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对ccRCC中琥珀酸代谢相关基因进行综合生物信息学研究,随后对SLC25A4在肿瘤发生中的作用进行初步验证。

An integrated bioinformatic investigation of succinic acid metabolism related genes in ccRCC followed by preliminary validation of SLC25A4 in tumorigenesis.

作者信息

Yue Dong, Dong Fengyun, Wang Sen, Zheng Miao

机构信息

Department of Urology, Affiliated Hospital of Jining Medical University, Jining, China.

Department of Clinical Laboratory, Affiliated Hospital of Jining Medical University, Jining, China.

出版信息

Sci Rep. 2025 Jun 5;15(1):19736. doi: 10.1038/s41598-025-03102-8.


DOI:10.1038/s41598-025-03102-8
PMID:40473684
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12141529/
Abstract

The defective function of succinate dehydrogenase promotes the development and progression of kidney renal clear cell renal cell carcinoma (ccRCC). However, the molecular mechanism of succinate metabolism-related genes (SMRGs) has not been extensively studied in KIRC. First, differentially expressed SMRGs (DE-SMRGs) were screened among genesets. Next, functional enrichment analysis was performed to investigate the functions of DE-SMRGs. The univariate Cox algorithm, LASSO, and multivariate Cox analysis were performed to obtain biomarkers and build a prognostic model. Afterward, enrichment and immune microenvironment analysis were carried out in two different risk subgroups. Finally, expression validation and expression intensity of prognostic gene was verified by in situ and in vitro experiments. In total, 138 DE-SMRGs were screened by overlapping SMRGs and differentially expressed genes. The functional enrichment results revealed that DE-SMRGs were implicated in retinoic acid metabolic process and retinol metabolism. Then, 8 succinate metabolism-related biomarkers were obtained, and prognostic model was developed and SLC25A4 ranked the highest in importance. SLC25A4 was down-regulated in KIRC, and its upregulation was related to better overall survival in patients from public datasets and in clinical cases. SLC25A4 attenuated cell proliferation, cell invasion, and exerted its biological function by inhibiting the STAT3 signaling pathway. Our study reveals that succinate metabolism-related biomarkers can provide a basis for exploring the prediction of prognosis in ccRCC.

摘要

琥珀酸脱氢酶的功能缺陷促进肾透明细胞癌(ccRCC)的发生发展。然而,琥珀酸代谢相关基因(SMRGs)在肾透明细胞癌(KIRC)中的分子机制尚未得到广泛研究。首先,在基因集中筛选差异表达的SMRGs(DE-SMRGs)。其次,进行功能富集分析以研究DE-SMRGs的功能。采用单因素Cox算法、LASSO和多因素Cox分析来获得生物标志物并建立预后模型。随后,在两个不同风险亚组中进行富集和免疫微环境分析。最后,通过原位和体外实验验证预后基因的表达及表达强度。通过重叠SMRGs和差异表达基因,共筛选出138个DE-SMRGs。功能富集结果显示,DE-SMRGs与视黄酸代谢过程和视黄醇代谢有关。然后,获得了8个与琥珀酸代谢相关的生物标志物,建立了预后模型,其中SLC25A4的重要性排名最高。SLC25A4在KIRC中表达下调,其上调与公共数据集和临床病例中患者更好的总生存期相关。SLC25A4通过抑制STAT3信号通路减弱细胞增殖和细胞侵袭,并发挥其生物学功能。我们的研究表明,琥珀酸代谢相关生物标志物可为探索ccRCC预后预测提供依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/4c0dc746088c/41598_2025_3102_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/d808b5eccdd3/41598_2025_3102_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/a0c03f33baed/41598_2025_3102_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/2123c3c7ad6c/41598_2025_3102_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/fe8fd7c5e25f/41598_2025_3102_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/8844d581d196/41598_2025_3102_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/fa87fdf168da/41598_2025_3102_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/18df815976b4/41598_2025_3102_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/4c0dc746088c/41598_2025_3102_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/d808b5eccdd3/41598_2025_3102_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/a0c03f33baed/41598_2025_3102_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/2123c3c7ad6c/41598_2025_3102_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/fe8fd7c5e25f/41598_2025_3102_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/8844d581d196/41598_2025_3102_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/fa87fdf168da/41598_2025_3102_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/18df815976b4/41598_2025_3102_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b15/12141529/4c0dc746088c/41598_2025_3102_Fig8_HTML.jpg

相似文献

[1]
An integrated bioinformatic investigation of succinic acid metabolism related genes in ccRCC followed by preliminary validation of SLC25A4 in tumorigenesis.

Sci Rep. 2025-6-5

[2]
Integrated Multi-Omics Analysis Unveils Distinct Molecular Subtypes and a Robust Immune-Metabolic Prognostic Model in Clear Cell Renal Cell Carcinoma.

Int J Mol Sci. 2025-3-28

[3]
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[4]
Co-Highly Expressed and as Potential Prognostic Biomarkers and Therapeutic Targets in Clear Cell Renal Cell Carcinoma.

Front Biosci (Landmark Ed). 2025-4-18

[5]
Identification of HDAC10 as a candidate oncogene in clear cell renal carcinoma that facilitates tumor proliferation and metastasis.

Diagn Pathol. 2024-9-5

[6]
Identification and validation of prognostic biomarkers in ccRCC: immune-stromal score and survival prediction.

BMC Cancer. 2025-1-27

[7]
Prognostic value of KLFs family genes in renal clear cell carcinoma.

Sci Rep. 2024-8-30

[8]
Deciphering glutamine metabolism patterns for malignancy and tumor microenvironment in clear cell renal cell carcinoma.

Clin Exp Med. 2024-7-6

[9]
Integrated analysis of a competing endogenous RNA network reveals a ferroptosis-related 6-lncRNA prognostic signature in clear cell renal cell carcinoma.

Adv Clin Exp Med. 2024-12

[10]
A Gene Signature of Survival Prediction for Kidney Renal Cell Carcinoma by Multi-Omic Data Analysis.

Int J Mol Sci. 2019-11-14

本文引用的文献

[1]
KEGG: biological systems database as a model of the real world.

Nucleic Acids Res. 2025-1-6

[2]
Mitochondrial complex I promotes kidney cancer metastasis.

Nature. 2024-9

[3]
Identification of a novel ADCC-related gene signature for predicting the prognosis and therapy response in lung adenocarcinoma.

Inflamm Res. 2024-5

[4]
scRNA-seq revealed high stemness epithelial malignant cell clusters and prognostic models of lung adenocarcinoma.

Sci Rep. 2024-2-14

[5]
Machine learning-based models for the prediction of breast cancer recurrence risk.

BMC Med Inform Decis Mak. 2023-11-29

[6]
STAT3 phosphorylation at serine 727 activates specific genetic programs and promotes clear cell renal cell carcinoma (ccRCC) aggressiveness.

Sci Rep. 2023-11-9

[7]
Recognition of refractory Mycoplasma pneumoniae pneumonia among Myocoplasma pneumoniae pneumonia in hospitalized children: development and validation of a predictive nomogram model.

BMC Pulm Med. 2023-10-10

[8]
Combining network pharmacology, molecular docking, molecular dynamics simulation, and experimental verification to examine the efficacy and immunoregulation mechanism of FHB granules on vitiligo.

Front Immunol. 2023

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Clinicopathological significance of unraveling mitochondrial pathway alterations in non-small-cell lung cancer.

FASEB J. 2023-7

[10]
Molecular characterization of PANoptosis-related genes with features of immune dysregulation in systemic lupus erythematosus.

Clin Immunol. 2023-8

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