Cuproptosis-Related Genes MTF1 and LIPT1 as Novel Prognostic Biomarker in Acute Myeloid Leukemia.

Li Y ，Kan X 《-》

Identification and Validation of Cuproptosis-Related Prognostic Signature and Associated Regulatory Axis in Uterine Corpus Endometrial Carcinoma.

Background: Uterine corpus endometrial carcinoma (UCEC) is a common gynecological malignancy globally with high recurrence and mortality rates. Cuproptosis is a new type of programmed cell death involved in tumor cell proliferation and growth, angiogenesis, and metastasis. Methods: The difference in cuproptosis-related genes (CRGs) between UCEC tissues and normal tissues deposited in The Cancer Genome Atlas database was calculated using the "limma" R package. LASSO Cox regression analysis was conducted to construct a prognostic cuproptosis-related signature. Kaplan-Meier analysis was conducted to compare the survival of UCEC patients. A ceRNA network was constructed to identify the lncRNA-miRNA-mRNA regulatory axis. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to verify CRG expression in UCEC. Results: The expression of FDX1, LIAS, DLAT, and CDKN2A were upregulated, whereas the expression of LIPT1, DLD, PDHB, MTF1, and GLS were downregulated in UCEC versus normal tissues. The genetic mutation landscape of CRGs in UCEC was also summarized. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that these CRGs were enriched in the tricarboxylic acid (TCA) cycle, glycolysis, and HIF-1 signaling pathway. LASSO Cox regression analysis was performed and identified a cuproptosis-related prognostic signature including these three prognostic biomarkers (CDKN2A, GLS, and LIPT1). UCEC patients with high risk scores had a poor prognosis with an area under the curve of 0.782 and 0.764 on 3- and 5-year receiver operating characteristic curves. Further analysis demonstrated a significant correlation between CDKN2A and pTNM stage, tumor grade, immune cell infiltration, drug sensitivity, tumor mutational burden (TMB) score, and microsatellite instable (MSI) score. The data validation of qRT-PCR further demonstrated the upregulation of CDKN2A and the downregulation of LIPT1 and GLS in UCEC versus normal tissues. The ceRNA network also identified lncRNA XIST/miR-125a-5p/CDKN2A regulatory axis for UCEC. Conclusion: The current study identified a cuproptosis-related prognostic signature including these three prognostic biomarkers (CDKN2A, GLS, and LIPT1) for UCEC. The ceRNA network also identified that lncRNA XIST/miR-125a-5p/CDKN2A regulatory axis may be involved in the progression of UCEC. Further in vivo and in vitro studies should be conducted to verify these results.

Chen Y 《Frontiers in Genetics》

Database Mining Detected a Cuproptosis-Related Prognostic Signature and a Related Regulatory Axis in Breast Cancer.

Breast cancer is the frequent cause of disease burden related to cancer among women. It affects one in 20 women globally and up to one in eight women in high-income countries. Cuproptosis is a copper-induced modality of mitochondrial cell death that is involved in tumor proliferation and metastasis. To construct a prognostic cuproptosis-related signature, LASSO Cox regression analysis was employed. Additionally, ceRNA was developed with an aim of exploring the possible lncRNA-miRNA-mRNA regulatory axis in breast cancer. The expression of FDX1, DLD, DLAT, LIAS, LIPT1, GLS MTF1, and PDHA1 was downregulated, while CDKN2A expression level was elevated in breast cancer in contrast with normal tissue. We furthermore reviewed the genetic mutation landscape of genes linked to cuproptosis in breast cancer. Prognosis analysis revealed poor OS and RFS rates in breast cancer patients with elevated levels of CDKN2A and PDHA1 and low levels of MTF1, DLD, LIPT1, and FDX1. We then constructed a cuproptosis-related signature with six genes (DKN2A, MTF1, PDHA1, DLD, LIPT1, and FDX1) for breast cancer, which predicted the OS rate with an accuracy that ranged from medium to high. Further analysis demonstrated a significant correlation between the cuproptosis-related prognostic signature and pTNM stage, MSI score, drug sensitivity, TMB score, and immune cell infiltration. Moreover, we identified the lncRNA XIST/miR-92b-3p/MTF1 regulatory axis for breast cancer. Multiomics approaches were used to create a cuproptosis-related signature with six genes (DKN2A, MTF1, PDHA1, DLD, LIPT1, and FDX1) for breast cancer. We discovered the lncRNA XIST/miR-92b-3p/MTF1 regulatory axis for breast cancer, which has not yet been investigated previously.

Jiang B ，Zhu H ，Feng W ，Wan Z ，Qi X ，He R ，Xie L ，Li Y ... -  《-》

Comprehensive analysis of a cuproptosis-related ceRNA network implicates a potential endocrine therapy resistance mechanism in ER-positive breast cancer.

While adjuvant endocrine therapy (ET) may decrease the mortality rate of estrogen receptor-positive (ER+) breast cancer (BC), the likelihood of relapse and metastasis due to ET resistance remains high. Cuproptosis is a recently discovered regulated cell death (RCD), whose role in tumors has yet to be elucidated. Thus, there is a need to study its specific regulatory mechanism in resistance to ET in BC, to identify novel therapeutic targets. The prognostic cuproptosis-related genes (CRGs) in ER+ BC were filtered by undergoing Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses in TCGA-BRCA, and a CRGs risk signature was constructed using the correlation coefficient. Immune infiltration analysis, immune function analysis, tumor microenvironment (TME) analysis, immune checkpoint analysis, immunotherapy response analysis, drug sensitivity analysis, and pathway activation analysis were carried out among the high- and low-risk groups in turn. The central CRG of cuproptosis in ER+ BC resistance to ET was acquired through the intersection of protein interaction network (PPI) analysis, genes differentially expressed (DEGs) between human BC cells LCC9 and MCF-7 (GSE159968), and CRGs with prognostic significance in TCGA-BRCA ER+ BC. The miRNAs upstream of the core CRGs were predicted based on the intersection of 4 databases, miRDB, RNA22, miRWalk, and RNAlnter. Candidate miRNAs consisted of the intersection of predicted miRNAs and miRNAs differentially expressed in the LCC9 and MCF-7 cell lines (GSE159979). Candidate lncRNAs were the intersection of the differential lncRNAs from the LCC9 and MCF-7 cell lines and the survival-related lncRNAs obtained from a univariate Cox regression analysis. Pearson's correlation analysis was performed between mRNA-miRNA, miRNA-lncRNA, and mRNA-lncRNA expression separately. We constructed A risk signature of 4-CRGs to predict the prognosis of ER+ BC in TCGA-BRCA, a risk score = DLD*0.378 + DBT*0.201 + DLAT*0.380 + ATP7A*0.447 was used as the definition of the formula. There were significant differences between the high- and low-risk groups based on the risk score of 4-CRGs in aspects of immune infiltration, immune function, expression levels of immune checkpoint genes, and signaling pathways. DLD was determined to be the central CRG of cuproptosis in ER+ BC resistance to ET through the intersection of the PPI network analysis, DEGs between LCC9 and MCF-7 and 4-CRGs. Two miRNAs hsa-miR-370-3p and hsa-miR-432-5p were found taking DLD mRNA as a target, and the lncRNA C6orf99 has been hypothesized to be a competitive endogenous RNA that regulates DLD mRNA expression by sponging off hsa-miR-370-3p and hsa-miR-432-5p. This study built a prognostic model based on genes related to cuproptosis in ER+ BC. We considered DLD to be the core gene associated with resistance to ET in ER+ BC via copper metabolism. The search for promising therapeutic targets led to the establishment of a cuproptosis-related ceRNA network C6orf99/hsa-miR-370-3p and hsa-miR-432-5p/DLD.

Zhang D ，Lu W ，Zhuo Z ，Wang Y ，Zhang W ，Zhang M ... -  《BMC Medical Genomics》

A cuproptosis-related gene signature and associated regulatory axis in stomach adenocarcinoma based on bioinformatics analysis.

Stomach adenocarcinoma (STAD) is a highly aggressive and extremely heterogeneous gastric cancer characterized by high morbidity and mortality. Cuproptosis, a copper (Cu)-triggered modality of mitochondrial cell death, could regulate tumor proliferation and metastasis. Least absolute shrinkage and selection operator cox regression analysis was constructed to develop a prognostic cuproptosis-related signature. A lncRNA-miRNA-mRNA regulatory axis was performed to explore cuproptosis-related mechanism for STAD. The expression of FDX1, LIPT1, DLD, DLAT, PDHA1, PDHB, MTF1, GLS, and CDKN2A was upregulated in STAD versus normal tissue. We also summarized single nucleotide variants and copy number variation landscape of cuproptosis-related gene in STAD. Further analysis demonstrated that STAD patients with high expression of CDKN2A, DLD, GLS, and MTF1 and low expression of DLAT, FDX1, PDHA1 and PDHB had a poor overall survival (OS) and post progression survival (PPS) rate. By performing least absolute shrinkage and selection operator cox regression analysis, we constructed a cuproptosis-related prognostic signature for STAD. Further analysis demonstrated a significant correlation between FDX1 expression and immune cell infiltration, tumor mutational burden (TMB) score, microsatellite instability (MSI) score and drug sensitivity. Univariate and multivariate analysis indicated FDX1 expression and clinical stage as independent factors affecting the prognosis of STAD patients. We also identified a lncRNA MALAT1/miR-328-3p/FDX1 regulatory axis for STAD. Multi-omics approaches were performed to develop a cuproptosis-related signature with 2 genes (FDX1 and MTF1) for STAD. We also identified a lncRNA MALAT1/miR-328-3p/FDX1 regulatory axis for STAD.

Ding D ，Wang D ，Qin Y 《-》