RESUMEN
Cervical cancer (CC) is a gynaecological malignancy tumour that seriously threatens women's health. Recent evidence has identified that interferon regulatory factor 5 (IRF5), a nucleoplasm shuttling protein, is a pivotal transcription factor regulating the growth and metastasis of various human tumours. This study aimed to investigate the function and molecular basis of IRF5 in CC development. IRF5, protein phosphatase 6 catalytic subunit (PPP6C) and methyltransferase-like 3 (METTL3) mRNA levels were evaluated by quantitative real-time (qRT)-polymerase chain reaction (PCR). IRF5, PPP6C, METTL3, B-cell lymphoma 2 and Bax protein levels were detected using western blot. Cell proliferation, migration, invasion, angiogenesis and apoptosis were determined by using colony formation, 5-ethynyl-2'-deoxyuridine (EdU), transwell, tube formation assay and flow cytometry assay, respectively. Glucose uptake and lactate production were measured using commercial kits. Xenograft tumour assay in vivo was used to explore the role of IRF5. After JASPAR predication, binding between IRF5 and PPP6C promoter was verified using chromatin immunoprecipitation and dual-luciferase reporter assays. Moreover, the interaction between METTL3 and IRF5 was verified using methylated RNA immunoprecipitation (MeRIP). IRF5, PPP6C and METTL3 were highly expressed in CC tissues and cells. IRF5 silencing significantly inhibited cell proliferation, migration, invasion, angiogenesis and glycolytic metabolism in CC cells, while induced cell apoptosis. Furthermore, the absence of IRF5 hindered tumour growth in vivo. At the molecular level, IRF5 might bind with PPP6C to positively regulate the expression of PPP6C mRNA. Meanwhile, IRF5 was identified as a downstream target of METTL3-mediated m6A modification. METTL3-mediated m6A modification of mRNA might promote CC malignant progression by regulating PPP6C, which might provide a promising therapeutic target for CC treatment.
Asunto(s)
Proliferación Celular , Factores Reguladores del Interferón , Metiltransferasas , Fosfoproteínas Fosfatasas , Regulación hacia Arriba , Neoplasias del Cuello Uterino , Animales , Femenino , Humanos , Ratones , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones Desnudos , Invasividad Neoplásica , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Neovascularización Patológica/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/metabolismo , Fosfoproteínas Fosfatasas/genética , Fosfoproteínas Fosfatasas/metabolismoRESUMEN
BACKGROUND: A novel predictive model was rarely reported based on inflammation-related genes to explore clinical outcomes of lung adenocarcinoma (LUAD) patients. METHODS: Using TCGA database, we screened nine inflammation-related genes with a prognostic value, and LASSO regression was applied for model construction. The predictive value of the prognostic signature developed from inflammation-related genes was assessed by survival assays and multivariate assays. PCA and t-SNE analysis were performed to demonstrate clustering abilities of risk scores. RESULTS: Thirteen inflammation-related genes (BTG2, CCL20, CD69, DCBLD2, GPC3, IL7R, LAMP3, MMP14, NMUR1, PCDH7, PIK3R5, RNF144B, and TPBG) with prognostic values were finally identified. LASSO regression further screened nine candidates (BTG2, CCL20, CD69, IL7R, MMP14, NMUR1, PCDH7, RNF144B, and TPBG). Then, a prognostic prediction model using the above nine genes was constructed. A reliable clustering ability of risk score was demonstrated by PCA and t-SNE assays in 500 LUAD patients. The survival assays revealed that the overall survivals of the high-risk group were distinctly poorer than those of the low-risk group with 1-, 3-, and 5-year AUC values of 0.695, 0.666, and 0.694, respectively. Finally, multivariate assays demonstrated the scoring system as an independent prognostic factor for overall survival. CONCLUSIONS: Our study shows that the signature of nine inflammation-related genes can be used as a prognostic marker for LUAD.