摘要
Abstract
Objective To investigate the effect and mechanism of dimethyl fumarate(DMF)on the radiosensitivity of human nasopharyngeal carcinoma cell line 5-8F(referred to as 5-8F cells).Methods Tissue specimens and magnetic resonance imaging(MRI)images of 62 patients with nasopharyngeal carcinoma(who had not received any nasopharyngeal carcinoma-related treatment before)admitted to the Otolaryngology Department of Hepingli Hospital from January 2020 to December 2022 were selected and divided into the radiosensitive group(40 cases)and the radioresistant group(22 cases)according to their different radiosensitivity.MTT,colony formation and flow cytometry assay were conducted to evaluate the effects of DMF on cell viability,proliferation,cell cycle,and apoptosis of 5-8F cells.Immunofluorescence staining and Western blot were used to detect the expression levels of nuclear factor-κB subunit p65(NF-κB p65)protein in the nucleus and cytoplasm,and the epithelial-mesenchymal transition(EMT)markers such as E-cadherin,N-cadherin,and Vimentin protein.Eighteen mice were randomly divided into the control group(without IR or DMF treatment),ionizing radiation(IR)group,and IR+DMF group,with six mice in each group.All mice were replicated with nasopharyngeal carcinoma subcutaneous transplantation tumor models to investigate the effect of DMF on the radiosensitivity of nasopharyngeal carcinoma in mice.Results After two months of radiotherapy,patients in the radiosensitive group showed significant tumor regression and low-expressions of NF-κB p65 and p-NF-κB p65,while patients in the radioresistant group showed slow tumor regression and high-levels of NF-κB p65 and p-NF-κB p65.DMF inhibited the activity of 5-8F cells in a concentration-time-dependent manner,the inhibition rate of 50 µmol/L DMF for 24 h was lower than 10%,and the cell viability decreased sharply at 48 and 72 h of treatment(74.21%,54.81%,P<0.05),so 50.0 µmol/L DMF treatment for 24 h was selected for subsequent experiments.Compared with those in the IR group,the clone formation number and survival fraction of 5-8F cells significantly reduced(P<0.05),the number of phosphorylated histone(γ-H2AX)foci significantly increased(P<0.05),the proportion of G2/M stage nasopharyngeal carcinoma cell and apoptosis rate significantly increased(P<0.05),and the expression levels of NF-κB p65 and N-cadherin,Vimentin protein in the nucleus and cytoplasm significantly reduced(P<0.05),while the expression level of E-cadherin protein significantly increased in the IR+DMF group(P<0.05).In the subcutaneous transplant tumor model mice of nasopharyngeal carcinoma,compared with those in the IR group,the tumor volume and mass of mice significantly reduced after 1,2,and 3 weeks of administration(P<0.05),the expression levels of NF-κB p65,N-cadherin,and Vimentin protein in the nucleus and cytoplasm significantly reduced(P<0.05),while the expression level of E-cadherin protein significantly increased in the IR+DMF group(P<0.05).Conclusion DMF can delay DNA double-strand breaks by inhibiting the NF-κB signaling pathway and EMT,induce the arrest and apoptosis of G2/M stage nasopharyngeal carcinoma cells,thereby enhancing the radiosensitivity of nasopharyngeal carcinoma cells.关键词
富马酸二甲酯/人鼻咽癌细胞5-8F/辐射敏感性/细胞周期/细胞凋亡/核因子-κB/上皮间质转换/作用机制Key words
dimethyl fumarate/human nasopharyngeal carcinoma cells 5-8F/radiosensitivity/cell cycle/apoptosis/nuclear factor-κB/epithelial mesenchymal transition/mechanism分类
医药卫生
