RESUMEN
PURPOSE: Given the high incidence and mortality rates of colorectal cancer (CRC) and the inadequacy of existing treatments for many patients, this study aimed to explore the potential of Capping Actin Protein (CAPG), a protein involved in actin-related movements, as a novel therapeutic target for CRC. METHODS: Bioinformatic analysis of gene expression was conducted using the UALCAN website. Cell proliferation was measured using the CCK-8 kit. Cell cycle, apoptosis, and ferroptosis were analyzed using flow cytometry. Tumorigenesis was evaluated by the subcutaneous inoculation of CRC cells into BALB/c nude female mice. Differentially expressed genes and signaling pathways were identified using RNA sequencing. RESULTS: CAPG was significantly overexpressed in human CRC tissues and its upregulation was correlated with poor overall survival. CAPG knockdown led to notable inhibition of CRC cells in vitro and in vivo. Interference with CAPG blocked the cell cycle at the G1 phase and triggered apoptosis and ferroptosis by upregulating the P53 pathway in CRC cells. CONCLUSION: CRC patients with higher CAPG levels have a poorer prognosis. CAPG inhibits apoptosis and ferroptosis, while promoting CRC cell proliferation by repressing the P53 pathway. Our study suggests that CAPG may be a potential therapeutic target for CRC prognosis and treatment.
Asunto(s)
Neoplasias Colorrectales , Ferroptosis , Animales , Femenino , Humanos , Ratones , Actinas/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/fisiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Ferroptosis/genética , Proteínas de Microfilamentos/metabolismo , Proteínas Nucleares/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Although many studies have revealed essential roles of HIF1A (hypoxia inducible factor 1 subunit alpha) in regulating various pathways associated with cancer development, a systematic investigation of associations of HIF1A expression with tumor immunity, the tumor microenvironment and other tumor phenotypes in pan-cancer is lacking. METHODS: Using cancer genomics datasets of 10 cancer cohorts from the Cancer Genome Atlas (TCGA) program, we investigated associations of HIF1A expression with tumor immune and stromal signatures, and various tumor phenotypes, including cell proliferation, stemness, epithelial-mesenchymal transition (EMT), tumor purity, oncogenic signaling, and clinical outcomes. RESULTS: HIF1A upregulation was found to be associated with increased immune and stromal signatures, aggressive phenotypes, and worse survival rates in various cancers. Moreover, HIF1A upregulation was not only associated with activation of various oncogenic signaling pathways, but also with increased tumor suppressive signatures, including apoptosis and anti-tumor immune response, indicative of a dual role of HIF1A in cancer development. However, HIF1A expression showed a stronger correlation with immune-inhibiting signatures than with immune-promoting signatures. Furthermore, HIF1A expression was found to be positively associated with both tumor immune infiltration and PD-L1 expression, indicating that tumors with elevated expression of HIF1A may exhibit a more active immunotherapy response. This indication was substantiated in a kidney cancer cohort receiving anti-PD-1/PD-L1 immunotherapy. CONCLUSIONS: HIF1A upregulation correlates with increased tumor immune and stromal signatures and aggressive phenotypes in human cancers. Our analysis may provide new insights into the role of HIF1A in tumor biology and clinical management.
