RESUMEN
BACKGROUND: The role and mechanisms of lipid metabolism in oral squamous cell carcinomas (OSCC) metastasis have not been clarified. This study aims to identify lipid metabolism-related genes and transcription factors regulated by metastasis-associated enhancers (MAEs) in OSCC. METHODS: Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed for lipid metabolism enrichment. TCGA data were used to analyze the differentially expressed lipid metabolism-related genes. MAEs were analyzed using GSE120634. Overlapping analysis was used to screen the MAE-regulated lipid metabolism-related genes, and the prognosis of these genes was analyzed. Transcription factor prediction was performed for the MAE-regulated lipid metabolism-related genes with prognostic value. Validation of the metastatic specificity of MAEs at ACAT1, OXSM and VAPA locus was performed using GSE88976 and GSE120634. ChIP-qPCR, qRT-PCR and Western blotting were used to verify the regulation of ACAT1, OXSM and VAPA expression by CBFB. Effects of CBFB knockdown on proliferation, invasion and lipid synthesis in metastatic OSCC cells were analyzed. RESULTS: Lipid metabolism was significantly enhanced in metastatic OSCC compared to non-metastatic OSCC. The expression of 276 lipid metabolism-related genes was significantly upregulated in metastatic OSCC, which were functionally related to lipid uptake, triacylglycerols, phospholipids and sterols metabolism. A total of 6782 MAEs and 176 MAE-regulated lipid metabolism-related genes were filtered. Three MAE-regulated lipid metabolism-related genes, ACAT1, OXSM and VAPA, were associated with a poor prognosis in OSCC patients. Enhancers at ACAT1, OXSM and VAPA locus were metastasis-specific enhancers. CBFB regulated ACAT1, OXSM and VAPA expression by binding to the enhancers of these genes. Knockdown of CBFB inhibited proliferation, invasion and lipid synthesis in metastatic OSCC cells. CONCLUSION: The MAE-regulated lipid metabolism-related genes (ACAT1, OXSM and VAPA) and the key transcription factor (CBFB) were identified. CBFB knockdown inhibited proliferation, invasion and lipid synthesis of OSCC cells. These findings provide novel candidates for the development of therapeutic targets for OSCC.
Asunto(s)
Neoplasias de Cabeza y Cuello , Metabolismo de los Lípidos , Neoplasias de la Boca , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias de la Boca/patología , Metástasis de la Neoplasia , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The host protective immunity against viral infection requires the effective detection of viral antigens and the subsequent production of type I interferons (IFNs) by host immune cells. Retinoic acid-inducible gene I (RIG-I) is the crucial signaling element responsible for sensing viral RNA component and initiating the downstream antiviral signaling pathways, leading to the production of type I IFNs. In this work, we identified microRNA-218 (miR-218) as a new virus-induced miRNA that dampens the expression of RIG-I in mouse and human macrophages, leading to the impaired production of type I IFNs. Interfering miR-218 expression rescued RIG-I-mediated antiviral signaling and thus protected macrophages from viral infection. Hence, our results provide new understanding of miRNA-mediated viral immune evasion and may be potentially useful for the treatment of viral infection in the future.