Research Paper Advance Articles
The crosstalk role of CDKN2A between tumor progression and cuproptosis resistance in colorectal cancer
- 1 Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
- 2 Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
- 3 School of Ophthalmology and Optometry, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
- 4 Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330031, China
- 5 Department of Gastroenterology and Hepatology, Shenzhen Hospital of Southern Medical University, Shenzhen 518000, China
- 6 Department of Oncology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
Received: December 5, 2023 Accepted: April 15, 2024 Published: June 17, 2024
https://doi.org/10.18632/aging.205945How to Cite
Copyright: © 2024 Cheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Cuproptosis is a type of cell death characterized by excessive copper-lipid reactions in the tricarboxylic acid cycle, resulting in protein toxicity stress and cell death. Although known as a cuproptosis inhibitor through CRISPR-Cas9 screening, the role of cyclin-dependent kinase inhibitor 2A (CDKN2A) in cuproptosis resistance and its connection to tumor development remains unclear.
Methods: In this study, we combined single-cell sequencing, spatial transcriptomics, pathological image analysis, TCGA multi-omics analysis and in vitro experimental validation to comprehensively investigate CDKN2A distribution, expression, epigenetic modification, regulation and genomic features in colorectal cancer cells. We further explored the associations between CDKN2A and cellular pathway, immune infiltration and spatial signal communication.
Results: Our findings showed an increasing trend in cuproptosis in the trajectory of tumor progression, accompanied by an upward trend of CDKN2A. CDKN2A underwent transcriptional activation by MEF2D and via the SNHG7/miR-133b axis, upregulating glycolysis, copper metabolism and copper ion efflux. CDKN2A likely drives epithelial-mesenchymal transition (EMT) and progression by activating Wnt signaling. CDKN2A is associated with high genomic instability and sensitivity to radiation and chemotherapy. Tumor regions expressing CDKN2A exhibit distinctive SPP1+ tumor-associated macrophage (TAM) infiltration and MMP7 enrichment, along with unique signaling crosstalk with adjacent areas.
Conclusions: CDKN2A mediates cuproptosis resistance through regulating glycolysis and copper homeostasis, accompanied by a malignant phenotype and pro-tumor niche. Radiation and chemotherapy are expected to potentially serve as therapeutic approaches for cuproptosis-resistant colorectal cancer with high CDKN2A expression.
Abbreviations
5-FU-R: 5-fluorouracil-resistant; 5-FU-S: 5-fluorouracil-sensitive; CDKN2A: Cyclin-dependent kinase inhibitor 2A; ceRNA: Competitive endogenous RNA; CNV: Copy Number Variation; EMT: Epithelial-Mesenchymal Transition; GEO: Gene Expression Omnibus; LncRNAs: Long noncoding RNAs; miRNAs: microRNAs; MEF2D: Myocyte Enhancer Factor 2D; MMP7: Matrix Metallopeptidase 7; PCA: Principal Component Analysis; SCENIC: Single-cell regulatory network inference and clustering; siRNA: Small interfering RNA; SNHG7: Small Nucleolar RNA Host Gene 7; TAM: Tumor-associated macrophage; TME: Tumor microenvironment.