Abstract
Cell senescence genes play a vital role in the pathogenesis of colorectal cancer, a process that may involve the triggering of genetic variations and reversible phenotypes caused by epigenetic modifications. However, the specific regulatory mechanisms remain unclear. Using CellAge and The Cancer Genome Atlas databases and in-house RNA-seq data, DNA methylation-modified cellular senescence genes (DMCSGs) were validated by Support Vector Machine and correlation analyses. In 1150 cases and 1342 controls, we identified colorectal cancer risk variants in DMCSGs. The regulatory effects of gene, variant, and DNA methylation were explored through dual-luciferase and 5-azacytidine treatment experiments, complemented by multiple database analyses. Biological functions of key gene were evaluated via cell proliferation assays, SA-β-gal staining, senescence marker detection, and immune infiltration analyses. The genetic variant rs4558926 in the downstream of TACC3 was significantly associated with colorectal cancer risk (OR = 1.35, P = 3.22 × 10–4). TACC3 mRNA expression increased due to rs4558926 C > G and decreased DNA methylation levels. The CpG sites in the TACC3 promoter region were regulated by rs4558926. TACC3 knockdown decreased proliferation and senescence in colorectal cancer cells. In addition, subjects with high-TACC3 expression presented an immunosuppressive microenvironment. These findings provide insights into the involvement of genetic variants of cellular senescence genes in the development and progression of colorectal cancer.
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Data availability
Raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher. Supplementary material including antibody, primer sequence and small interfering RNA sequence is included with the article. TCGA, GEO (GSE39582), GTEx and HPA datasets were used to analyze the expression of TACC3 and other genes in multiple tissues and cell types. Additional data are available upon request from the corresponding author.
Abbreviations
- 5-Aza:
-
5-Azacytidine
- CCK-8:
-
Cell Counting Kit-8
- CIs:
-
Confidence intervals
- CSGs:
-
Cell senescence genes
- CTCF:
-
CCCTC-binding factor
- DEGs:
-
Differentially expressed genes
- DMCSGs:
-
DNA methylation-related cell senescence genes
- DNMT:
-
DNA methyltransferase
- EdU:
-
5-Ethynyl-2'-deoxyuridine
- eQTL:
-
Expression quantitative trait locus
- FDR:
-
False discovery rate
- GEO:
-
Gene Expression Omnibus
- GSEA:
-
Gene set enrichment analysis
- GTEx:
-
Genotype-Tissue Expression
- HWE:
-
Hardy–Weinberg equilibrium
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
- LD:
-
Linkage disequilibrium
- MAF:
-
Minor allele frequency
- meQTLs:
-
Methylation quantitative trait loci
- MSI:
-
Microsatellite instability
- MSS:
-
Microsatellite stable
- MSI-H:
-
Microsatellite instability-high
- ORs:
-
Odds ratios
- PCA:
-
Principal component analysis
- qRT‒PCR:
-
Quantitative reverse transcription polymerase chain reaction
- SVM:
-
Support Vector Machine
- sQTLs:
-
Splicing quantitative trait loci
- ssGSEA:
-
Single-sample gene set enrichment analysis
- TACC3:
-
Transforming acid coiled coil containing protein 3
- TCGA:
-
The Cancer Genome Atlas
- TMB:
-
Tumor mutational burden
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Acknowledgements
We sincerely thank Professor Meilin Wang of Nanjing Medical University for his selfless help and valuable advice. His expertise and guidance played a key role in our research, enabling us to complete this work successfully.
Funding
This work was supported by the National Natural Science Foundation of China (82172956, 82103915), and the Natural Science Foundation of Jiangsu Province (BK20210535).
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SL, ZF were the overall principal investigators in this study who conceived the study and obtained financial support, SL, ZF were responsible for the study design and supervised the entire study. HS, YC, and MX performed statistical analyses, interpreted the results, and drafted the initial manuscript. HS, YC, MX, JZ, CH, and ZW performed laboratory experiments, JZ, CH, ZW, YS, HZ, and YL were responsible for patient recruitment and sample preparation. All authors approved the final report for publication. HS, YC, and MX were contribute equally to this work.
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Shen, H., Chen, Y., Xu, M. et al. Cellular senescence gene TACC3 associated with colorectal cancer risk via genetic and DNA methylated alteration. Arch Toxicol 98, 1499–1513 (2024). https://doi.org/10.1007/s00204-024-03702-9
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DOI: https://doi.org/10.1007/s00204-024-03702-9