Background: Cuproptosis, a newly defined regulated form of cell death, is mediated by the accumulation of copper ions in cells and related to protein lipoacylation. Seven genes have been reported as key genes of cuproptosis phenotype. Cuproptosis may be developed by subsequent research as a target to treat cancer, such as breast cancer. Long-noncoding RNA (lncRNA) has been proved to play a vital role in regulating the biological process of breast cancer. However, the role of lncRNAs in cuproptosis is poorly studied. Methods: Based on TCGA (The Cancer Genome Atlas) database and integrated several R packages, we screened out 153 cuproptosis-related lncRNAs and constructed a novel cuproptosis-related prognostic 2-lncRNAs signature (BCCuS) in breast cancer and then verified. By using pRRophetic package and machine learning, 72 anticancer drugs, significantly related to the model, were screened out. qPCR was used to detect the differentially expression of two model lncRNAs and seven cuproptosis genes between 10 pairs of breast cancer tissue samples and adjacent samples. Results: We constructed a novel cuproptosis-related prognostic 2-lncRNAs (USP2-AS1, NIFK-AS1) signature (BCCuS) in breast cancer. Univariate COX analysis (p < .001) and multivariate COX analysis (p < .001) validated that BCCuS was an independent prognostic factor for breast cancer. Overall survival Kaplan Meier-plotter, ROC curve and Risk Plot validated the prognostic value of BCCuS both in test set and verification set. Nomogram and C-index proved that BCCuS has strong correlation with clinical decision-making. BCCuS still maintain inspection efficiency when patients were splitting into Stage I−II (p = .024) and Stage III−IV (p = .003) breast cancer. BCCuS-high group and BCCuS-low group showed significant differences in gene mutation frequency, immune function, TIDE (tumor immune dysfunction and exclusion) score and other phenotypes. TMB (tumor mutation burden)-high along with BCCuS-high group had the lowest Survival probability (p = .005). 36 anticancer drugs whose sensitivity (IC50) was significantly related to the model were screened out using pRRophetic package. qPCR results showed that two model lncRNAs (USP2-AS1, NIFK-AS1) and three Cuproptosis genes (FDX1, PDHA1, DLAT) expressed differently between 10 pairs of breast cancer tissue samples and adjacent samples. Conclusion: The current study reveals that cuproptosis-related prognostic 2-lncRNAs signature (BCCuS) may be useful in predicting the prognosis, biological characteristics, and appropriate treatment of breast cancer patients.

/pdf/a-novel-cuproptosis-related-prognostic-2-lncrnas-signature-2h179xsh.pdf

A novel cuproptosis-related prognostic 2-lncRNAs signature in breast cancer

Ferroptosis is an iron-dependent form of oxidative cell death. Competitive endogenous RNAs diminish the inhibitory impact of microRNAs on other transcripts by chelating effects, which affects ferroptosis and reactive oxygen species (ROS) levels. However, the role of ferroptosis in excessive copper (Cu)-induced renal injury via the ceRNA axis has not been fully illustrated yet. Herein, we found that Cu induced ferroptosis in duck renal tubular epithelial cells, as indicated by the increase in intracellular iron levels and lipid peroxidation, upregulation of PTGS2 and ACSL4 levels, reduced GPX4 and GSH levels. In addition, knockdown miR-novel-100 could effectively decreased ferroptosis induced by Cu. Overexpression of miR-novel-100 or TC2N knockdown resulted in the stimulation of ROS and the upregulation of ferroptosis indicators. However, butylated hydroxyanisole (BHA) decreased the stimulation of ROS and the ferroptosis effect caused by miR-novel-100 overexpression. In conclusion, Cu induced ferroptosis by activating the lncRNA-TCONS-6251/miR-novel-100/TC2N axis to cause ROS accumulation. 

Copper as the driver of the lncRNA-TCONS-6251/miR-novel-100/TC2N axis: Unraveling ferroptosis in duck kidney

Cell death constitutes a critical component of the pathophysiology of cardiovascular diseases. A growing array of non-apoptotic forms of regulated cell death (RCD)—such as necroptosis, ferroptosis, pyroptosis, and cuproptosis—has been identified and is intimately linked to various cardiovascular conditions. These forms of RCD are governed by genetically programmed mechanisms within the cell, with epigenetic modifications being a common and crucial regulatory method. Such modifications include DNA methylation, RNA methylation, histone methylation, histone acetylation, and non-coding RNAs. This review recaps the roles of DNA methylation, RNA methylation, histone modifications, and non-coding RNAs in cardiovascular diseases, as well as the mechanisms by which epigenetic modifications regulate key proteins involved in cell death. Furthermore, we systematically catalog the existing epigenetic pharmacological agents targeting novel forms of RCD and their mechanisms of action in cardiovascular diseases. This article aims to underscore the pivotal role of epigenetic modifications in precisely regulating specific pathways of novel RCD in cardiovascular diseases, thus offering potential new therapeutic avenues that may prove more effective and safer than traditional treatments.

Epigenetic regulation of diverse regulated cell death modalities in cardiovascular disease: Insights into necroptosis, pyroptosis, ferroptosis, and cuproptosis

Abstract Background Short-term inhalation of occupationally relevant ultrafine zinc/copper (Zn/Cu) containing welding fumes has been shown to induce subclinical systemic inflammation, associated with an elevated risk for cardiovascular diseases. The involvement of noncoding RNAs (lncRNAs) in this setting is currently unknown. However, lncRNAs have been reported to fulfill essential roles in, e.g., cardiovascular diseases, inflammation, infectious diseases, and pollution-related lung disorders. Methods In this study, the specific lncRNAs levels of the 4 lncRNAs CoroMarker, MALAT1, CDR1as and LINC00460 were determined by RT-qPCR in THP-1 macrophages exposed to Zn/Cu metal fume suspensions for 1, 2, and 4 hours in vitro. Furthermore, 14 subjects were exposed to Zn/Cu containing welding fumes (at 2.5 mg/m 3 ) for 6 hours. Before, 6, 10, and 29 hours after exposure start, whole blood cell lncRNAs levels were determined by RT-qPCR. Results In THP-1 macrophages, we observed a 2.3-fold increase of CDR1as at 1 h (Wilcoxon p = 0.03), a non-significant increase of CoroMarker at 1 h, and an increase of LINC00460 at 2 h ( p = 0.03) and at 4 h ( p = 0.06). In whole blood cells, we determined a non-significant upregulation of CDR1as at 6 h ( p = 0.2), a significant downregulation of CoroMarker at 6 h ( p = 0.04), and a significant upregulation of LINC00460 levels at 10 h ( p = 0.04) and 29 h ( p = 0.04). MALAT-1 remained unchanged in both settings. Conclusion The orientation of regulation of the lncRNAs is (except for CoroMarker) similar in the in vitro and in vivo experiments and in line with their described functions. Therefore, these results, e.g. the upregulation of the potential risk marker for cardiovascular diseases, CDR1as, contribute to understanding the underlying mechanisms of Zn/Cu-induced subclinical inflammation in metal workers. 

/pdf/the-human-long-noncoding-rnas-coromarker-malat1-cdr1as-and-14gp3dyz.pdf

The human long noncoding RNAs CoroMarker, MALAT1, CDR1as, and LINC00460 in whole blood of individuals after controlled short-term exposure with ultrafine metal fume particles at workplace conditions, and in human macrophages in vitro

Correction: The human long noncoding RNAs CoroMarker, MALAT1, CDR1as, and LINC00460 in whole blood of individuals after controlled short‑term exposure with ultrafine metal fume particles at workplace conditions, and in human macrophages in vitro

Inflammatory Responses to Zn/Cu-Containing Welding Fume in Human Alveolar Epithelial and Macrophage Cell Lines, with MIP-1β/CCL4 as a Much More Sensitive Macrophage Activation Marker than IL-8 and TNF-α

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The human long noncoding RNAs CoroMarker, MALAT1, CDR1as, and LINC00460 in whole blood of individuals after controlled short-term exposure with ultrafine metal fume particles at workplace conditions, and in human macrophages in vitro

Correction: The human long noncoding RNAs CoroMarker, MALAT1, CDR1as, and LINC00460 in whole blood of individuals after controlled short‑term exposure with ultrafine metal fume particles at workplace conditions, and in human macrophages in vitro

Inflammatory Responses to Zn/Cu-Containing Welding Fume in Human Alveolar Epithelial and Macrophage Cell Lines, with MIP-1β/CCL4 as a Much More Sensitive Macrophage Activation Marker than IL-8 and TNF-α