Cuproptosis-related gene DLAT is a prognostic and immunological biomarker in pan-cancer

doi:10.21203/rs.3.rs-2486438/v1

Download PDF

Research Article

Cuproptosis-related gene DLAT is a prognostic and immunological biomarker in pan-cancer

https://doi.org/10.21203/rs.3.rs-2486438/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Dihydrolipoamide S-acetyltrans-ferase (DLAT), a mitochondrial protein involved in glucose metabolism, has been identified as a key gene associated with cuproptosis recently. However, studies on DLAT in pan-cancer have not been found. Aim of this study is to explore the expression profiles and clinical value of DLAT in pan-cancer. DLAT expression profiles were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), UALCAN and the Human Protein Atlas (HPA) websites. The prognostic and diagnostic values of DLAT and its relationship with immune cell infiltration were analyzed based on TCGA data. cBioPortal and UALCAN websites were used to search gene alteration and methylation status of DLAT in tumors, respectively. CancerSEA database was used to investigate the biological functions of DLAT at the single-cell level. Finally, STRING, GAPIA2.0 and TIMER databases were used to construct protein-protein interaction (PPI) networks and functional enrichment analyses. High DLAT expression was found in most cancers and predicted poor prognosis in patients with several tumors, such as breast cancer, esophageal cancer, head and neck squamous cell carcinoma. DLAT showed early diagnostic value in 17 tumors, especially in acute myeloid leukemia (LAML). Abnormal gene alterations and DNA methylation of DLAT were verified in pan-cancer. Single cell RNA sequencing (scRNAseq) analysis reflected that DLAT could regulate various biological functions of cancer cells. Abnormal expression of DLAT regulated infiltration of multiple immune cells in a variety of tumors. Gene enrichment analysis showed that DLAT was involved in mitochondrial matrix, coated vesicle and ribonucleoprotein granule. DLAT can be used as an important indicator of early diagnosis, prognosis and immunotherapy for a variety of tumors.

Dihydrolipoamide S-acetyltrans-ferase (DLAT)

Pan-cancer

Prognosis

Immune cell infiltration

Cuproptosis

Due to the aging of population and various causes for cancer, the incidence and mortality of cancer are increasing year by year worldwide. According to statistics, there were about 19.3 million new cancer cases and 10 million deaths worldwide in 2020 (Sung et al. 2021). Although the emergence of various targeted therapies, some cancer patients still have poor therapeutic effects due to the complexity of tumor mechanisms (Boopathi and Thangavel 2021). Therefore, searching for valuable pan-cancer genes is of great importance to elucidate the pathogenesis of different cancers.

As a cofactor for essential enzymes, copper is found in very low levels in living organisms. Once overloaded, copper can participate in cytotoxicity by inducing apoptosis and reactive oxygen species (ROS) reaction (Theophanides and Anastassopoulou 2002). A recent study confirmed that cuproptosis is a new type of cell death, and its mechanism involves the direct binding of copper to lipoylated TCA cycle proteins (Tsvetkov et al. 2022). The link between copper and cancer has long been recognized. Many studies have shown that tumor cells proliferation requires higher levels of copper compared to healthy tissues. Increasing evidence have reported that many cancer patients have elevated copper levels in their serum or solid tumor tissues, including breast (Feng et al. 2020), lung (Zhang et al. 2022), gastrointestinal (Stepien et al. 2017), oral (Chen et al. 2019), thyroid (Kazi Tani et al. 2021), bladder (Mortada et al. 2020), gynecological (Michalczyk and Cymbaluk-Płoska 2020) and prostate cancers (Saleh et al. 2020). Up to now, a few genes associated with cuproptosis have been identified, such as ferredoxin 1 (FDX1), dihydrolipoamide S-acetyltrans-ferase (DLAT).

DLAT, a mitochondrial protein, is involved in many metabolic pathways by catalyzing the conversion of pyruvate to acetyl-coA (Huang et al. 2019). Recent studies have shown that DLAT was highly expressed in liver cancer and low expressed in renal clear cell carcinoma (Bai et al. 2022, Bian, Fan and Xie 2022). In lung cancer, up-regulated expression of DLAT was reported to promote tumor occurrence and development by enhancing glycolysis (Chen et al. 2022). However, the expression levels and functions of DLAT in various malignant tumors remain unclear.

In this research, we used a large amount of public data to explore the expression levels and prognostic value of DLAT in pan-cancer. Gene functional enrichment and single cell RNA sequencing (scRNAseq) analysis were performed to understand the detailed functions of DLAT in human cancers. Moreover, the relationship between DLAT and tumor immunity were discussed.

Expression levels of DLAT in human cancers

The RNA sequencing (RNAseq) data and related clinical parameters of 33 kinds of cancers and their normal tissues were obtained from TCGA (https://portal.gdc.cancer.gov/). We collected RNAseq data of 31 normal human tissues from GTEx database (https://commonfund.nih.gov/GTEx) and analyzed DLAT expression levels in normal tissues and cancer tissues combined with TCGA data. In addition, mRNA expression data of 18 paired tumor samples were obtained through TCGA.

The protein expression levels of DLAT in different cancers were analyzed using UALCAN database (http://ualcan.path.uab.edu/index.html). DLAT immunohistochemical expression images of some cancers and their corresponding normal tissues were downloaded from the HPA database (https://www.proteinatlas.org/). Wilcoxon rank-sum test was applied to compare DLAT expression in tumor tissues and normal tissues. “ggplot2.0” package of R software version 3.6.3 was used for data statistical analysis and visualization. A P value< 0.05 was regarded as statistically significant.

Prognostic value assessment

Survival data of pan-cancer were collected from TCGA database. Overall survival (OS), progress free interval (PFI), and disease specific survival (DSS) analyses were conducted to excavate prognostic value of DLAT in human cancers. Kaplan–Meier (K-M) survival method and Cox regression were used to compare survival rate between high and low DLAT expression groups. For survival analysis, “survival” package of R software was used. The survival curves were visualized using R package “survmine”. Moreover, forest maps drawn by R package “ggplot2” were used to comprehensively analyze prognostic value of DLAT expression in pan-cancer. A P value< 0.05 was regarded as statistically significant.

Diagnostic value assessment

“pROC” and “ggplot2” packages were used to analyze and draw receiver operating characteristic (ROC) curve. The potential diagnostic capacity of DLAT for cancers was predicted using the area under the ROC curve (AUC). AUC > 0.9, indicating high accuracy; AUC ranges from 0.7 to 0.9, indicating a certain degree of accuracy; AUC ranges from 0.5 to 0.7, indicating low accuracy (Smoot, Wong and Dodd 2011).

Genetic alteration and DNA methylation analyses

cBioPortal (https://www.cbioportal.org/) is a public website for discovering genetic alteration data based on TCGA data. Through “Cancer Types Summary” module of cBioPortal, frequency and types of DLAT alteration were explored and downloaded. Genomic alteration site information and 3D structure of DLAT were analyzed and downloaded using the “Mutations” module. DNA promoter methylation of DLAT in human cancers was analyzed using UALCAN website.

Relationship between DLAT and immune cell infiltration

To determine whether DLAT affects tumor immunity, the association of DLAT with 24 types of immune cell markers was investigated in 33 cancer types. These immune cell markers comprise activated dendritic cells (aDC), B cells, CD8 T cells, cytotoxic cells, dendritic cells (DC), eosinophils, immature DC (iDC), macrophages, mast cells, neutrophils, CD56bright NK cells, CD56dim NK cells, NK cells, plasmacytoid DC (pDC), T cells, T helper cells, T central memory cells (Tcm), T effector memory cells (Tem), T follicular helper cells (TFH), T gamma delta cells (Tgd), Th1 cells, Th17 cells, Th2 cells and T regulatory cells (TReg) (Bindea et al. 2013). The tumor immune cell infiltration levels were calculated using the single-sample GSEA (ssGSEA) method (Hänzelmann, Castelo and Guinney 2013) of R “GSVA” package. The heatmap of correlation between DLAT and immune cell markers in 33 cancers was drawn by R “ggplot2” package. A P value< 0.05 was regarded as statistically significant.

Single cell RNAseq (scRNAseq) analysis

CancerSEA database (http://biocc.hrbmu.edu.cn/CancerSEA/), a free public website for scRNAseq analysis, was used to explore the correlation between DLAT and tumor cells functional status in 17 cancer types at a single cell level.

Functional enrichment analysis

Protein-protein interaction (PPI) network of DLAT in human cancers was constructed using STRING website (http://cn.string-db.org/). DLAT-related genes of top 100 were acquired through “Similar Genes Detection” module of GEPIA2.0 database (http://gepia2.cancer-pku.cn/#index). The relationship between DLAT and the top 10 DLAT-related genes was analyzed through “Correlation analysis” module. A heatmap drawn by TIMER2.0 database (http://timer.cistrome.org/) was used to display the association of DLAT and top 10 DLAT-related genes in pan-cancer. GO and KEGG enrichment analyses of the top 100 DLAT-related genes were performed using R “clusterProfiler” package. A P value< 0.05 was regarded as statistically significant.

DLAT mRNA was abnormally expressed in pan-cancer

To observe DLAT mRNA expression levels in human cancers, we first obtained RNAseq data from TCGA database. From Fig.1A, it can be seen that DLAT expression levels varied in different types of cancers. Compared to normal tissues, DLAT expression was lower in 8 types of cancer, including breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), rectal cancer (READ), prostate cancer (PRAD), and thyroid cancer (THCA). While, DLAT expression was higher in 7 types of cancer, including cholangiocarcinoma (CHOL), kidney chromophobe (KICH), lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), lung squamous cell carcinoma (LUSC), uterine corpus endometrial carcinoma (UCEC), stomach cancer (STAD), compared to normal tissues. Considering that normal samples were fewer in TCGA database, we further verified DLAT expression in 33 cancers by intergrating TCGA and GTEx databases. As shown in Fig. 1B, it can be found that DLAT was abnormally expressed in 27 types of cancer. We found that DLAT was highly expressed in 22 types of cancer, including BRCA, CHOL, COAD, diffuse large B-cell Lymphoma (DLBCL), esophageal carcinoma (ESCA), glioblastoma (GBM), KICH, lower grade glioma (LGG), LIHC, LUAD, LUSC, ovarian cancer (OV), pancreatic cancer (PAAD), PRAD, READ, skin cutaneous melanoma (SKCM), STAD, testicular germ cell tumors (TGCT), THCA, thymoma (THYM), UCEC, uterine carcinosarcoma (UCS). However, it was lowly expressed only in 5 types of cancer, including adrenocortical carcinoma (ACC), bladder cancer (BLCA), HNSC, KIRC, and acute myeloid leukemia (LAML). Next, we analyzed DLAT expression in paired tumor samples, and found that DLAT was lowly expressed in COAD, KIRC, KICH, KIRP, LUSC, STAD, THCA, while highly expressed in CHOL, HNSC, LIHC, LUAD (Fig. 1C).

DLAT protein levels in pan-cancer

From the analysis of CPTAC samples on UALCAN platform, DLAT protein expression in BRCA, HNSC, GBM, KIRC and PAAD were significantly decreased, while the expression in UCEC were significantly increased (Fig. 2). In addition, we further analyzed the IHC staining patterns of DLAT in some tumors using the HPA database, and the results indicated that DLAT protein levels were consistent with the UALCAN results (Fig. 2).

DLAT was a prognostic biomarker in pan-cancer

Given that DLAT was aberrantly expressed in numerous cancer types, we speculated whether DLAT influences the survival of cancer patients. Hence, the correlation between DLAT expression and cancer patients’ OS, DSS and PFI were explored. Our results revealed that DLAT expression could significantly influence OS in patients with BRCA, COAD, esophageal adenocarcinoma (ESAD), HNSC, KICH, KIRC, KIRP, LGG, LIHC, PAAD, READ, STAD, and uveal melanoma (UVM) (Fig. 3A). According K-M survival curves, it can be found that low expression of DLAT predicted favorable OS in patients with BRCA, ESAD, HNSC, KICH, LGG, LIHC, PAAD, UVM. However, in patients with COAD, KIRC, KIRP, READ, STAD, those with low DLAT expression had unfavorable OS (Fig. 3B-N).

Moreover, the relationship between DSS and DLAT expression in human cancers were presented in Fig.4A. We demonstrated that ACC, BRCA, LGG, LIHC, PAAD, PRAD, sarcoma (SARC), and UVM patients with DLAT over-expression exhibited a shorter DSS. However, COAD, KIRC, KIRP, STAD patients with DLAT over-expression exhibited a longer DSS (Fig. 4B-M).

From Fig. 5A, it can be seen that DLAT expression had significantly effects on PFI in 13 cancer types, including ACC, BLCA, COAD, HNSC, KIRC, KIRP, LGG, LIHC, LUSC, PAAD, READ, STAD, and UVM. DLAT up-regulation exhibited a poor PFI in patients with ACC, BLCA, HNSC, LGG, LIHC, PAAD, UVM. However, in patients with COAD, KIRC, KIRP, LUSC, READ, STAD, those with DLAT up-regulation expression exhibited a good PFI (Fig. 5B-N).

DLAT was a diagnostic biomarker in pan-cancer

To determine the diagnostic value of DLAT, we performed ROC curves to calculate AUC value in cancers. According to the value of AUC, DLAT expression had high value for LAML, PAAD, CHOL, and KIRC early diagnosis (AUC: > 0.9), relative value for GBM, OV, LGG, LUAD, DLBCL, HNSC, LIHC, KIRP, THYM, READ, LUSC, STAD, KICH early diagnosis (AUC: 0.7-0.9)，low value for ESAD, THCA, UCS, ACC, UCEC, ESCA, COAD, PRAD, TGCT, CESC, SKCM, BRCA, BLCA early diagnosis (AUC: 0.5-0.7) (Fig. 6).

DLAT genetic alteration in pan-cancer

We found a high DLAT amplification rate in UCS (1.75%), a high mutation rate in UCEC (2.65%), the highest incidence of “deep deletion” in TGCT (3.36%) (Fig. 7A). Missense and truncation were the main types of DLAT mutations (Fig. 7B). V242Wfs*5/E239G alteration in the 3D structure of DLAT was shown in Fig. 7C.

DLAT promoter methylation levels in pan-cancer

Increasing evidence have demonstrated that elevated/decreased gene methylation contribute to tumors development through inhibiting/activating the oncogenes expression. We demonstrated that aberrant promoter methylation of DLAT was involved in 13 cancer types. In BRCA, KIRC, LIHC, LUAD, PCPG, and SARC, DLAT promoter methylation levels were significantly decreased (Fig. 8A). While, elevated DLAT promoter methylation levels were found in BLCA, CESC, COAD, ESCA, HNSC, PRAD, and READ (Fig. 8B).

DLAT was associated with immune cell infiltration in pan-cancer

Extensive studies have illustrated that the infiltration of immune cells is related to the malignant biological behavior of tumors and can affect the prognosis of cancer patients. Therefore, the correlation between DLAT and 24 kinds of immune cell markers was investigated. From Fig. 9, the results revealed that DLAT was significantly associated with immune cell infiltration in the vast majority of tumors. Especially, we found that DLAT was positively associated with immune cell markers in GBM, including DC, B cells, macrophages, T cells, mast cells, NK cells, and so on.

Functional analysis of DLAT at single cell level

The results of CancerSEA database provided different functional states of DLAT in 17 tumors, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), Chronic myelogenous leukemia (CLL), GBM, glioma, astrocytoma (AST), high-grade glioma (HGG), oligodendroglioma (ODG), LUAD, non-small cell lung cancer (NSCLC), melanoma (MEL), renal cell carcinoma (RCC), BRCA, head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), retinoblastoma (RB), and uveal menaloma (UM) (Fig. 10A). Fig. 10B showed the positively relationship between DLAT expression and DNA damage and stemness in ALL. The positively relationship between DLAT expression and DNA damage and stemness in BRCA was displayed in Fig. 10C. In RB, DLAT expression was positively related to angiogenesis, differentiation, inflammation, negatively related to DNA repair, cell cycle, DNA damage (Fig. 10D). In UM, DLAT expression was negatively related to a variety of cancer-related functional states, including DNA repair, DNA damage, apoptosis, and metastasis (Fig. 10E). In addition, single-cell level LIPT1 expression profiles from ALL, BRCA, RB and UM were shown by T-SNE diagrams ((Fig. 10F-I).

Functional enrichment analysis of DLAT-related genes in pan-cancer

PPI network and functional enrichment analyses were performed to further explore role of DLAT in tumorigenesis. As shown in Fig. 11A, 10 proteins interacting with DALT were identified through STRING website. Next, we used GEPIA2.0 platform to obtain the top 100 DLAT-related genes in pan-cancer (Table. S1). The top 10 DLAT-related genes, including C11ORF57, CUL5, NDUFS1, PAFAH1B2, PDE12, RBM7, SDHD, TFAM, UBE4A, and ZW10, were significantly positively correlated with DLAT expression (Fig. 11B and C). The GO and KEGG analyses for the top 100 DLAT-related genes indicated that DLAT may play critical roles in mitochondrial matrix, coated vesicle and ribonucleoprotein granule (Fig. 11D).

Cuproptosis is a new form of cell death recently proposed by Tsvetkov et al, which is completely distinct from other cell deaths, such as autophagy, apoptosis, and pyroptosis, and has become the focus of research in recent years (Tsvetkov et al. 2022). Like all essential trace elements, copper maintains a dynamic balance in cells through a variety of mechanisms. Therefore, cytotoxicity occurs when intracellular copper concentrations exceed the threshold for maintaining homeostasis. The role of cuproptosis in cancer is gradually recognized. Studies have found that copper induced tumor growth and progression by regulating autophagy through ULK1 and ULK2 (Tsang et al. 2020). Copper can also contribute to tumor development, growth and metastasis by promoting tumor angiogenesis (Karginova et al. 2019).

As a key gene associated with cuproptosis, DLAT is involved in TCA cycle and the glucose metabolism (Tsvetkov et al. 2022, Shatokhina et al. 2022). Goh and his colleagues found that DLAT was over-expressed in gastric cancer and could regulate pyruvate levels in gastric cancer cells (Goh et al. 2015). However, studies on DLAT in pan-cancer have not been found. In this research, we performed a systematic and comprehensive analysis of DLAT in 33 cancers using multiple databases. Through TCGA, we found that DLAT was abnormally expressed in 15 human cancers. Among them, increased expression of DLAT was found in CHOL, KICH, LIHC, LUAD, LUSC, STAD, UCEC. Through integration of GTEx with TCGA, we further confirmed that DLAT was aberrantly expressed in 27 human cancers. Moreover, from the analysis of 18 paired tumor samples of TCGA, DLAT was abnormally expressed in 11 tumors. Tumor patients with decreased DLAT expression, such as BRCA, ESAD, HNSC, KICH, LGG, LIHC, PAAD and UVM, showed a better prognosis. However, in other tumor patients, such as COAD, KIRC, KIRP, READ, and STAD, low DLAT expression predicted a poor prognosis. Additionally, ROC curves were used to determine the diagnostic value of DLAT. We found that DLAT has high value for 4 forms of tumors early diagnosis, including LAML, PAAD, CHOL, and KIRC.

Abnormal gene expression can be attributed to genetic alterations, such as mutations and deep deletion. Previous studies have revealed that DLAT mutation can cause pyruvate dehydrogenase deficiency (Head et al. 2005). However, the effect of DLAT gene alterations on tumorigenesis has not been reported. Herein, DLAT gene alterations existed in a wide variety of tumors, especially in UCS, UCEC, which may explain why DLAT was up-regulated expression in these tumors. Abnormal DNA methylation is also a common mechanism that can regulate gene transcription. Abnormal DNA methylation levels have been found in some malignancies, such as breast (Győrffy et al. 2016), thyroid (Faam et al. 2021), liver (Li et al. 2019), and lung cancers (Hong and Kim 2021), and affect tumor progression and prognosis. Our findings that increased DNA methylation levels in some tumor types, especially in BLCA and HNSC, which may be one of the reasons for the downregulation of DLAT expression in these tumors.

Tumor microenvironment may affect tumor cell growth, invasion, metastasis, and cell drug resistance. Studies have revealed the association of CD8 T cells infiltration levels with tumor development, metastasis (Li et al. 2021). It is well known that TReg cells can suppress human immune response and promote tumor cells immune escape through various ways (Lainé et al. 2021, Alvisi et al. 2020). By analyzing the association of DALT expression with immune cell infiltration, we found that expression of DALT was negatively correlated with most immune cell infiltration. These results suggested that DLAT may be a potential target for tumor immunotherapy.

scRNA-seq can reveal the unique gene states of individual cells on a large scale, and has become one of the hottest technologies in the field of biology in recent years. Herein, we used CancerSEA database to analyze the functional status of DLAT in 17 tumors, and showed that expression of DLAT was associated with several cell functions, such as DNA damage, DNA repair, and apoptosis. Our results confirmed that DLAT was an important tumor suppressor gene with multiple effector functions, which may provide a new target for future tumor therapy. To further explore the possible mechanism of DLAT-mediated tumor, we performed functional enrichment analysis of DLAT-related genes, confirming DLAT may play critical roles in mitochondrial matrix, coated vesicle and ribonucleoprotein granule.

To sum up, by pan-cancer analysis, DLAT was confirmed to be abnormally expressed in many tumor tissues. Elevated expression of DLAT was associated with unfavorable prognosis in patients with some tumor types. Our results suggested that DLAT was a prognostic marker in pan-cancer. DNA methylation, gene alteration, PPI network, GO and KEGG enrichment analyses of DLAT further elucidated the molecular mechanism of DLAT in tumor. Analysis of tumor immune cell infiltration level showed that DLAT expression was significantly correlated with tumor immunity, which provided a new direction for tumor immunotherapy.

Abnormally expressed of DLAT was confirmed by data extracted from multiple databases. DLAT exhibited high value of prognosis and diagnosis in a large number of tumors. scRNAseq analysis reflected that DLAT could regulate various biological functions of cancer cells, especially DNA damage, DNA repair and apoptosis. Abnormal expression of DLAT may participate in cancers development by regulating mitochondrial matrix, coated vesicle, ribonucleoprotein granule, and infiltration of immune cells.

Acknowledgements

Not applicable

Authors’ contributions

Liping Zeng and Xianlei Fang designed the research. Xiaomin Lu and Heng Long analyzed the data. Liping Zeng and Xianlei Fang wrote the paper. Zhen-Bo Feng edited and validated the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by National Natural Science Foundation of China (Grant No. 82260581); Scientific Research Foundation of Hunan Provincial Education Department (22B1038; 21B0907); Hunan Provincial Natural Science Foundation of China (2022JJ50291); Hunan Province College Students’ Innovation and Entrepreneurship Training Program (S202112214015); National University Students’ Innovation and Entrepreneurship Training Program (202112214004); Hunan University of Medicine Scientific Research incubator construction project (2022).

Data Availability

Data and materials are available at TCGA, GTEx, UALCAN, HPA, CancerSEA, STRING, GAPIA2.0 and TIMER databases.

Conflict of interest

None

Ethics Approval

Not applicable

Alvisi, G., J. Brummelman, S. Puccio, E. M. Mazza, E. P. Tomada, A. Losurdo, V. Zanon, C. Peano, F. S. Colombo, A. Scarpa, M. Alloisio, A. Vasanthakumar, R. Roychoudhuri, M. Kallikourdis, M. Pagani, E. Lopci, P. Novellis, J. Blume, A. Kallies, G. Veronesi & E. Lugli (2020) IRF4 instructs effector Treg differentiation and immune suppression in human cancer. J Clin Invest 130: 3137-3150.https://doi.org/10.1172/jci130426
Bai, W. D., J. Y. Liu, M. Li, X. Yang, Y. L. Wang, G. J. Wang & S. C. Li (2022) A Novel Cuproptosis-Related Signature Identified DLAT as a Prognostic Biomarker for Hepatocellular Carcinoma Patients. World J Oncol 13: 299-310.https://doi.org/10.14740/wjon1529
Bian, Z., R. Fan & L. Xie (2022) A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma. Genes (Basel) 13.https://doi.org/10.3390/genes13050851
Bindea, G., B. Mlecnik, M. Tosolini, A. Kirilovsky, M. Waldner, A. C. Obenauf, H. Angell, T. Fredriksen, L. Lafontaine, A. Berger, P. Bruneval, W. H. Fridman, C. Becker, F. Pagès, M. R. Speicher, Z. Trajanoski & J. Galon (2013) Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39: 782-95.https://doi.org/10.1016/j.immuni.2013.10.003
Boopathi, E. & C. Thangavel (2021) Dark Side of Cancer Therapy: Cancer Treatment-Induced Cardiopulmonary Inflammation, Fibrosis, and Immune Modulation. Int J Mol Sci 22.https://doi.org/10.3390/ijms221810126
Chen, F., J. Wang, J. Chen, L. Yan, Z. Hu, J. Wu, X. Bao, L. Lin, R. Wang, L. Cai, L. Lin, Y. Qiu, F. Liu & B. He (2019) Serum copper and zinc levels and the risk of oral cancer: A new insight based on large-scale case-control study. Oral Dis 25: 80-86.https://doi.org/10.1111/odi.12957
Chen, Q., Y. Wang, L. Yang, L. Sun, Y. Wen, Y. Huang, K. Gao, W. Yang, F. Bai, L. Ling, Z. Zhou, X. Zhang, J. Xiong & R. Zhai (2022) PM2.5 promotes NSCLC carcinogenesis through translationally and transcriptionally activating DLAT-mediated glycolysis reprograming. J Exp Clin Cancer Res 41: 229.https://doi.org/10.1186/s13046-022-02437-8
Faam, B., M. A. Ghaffari, L. Khorsandi, A. A. Ghadiri, M. Totonchi, A. Amouzegar, S. A. Fanaei, F. Azizi, H. B. Shahbazian & M. Hashemi Tabar (2021) RAP1GAP Functions as a Tumor Suppressor Gene and Is Regulated by DNA Methylation in Differentiated Thyroid Cancer. Cytogenet Genome Res 161: 227-235.https://doi.org/10.1159/000516122
Feng, Y., J. W. Zeng, Q. Ma, S. Zhang, J. Tang & J. F. Feng (2020) Serum copper and zinc levels in breast cancer: A meta-analysis. J Trace Elem Med Biol 62: 126629.https://doi.org/10.1016/j.jtemb.2020.126629
Goh, W. Q., G. S. Ow, V. A. Kuznetsov, S. Chong & Y. P. Lim (2015) DLAT subunit of the pyruvate dehydrogenase complex is upregulated in gastric cancer-implications in cancer therapy. Am J Transl Res 7: 1140-51
Győrffy, B., G. Bottai, T. Fleischer, G. Munkácsy, J. Budczies, L. Paladini, A. L. Børresen-Dale, V. N. Kristensen & L. Santarpia (2016) Aberrant DNA methylation impacts gene expression and prognosis in breast cancer subtypes. Int J Cancer 138: 87-97.https://doi.org/10.1002/ijc.29684
Hänzelmann, S., R. Castelo & J. Guinney (2013) GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14: 7.https://doi.org/10.1186/1471-2105-14-7
Head, R. A., R. M. Brown, Z. Zolkipli, R. Shahdadpuri, M. D. King, P. T. Clayton & G. K. Brown (2005) Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency. Ann Neurol 58: 234-41.https://doi.org/10.1002/ana.20550
Hong, Y. & W. J. Kim (2021) DNA Methylation Markers in Lung Cancer. Curr Genomics 22: 79-87.https://doi.org/10.2174/1389202921999201013164110
Huang, X., G. Gan, X. Wang, T. Xu & W. Xie (2019) The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance. Autophagy 15: 1258-1279.https://doi.org/10.1080/15548627.2019.1580105
Karginova, O., C. M. Weekley, A. Raoul, A. Alsayed, T. Wu, S. S. Lee, C. He & O. I. Olopade (2019) Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis. Mol Cancer Ther 18: 873-885.https://doi.org/10.1158/1535-7163.mct-18-0667
Kazi Tani, L. S., A. T. Gourlan, N. Dennouni-Medjati, P. Telouk, M. Dali-Sahi, Y. Harek, Q. Sun, J. Hackler, M. Belhadj, L. Schomburg & L. Charlet (2021) Copper Isotopes and Copper to Zinc Ratio as Possible Biomarkers for Thyroid Cancer. Front Med (Lausanne) 8: 698167.https://doi.org/10.3389/fmed.2021.698167
Lainé, A., O. Labiad, H. Hernandez-Vargas, S. This, A. Sanlaville, S. Léon, S. Dalle, D. Sheppard, M. A. Travis, H. Paidassi & J. C. Marie (2021) Regulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation. Nat Commun 12: 6228.https://doi.org/10.1038/s41467-021-26352-2
Li, K., T. Li, Z. Feng, M. Huang, L. Wei, Z. Yan, M. Long, Q. Hu, J. Wang, S. Liu, D. C. Sgroi & S. Demehri (2021) CD8(+) T cell immunity blocks the metastasis of carcinogen-exposed breast cancer. Sci Adv 7.https://doi.org/10.1126/sciadv.abd8936
Li, Z., Z. Li, L. Wang, C. Long, Z. Zheng & X. Zhuang (2019) ZCCHC13-mediated induction of human liver cancer is associated with the modulation of DNA methylation and the AKT/ERK signaling pathway. J Transl Med 17: 108.https://doi.org/10.1186/s12967-019-1852-0
Michalczyk, K. & A. Cymbaluk-Płoska (2020) The Role of Zinc and Copper in Gynecological Malignancies. Nutrients 12.https://doi.org/10.3390/nu12123732
Mortada, W. I., A. Awadalla, S. Khater, A. Ahmed, E. T. Hamam, M. El-Zayat & A. A. Shokeir (2020) Copper and zinc levels in plasma and cancerous tissues and their relation with expression of VEGF and HIF-1 in the pathogenesis of muscle invasive urothelial bladder cancer: a case-controlled clinical study. Environ Sci Pollut Res Int 27: 15835-15841.https://doi.org/10.1007/s11356-020-08113-8
Saleh, S. A. K., H. M. Adly, A. A. Abdelkhaliq & A. M. Nassir (2020) Serum Levels of Selenium, Zinc, Copper, Manganese, and Iron in Prostate Cancer Patients. Curr Urol 14: 44-49.https://doi.org/10.1159/000499261
Shatokhina, H. O., O. O. Khita, D. O. Minchenko, D. O. Tsymbal, O. R. Luzina, S. V. Danilovskyi, M. Y. Sliusar, L. O. Levadna & O. H. Minchenko (2022) ERN1 dependent impact of glutamine and glucose deprivations on the pyruvate dehydrogenase genes expression in glioma cells. Endocr Regul 56: 254-264.https://doi.org/10.2478/enr-2022-0027
Smoot, B. J., J. F. Wong & M. J. Dodd (2011) Comparison of diagnostic accuracy of clinical measures of breast cancer-related lymphedema: area under the curve. Arch Phys Med Rehabil 92: 603-10.https://doi.org/10.1016/j.apmr.2010.11.017
Stepien, M., M. Jenab, H. Freisling, N. P. Becker, M. Czuban, A. Tjønneland, A. Olsen, K. Overvad, M. C. Boutron-Ruault, F. R. Mancini, I. Savoye, V. Katzke, T. Kühn, H. Boeing, K. Iqbal, A. Trichopoulou, C. Bamia, P. Orfanos, D. Palli, S. Sieri, R. Tumino, A. Naccarati, S. Panico, H. B. A. Bueno-de-Mesquita, P. H. Peeters, E. Weiderpass, S. Merino, P. Jakszyn, M. J. Sanchez, M. Dorronsoro, J. M. Huerta, A. Barricarte, S. Boden, B. van Guelpen, N. Wareham, K. T. Khaw, K. E. Bradbury, A. J. Cross, L. Schomburg & D. J. Hughes (2017) Pre-diagnostic copper and zinc biomarkers and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. Carcinogenesis 38: 699-707.https://doi.org/10.1093/carcin/bgx051
Sung, H., J. Ferlay, R. L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal & F. Bray (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71: 209-249.https://doi.org/10.3322/caac.21660
Theophanides, T. & J. Anastassopoulou (2002) Copper and carcinogenesis. Crit Rev Oncol Hematol 42: 57-64.https://doi.org/10.1016/s1040-8428(02)00007-0
Tsang, T., J. M. Posimo, A. A. Gudiel, M. Cicchini, D. M. Feldser & D. C. Brady (2020) Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. Nat Cell Biol 22: 412-424.https://doi.org/10.1038/s41556-020-0481-4
Tsvetkov, P., S. Coy, B. Petrova, M. Dreishpoon, A. Verma, M. Abdusamad, J. Rossen, L. Joesch-Cohen, R. Humeidi, R. D. Spangler, J. K. Eaton, E. Frenkel, M. Kocak, S. M. Corsello, S. Lutsenko, N. Kanarek, S. Santagata & T. R. Golub (2022) Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 375: 1254-1261.https://doi.org/10.1126/science.abf0529
Zhang, L., J. Shao, S. W. Tan, H. P. Ye & X. Y. Shan (2022) Association between serum copper/zinc ratio and lung cancer: A systematic review with meta-analysis. J Trace Elem Med Biol 74: 127061.https://doi.org/10.1016/j.jtemb.2022.127061

No competing interests reported.

TableS1.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

Cuproptosis-related gene DLAT is a prognostic and immunological biomarker in pan-cancer

Status:

Version 1

Abstract

Figures

Intrduction

Materials And Methods

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1