Cuproptosis-Related lncRNA Gene Signature Establishes a Prognostic Model of Gastric Adenocarcinoma and Evaluate the Effect of Antineoplastic Drugs

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Abstract

Background: One of the most frequent malignancies of the digestive system is stomach adenocarcinoma (STAD). Recent research has demonstrated how cuproptosis (copper-dependent cell death) differs from other cell death mechanisms that were previously understood. Cuproptosis regulation in tumor cells could be a brand-new treatment strategy. Our goal was to create a cuproptosis-related lncRNA signature. Additionally, in order to evaluate the possible immunotherapeutic advantages and drug sensitivity, we attempted to study the association between these lncRNAs and the tumor immune microenvironment of STAD tumors. Methods: The TCGA database was accessed to download the RNA sequencing data, genetic mutations, and clinical profiles for TCGA STAD. To locate lncRNAs related to cuproptosis and build risk-prognosis models, three techniques were used: co-expression network analysis, Cox-regression techniques, and LASSO techniques. Additionally, an integrated methodology was used to validate the models’ predictive capabilities. Then, using GO and KEGG analysis, we discovered the variations in biological functions between each group. The link between the risk score and various medications for STAD treatment was estimated using the tumor mutational load (TMB) and tumor immune dysfunction and rejection (TIDE) scores. Result: We gathered 22 genes linked to cuproptosis based on the prior literature. Six lncRNAs related to cuproptosis were used to create a prognostic marker (AC016394.2, AC023511.1, AC147067.2, AL590705.3, HAGLR, and LINC01094). After that, the patients were split into high-risk and low-risk groups. A statistically significant difference in overall survival between the two groups was visible in the survival curves. The risk score was demonstrated to be an independent factor affecting the prognosis by both univariate and multivariate Cox regression analysis. Different risk scores were substantially related to the various immunological states of STAD patients, as further evidenced by immune cell infiltration and ssGSEA analysis. The two groups had differing burdens of tumor mutations. In addition, immunotherapy was more effective for STAD patients in the high-risk group than in the low-risk group, and risk scores for STAD were substantially connected with medication sensitivity. Conclusions: We discovered a marker for six cuproptosis-associated lncRNAs linked to STAD as prognostic predictors, which may be useful biomarkers for risk stratification, evaluation of possible immunotherapy, and assessment of treatment sensitivity for STAD.

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Copper induces cell death by targeting lipoylated TCA cycle proteins

Peter Tsvetkov, Shannon Coy, Boryana Petrova … (2022)

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms. Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al . investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK Lipoylation determines sensitivity to copper-induced cell death.

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Broadening horizons: the role of ferroptosis in cancer

Xin CHEN, Rui Kang, Guido Kroemer … (2021)

The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy.