RESUMEN
Cuproptosis is a newly reported type of programmed cell death that is involved in the progression of various diseases. Some studies have reported its potential significance in multiple tumors. Colorectal cancer (CRC) is one of the malignant tumors with high incidence and mortality. The purpose of this study was to further explore the importance of cuproptosis in the CRC development and treatment. We analyzed the expression, alterations, and promoter methylation of cuproptosis-related genes (CRGs) in patients with CRC. Three machine learning methods was used to determine cuproptosis-related feature genes and a diagnostic model was built based on them. Using the unsupervised clustering, patients with CRC were classified into distinct clusters. Then, the LASSO method was used to establish a cuproptosis risk model. We analyzed the association of risk scores with outcomes, immune microenvironment, response to immunotherapy, and sensitivity to chemotherapeutic drugs. The results showed that the expression of CRGs was dysregulated in CRC. The diagnostic model based on cuproptosis-related feature genes showed great clinical value. The patients in two clusters displayed different prognosis and microenvironment. Furthermore, the risk score was correlated with clinical characteristics, immune infiltration and response to immunotherapy and chemotherapy. Above all, the present findings revealed the involvement of cuproptosis in CRC development and provided a diagnostic tool to evaluate CRC occurrence risk. The immune infiltration and drug sensitivity analysis results helped to predict the response of patients in different subtypes of CRC to immunotherapy and chemotherapy.
RESUMEN
Background: Colorectal cancer (CRC) is the third most prevalent cancer worldwide and the second leading cause of cancer mortality. Signal transducer and activator of transcription (STAT) proteins are a group of transcription factors implicated in cell signal transduction and gene transcription in several cancer types. However, the level of expression, genetic alterations, and biological function of different STATs, as well as their prognostic and immunotherapeutic value in CRC remain unclear. Methods: The mRNA and protein expression levels, genetic alterations, prognostic value, gene-gene and protein-protein interaction networks, and biological function of STATs in CRC were studied using the GEPIA, HPA, cBioPortal, PrognoScan, Kaplan-Meier plotter, GeneMANIA, STRING, and Metascape databases. The expression of STATs in CRC was confirmed using immunohistochemistry (IHC). Finally, the relationship between STAT expression and immune infiltration as well as immunotherapy-associated indicators was also investigated. Results: The expression levels of STAT2/5A/5B are downregulated in CRC, and the STAT1/3/4/5B expressions were significantly associated with the tumor stage of patients with CRC. The abnormal expression of STAT2/4/5B in patients with CRC is related to the prognosis of patients with CRC. The STATs and their neighboring proteins are primarily associated with lymphocyte activation, cytokine-mediated signaling pathways, positive regulation of immune response, regulation of cytokine production, and growth hormone receptor signaling pathways in cancer. The expression of STATs was significantly associated with immune infiltration and immunotherapy response-associated indicators. Conclusion: This study may help further understand the molecular mechanism of CRC and provide new prognostic biomarkers and immunotherapy targets in patients with CRC.