of autophagy marker genes Atg5, Atg12, and BECN-1. This evidence suggests that there may be some interaction between FDX1 mediated Cuproptosis and autophagy. In summary, FDX1 may serve as a potential immunotherapy target and prognostic marker for Glioma.
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Project description:BackgroundCuproptosis is a type of programmed cell death that is involved in multiple physiological and pathological processes, including cancer. We constructed a prognostic cuproptosis-related long non-coding RNA (lncRNA) signature for acute myeloid leukemia (AML).MethodsRNA-seq and clinical data for AML patients were acquired from The Cancer Genome Atlas (TCGA) database. The cuproptosis-related prognostic lncRNAs were identified by co-expression and univariate Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) was performed to construct a cuproptosis-related lncRNA signature, after which the AML patients were classified into two risk groups based on the risk model. Kaplan-Meier, ROC, univariate and multivariate Cox regression, nomogram, and calibration curves analyses were used to evaluate the prognostic value of the model. Then, expression levels of the lncRNAs in the signature were investigated in AML samples by quantitative polymerase chain reaction (qPCR). KEGG functional analysis, single-sample GSEA (ssGSEA), and the ESTIMATE algorithm were used to analyze the mechanisms and immune status between the different risk groups. The sensitivities for potential therapeutic drugs for AML were also investigated.ResultsFive hundred and three lncRNAs related to 19 CRGs in AML samples from the TCGA database were obtained, and 21 differentially expressed lncRNAs were identified based on the 2-year overall survival (OS) outcomes of AML patients. A 4-cuproptosis-related lncRNA signature for survival was constructed by LASSO Cox regression. High-risk AML patients exhibited worse outcomes. Univariate and multivariate Cox regression analyses demonstrated the independent prognostic value of the model. ROC, nomogram, and calibration curves analyses revealed the predictive power of the signature. KEGG pathway and ssGSEA analyses showed that the high-risk group had higher immune activities. Lastly, AML patients from different risk groups showed differential responses to various agents.ConclusionA cuproptosis-related lncRNA signature was established to predict the prognosis and inform on potential therapeutic strategies for AML patients.
| S-EPMC9585311 | biostudies-literature
Project description:Background As a common primary intracranial tumor, the diagnosis and therapy of low-grade glioma (LGG) remains a pivotal barrier. Cuproptosis, a new way induces cell death, has attracted worldwide attention. However, the relationship between cuproptosis and LGG remains unknown. Our study is all about finding out if there are any genes related to coproptosis that can be used to predict the outcome of LGG. Methods RNA data and clinical information were selected from Cancer Genome Atlas (TCGA) datasets and the Genotype-Tissue Expression (GTEx), 5 lncRNAs (GAS5.AS1, MYLK.AS1, AC142472.1, AC011346.1, AL359643.3) were identified by Cox univariate and multivariate regression, as well as LASSO Cox regression. In the training and test sets, a dual validation of the predictive signature comprised of these 5 lncRNAs was undertaken. The findings demonstrate that the risk model is able to predict the survival regression of LGG patients and has a good performance in either the KM curve approach or the ROC curve. GO, GSEA and KEGG were carried out to explore the possible molecular processes that affecting the prognosis of LGG. The characteristics of immune microenvironment were investigated by using CIBERSORT, ESTIMATE and ssGSEA. Results We identified five lncRNAs related with cuproptosis that were closely associated with the prognosis of LGG and used these five lncRNAs to develop a risk model. Using this risk model, LGG patients were then divided into high-risk and low-risk groups. The two patient groups had significantly distinct survival characteristics. Analyses of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the differential genes of the two patient groups were primarily concentrated in neural active ligand-receptor interaction and cytokine-cytokine receptor interaction. The ssGSEA score determined the information related to immune infiltration, and the two groups were differentially expressed in immune subpopulations such as T cells and B cells as well. Conclusion Our study discovered 5 cuproptosis-related lncRNAs which contribute to predicting patients’ survival of LGG and provide ideas for the exploration of new targets for LGG in the future.
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Project description:Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Despite advances in treatment, the prognosis remains poor due to late diagnosis. Cuproptosis (driven by copper ion accumulation) and disulfidptosis (driven by disulfide bond accumulation) are novel forms of programmed cell death, closely linked to tumor initiation, progression, and resistance. However, the specific roles of these mechanisms in LUAD remain inadequately studied. This study integrated multi-omics data from TCGA and GEO databases to systematically evaluate the differential expression and prognostic significance of copper and disulfide-related genes (DCRGs), identify two DCRG molecular subtypes, and construct a DCRG scoring model based on four key genes. Multi-omics analysis results revealed that the DCRG score not only accurately predicts prognosis in LUAD patients but is also closely associated with immune cell infiltration patterns and EGFR inhibitor responses. RT-qPCR validated the high expression of FURIN and RHOV in LUAD cells, supporting their role as potential therapeutic targets. Further Mendelian randomization analysis confirmed the causal relationship between FURIN and LUAD development. These findings provide novel biomarkers for the prognosis evaluation of LUAD based on cuproptosis and disulfidptosis mechanisms and offer a theoretical basis for targeting FURIN in LUAD treatment.
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Project description:Solute carrier (SLC) transporters represent 52 families of membrane transport proteins that function in endogenous compound homeostasis and xenobiotic disposition, and have been exploited in drug delivery and therapeutic targeting strategies. In particular, the SLC16 family that encodes for the 14 isoforms of the monocarboxylate transporter (MCT) family plays a significant role in the absorption, tissue distribution, and clearance of both endogenous and exogenous compounds. MCTs are required for the transport of essential cell nutrients and for cellular metabolic and pH regulation. Recent publications have indicated their novel roles in disease, and thus their potential as biomarkers and new therapeutic targets in disease are under investigation. More research into MCT isoform function, specificity, expression, and regulation will allow researchers to exploit the potential utility of MCTs in the clinic as therapeutic targets and prognostic factors of disease.
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