High expression of cuproptosis-related gene FDX1 in relation to good prognosis and immune cells infiltration in colon adenocarcinoma (COAD)

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Abstract

Background

Cuproptosis induced by FDX1 is a newly discovered mechanism regulating cell death. However, the role of FDX1 in the pathogenesis of colon adenocarcinoma (COAD) remains to be studied.

Methods

FDX1 expression was analyzed with The Cancer Genome Atlas (TCGA) database and Human Protein Atlas (HPA) database. Association between FDX1 expression and COAD prognosis was investigated via the Kaplan–Meier (KM) survival curve. The differentially expressed genes (DEGs) of FDX1 were screened with R packages and the PPI were constructed via STRING database. Cytoscape software was used to detect the most profound modules in the PPIs network. CancerSEA database was used to analyze the effect of FDX1 expression levels on different functional status of COAD cells. The relationship between FDX1 expression and immune infiltration of COAD was analyzed by TIMER2.0 database. The COAD patients with high expression of FDX1 by Western blot, and the levels of immune infiltration were measured by flow cytometry.

Results

FDX1 was low expressed in most cancers, such as BRCA, KICH, and COAD. The overall survival (OS) and disease-specific survival (DSS) of COAD with high FDX1 expression were better than that of the low expression group. GO-KEGG enrichment analysis revealed that FDX1 and its co-expressed genes played an important role in the pathogenesis of COAD. Moreover, FDX1 expression in COAD were positively associated with “quiescence” and “inflammation” but negatively correlated with “invasion”. FDX1 expression was positively correlated with infiltration levels of CD8 ⁺ T cells, NK cells, and neutrophils. Oppositely, FDX1 expression was negatively correlated with that of CD4 ⁺ T cells and cancer-associated fibroblasts (CAFs). Finally, 6 COAD patients with high expression of FDX1 were screened, and the proportion of CD8 ⁺ T cells in cancer tissues of these patients was significantly higher than that in paracancerous, while the CD4 ⁺ T cells presented the opposite pattern.

Conclusion

FDX1 plays a role in inducing cuproptosis and modulating tumor immunity, which could be considered as potential therapeutic targets in COAD.

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Most cited references 41

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Cancer statistics in China, 2015.

Wanqing Chen, Rongshou Zheng, Peter D Baade … (2016)

With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. Because of China's massive population (1.37 billion), previous national incidence and mortality estimates have been limited to small samples of the population using data from the 1990s or based on a specific year. With high-quality data from an additional number of population-based registries now available through the National Central Cancer Registry of China, the authors analyzed data from 72 local, population-based cancer registries (2009-2011), representing 6.5% of the population, to estimate the number of new cases and cancer deaths for 2015. Data from 22 registries were used for trend analyses (2000-2011). The results indicated that an estimated 4292,000 new cancer cases and 2814,000 cancer deaths would occur in China in 2015, with lung cancer being the most common incident cancer and the leading cause of cancer death. Stomach, esophageal, and liver cancers were also commonly diagnosed and were identified as leading causes of cancer death. Residents of rural areas had significantly higher age-standardized (Segi population) incidence and mortality rates for all cancers combined than urban residents (213.6 per 100,000 vs 191.5 per 100,000 for incidence; 149.0 per 100,000 vs 109.5 per 100,000 for mortality, respectively). For all cancers combined, the incidence rates were stable during 2000 through 2011 for males (+0.2% per year; P = .1), whereas they increased significantly (+2.2% per year; P < .05) among females. In contrast, the mortality rates since 2006 have decreased significantly for both males (-1.4% per year; P < .05) and females (-1.1% per year; P < .05). Many of the estimated cancer cases and deaths can be prevented through reducing the prevalence of risk factors, while increasing the effectiveness of clinical care delivery, particularly for those living in rural areas and in disadvantaged populations.

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Global cancer statistics, 2012.

Lindsey A Torre, Freddie Bray, Rebecca Siegel … (2015)

Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries. Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment. Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests. © 2015 American Cancer Society.

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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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Author and article information

Contributors

Jingyun Xu: 20200011@wnmc.edu.cn

Journal

Journal ID (nlm-ta): J Cancer Res Clin Oncol

Journal ID (iso-abbrev): J Cancer Res Clin Oncol

Title: Journal of Cancer Research and Clinical Oncology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0171-5216

ISSN (Electronic): 1432-1335

Publication date (Electronic): 29 September 2022

Publication date PMC-release: 29 September 2022

Publication date (Print): 2023

Volume: 149

Issue: 1

Pages: 15-24

Affiliations

[1 ]GRID grid.452929.1, ISNI 0000 0004 8513 0241, General Practice Department, , The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), ; Wuhu, Anhui Province China

[2 ]GRID grid.443626.1, ISNI 0000 0004 1798 4069, School of Basic Medicine, , Wannan Medical College, ; NO. 22 Wenchang west road, Wuhu, Anhui Province China

Article

Publisher ID: 4382

DOI: 10.1007/s00432-022-04382-7

PMC ID: 9889456

PubMed ID: 36173462

SO-VID: 96fa33e2-a941-4482-9ec6-44f452b6ba7b

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 2 September 2022

Date accepted : 24 September 2022

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: fdx1,cuproptosis,prognosis,immune infiltrate,coad

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: fdx1, cuproptosis, prognosis, immune infiltrate, coad

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High expression of cuproptosis-related gene FDX1 in relation to good prognosis and immune cells infiltration in colon adenocarcinoma (COAD)

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Abstract

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Karger: Oncology

Most cited references 41

Cancer statistics in China, 2015.

Global cancer statistics, 2012.

Copper induces cell death by targeting lipoylated TCA cycle proteins

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