RESUMO
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.
Assuntos
Neoplasias Colorretais , Inibidor p16 de Quinase Dependente de Ciclina , Progressão da Doença , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Cobre/metabolismo , Regulação Neoplásica da Expressão Gênica , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Colorectal cancer and atrial fibrillation share several common risk factors, and the incidence of the two diseases also exhibits a certain correlation. The above facts suggest a potential interaction mechanism between them, which has obtained increasing attention in the scientific community but remains to be further explored. Participating in diverse physiological and pathological processes, miRNAs exert important roles in both occurrence and growth of colorectal cancer and atrial fibrillation. To fill the gap in the understanding of the potential linkage between two diseases, the present study collected dysregulated miRNAs of colorectal cancer and atrial fibrillation from previous studies and then selected the miRNAs with the same change trends in both diseases. Finally, we reviewed the potential crosstalk of two diseases focusing on the roles of 6 dysregulated miRNAs, including 3 co-downregulated miRNAs (hsa-mir-126, hsa-mir-133a and hsa-mir-150) and 3 co-upregulated miRNAs (hsa-mir-106a, hsa-mir-155 and hsa-mir-21). The molecular mechanisms mediated by these miRNAs in colorectal cancer and atrial fibrillation were reviewed, and the possible crosstalk between the two diseases was discussed from the perspective of miRNAs. This study also provides potential common targets for preventive and curative measures against both colorectal cancer and atrial fibrillation.
Assuntos
Fibrilação Atrial , Neoplasias Colorretais , MicroRNAs , Humanos , Fibrilação Atrial/genética , MicroRNAs/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Perfilação da Expressão GênicaRESUMO
Background: Considered a significant risk to health and survival, type 1 diabetes (T1D) is a heterogeneous autoimmune disease characterized by hyperglycemia caused by an absolute deficiency of insulin, which is mainly due to the immune-mediated destruction of pancreatic beta cells. Scope of review: In recent years, the role of immune checkpoints in the treatment of cancer has been increasingly recognized, but unfortunately, little attention has been paid to the significant role they play both in the development of secondary diabetes with immune checkpoint inhibitors and the treatment of T1D, such as cytotoxic T-lymphocyte antigen 4(CTLA-4), programmed cell death protein-1(PD-1), lymphocyte activation gene-3(LAG-3), programmed death ligand-1(PD-L1), and T-cell immunoglobulin mucin protein-3(TIM-3). Here, this review summarizes recent research on the role and mechanisms of diverse immune checkpoint molecules in mediating the development of T1D and their potential and theoretical basis for the prevention and treatment of diabetes. Major conclusions: Immune checkpoint inhibitors related diabetes, similar to T1D, are severe endocrine toxicity induced with immune checkpoint inhibitors. Interestingly, numerous treatment measures show excellent efficacy for T1D via regulating diverse immune checkpoint molecules, including co-inhibitory and co-stimulatory molecules. Thus, targeting immune checkpoint molecules may exhibit potential for T1D treatment and improve clinical outcomes.
