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      Oncogenic role of copper‑induced cell death‑associated protein DLD in human cancer: A pan‑cancer analysis and experimental verification

      research-article
      1 , 2
      Oncology Letters
      D.A. Spandidos
      cuproptosis, dihydrolipoamide dehydrogenase, cancer, prognosis, pan-cancer analysis

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          Abstract

          Copper ions can bind directly to lipoylated components of the tricarboxylic acid (TCA) cycle, triggering the aggregation of mitochondrial lipoylated proteins and the destabilization of Fe-S cluster proteins, resulting in copper-dependent cell death. Dihydrolipoamide dehydrogenase (DLD) is a key protein of the TCA cycle and constitutes the E3 component of the α-ketoglutarate dehydrogenase complex, which is deeply interconnected with the mitochondrial electron transfer chain in the TCA cycle. Tumor cells demonstrate dependency on glutaminolysis fuelling to carry out the TCA cycle and essential biosynthetic processes supporting tumor growth. Therefore, DLD plays an important role in the tumor biological process. However, to the best of our knowledge, no pan-cancer analysis is currently available for DLD. Therefore, the present study first explored the DLD expression profile in 33 tumors in publicly available datasets, including TIMER2, GEPIA2, UALCAN, cBioPortal and STRING. TIMER2, GEPIA2 and UALCAN were used for exploring gene expression; survival prognosis was detected by GEPIA2; genetic alteration was analysed by cBioPortal; immune infiltration data was obtained from TIMER2; interacting proteins of DLD were detected by STRING. DLD was found to be highly expressed in colon, liver, lung, stomach, renal, corpus uteri endometrial and ovarian cancers compared with normal tissues, and its high expression was associated with poorer prognosis in ovarian cancer. To the best of our knowledge, the present study provided the first comprehensive pan-cancer analysis of the oncogenic role of DLD across different tumors types. As the expression of DLD in ovarian cancer was high, and high expression is associated with poor prognosis, experimental verification of DLD in ovarian cancer was conducted. In the present study, DLD expression was found to be high in the ovarian cancer OC3 cell line, compared with the normal ovarian epithelial IOSE80 cell line by reverse transcription-quantitative PCR analysis. After knockdown of DLD expression, it was found that DLD regulated metabolic pathways by suppressing the intracellular NAD +/NADH ratio, which then in turn suppressed tumor cell proliferation detected by MTT assay. In conclusion, the present pan-cancer analysis of DLD demonstrated that DLD expression was associated with the clinical prognosis, immune infiltration and tumor mutational burden in 33 tumor types, and experimental verification in ovarian cancer was conducted. These results may contribute to the understanding of the role of DLD in tumorigenesis.

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          Most cited references26

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Copper induces cell death by targeting lipoylated TCA cycle proteins

            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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              jvenn: an interactive Venn diagram viewer

              Background Venn diagrams are commonly used to display list comparison. In biology, they are widely used to show the differences between gene lists originating from different differential analyses, for instance. They thus allow the comparison between different experimental conditions or between different methods. However, when the number of input lists exceeds four, the diagram becomes difficult to read. Alternative layouts and dynamic display features can improve its use and its readability. Results jvenn is a new JavaScript library. It processes lists and produces Venn diagrams. It handles up to six input lists and presents results using classical or Edwards-Venn layouts. User interactions can be controlled and customized. Finally, jvenn can easily be embeded in a web page, allowing to have dynamic Venn diagrams. Conclusions jvenn is an open source component for web environments helping scientists to analyze their data. The library package, which comes with full documentation and an example, is freely available at http://bioinfo.genotoul.fr/jvenn.
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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                May 2023
                06 April 2023
                06 April 2023
                : 25
                : 5
                : 214
                Affiliations
                [1 ]Department of Emergency Surgery, The Second People's Hospital of Lianyungang, Lianyungang, Jiangsu 222000, P.R. China
                [2 ]Department of Paediatric Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222000, P.R. China
                Author notes
                Correspondence to: Dr Dongsheng Zhu, Department of Paediatric Surgery, The First People's Hospital of Lianyungang, 182 Tongguan North Road, Lianyungang, Jiangsu 222000, P.R. China, E-mail: zhudongsheng@ 123456tmu.edu.cn
                Dr Han Qi, Department of Emergency Surgery, The Second People's Hospital of Lianyungang, 41 Hailian East Road, Lianyungang, Jiangsu 222000, P.R. China, E-mail: 312527644@ 123456qq.com
                [*]

                Contributed equally

                Article
                OL-25-5-13800
                10.3892/ol.2023.13800
                10131276
                6d07493f-432f-403f-bbcd-134ee71496b1
                Copyright: © Qi et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 27 June 2022
                : 02 March 2023
                Funding
                Funding: No funding was received.
                Categories
                Articles

                Oncology & Radiotherapy
                cuproptosis,dihydrolipoamide dehydrogenase,cancer,prognosis,pan-cancer analysis

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