| 胡陶,杜春燕,李正斯.SFXN2介导的线粒体自噬参与弥漫性大B细胞淋巴瘤的利妥昔单抗耐药机制研究.[J].中南医学科学杂志.,2025,(2):211-216. |
| SFXN2介导的线粒体自噬参与弥漫性大B细胞淋巴瘤的利妥昔单抗耐药机制研究 |
| Study on the role of SFXN2-mediated mitophagy in the mechanism of rituximab resistance in diffuse large B-cell lymphoma |
| 投稿时间：2023-11-27 |
| DOI：10.15972/j.cnki.43-1509/r.2025.02.005 |
| 中文关键词: 铁氧蛋白2 线粒体 自噬 弥漫性大B细胞淋巴瘤 利妥昔单抗 耐药 [ |
| 英文关键词:sideroflexin 2 mitochondrial autophagy diffuse large B-cell lymphoma rituximab resistance |
| 基金项目:四川省医学科研课题(s19068)；绵阳市卫健委课题(201913) |
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| 中文摘要: |
| 目的探讨铁氧蛋白2(SFXN2)介导的线粒体自噬参与弥漫性大B细胞淋巴瘤(DLBCL)的利妥昔单抗耐药机制。 方法将DLBCL细胞系(OCI-LY1和RL)和利妥昔单抗耐药细胞系(RL-4RH)实验分为空载体(Vector)/OCI-LY1组、SFXN2/OCI-LY1组、短发夹SFXN2(shSFXN2)/RL组及其阴性对照(shNC)/RL组、shNC/RL-4RH组、shSFXN2/RL-4RH组、线粒体自噬阻断剂氯喹(CQ)/RL-4RH组、CQ+shSFXN2/RL-4RH组。比较各组SFXN2蛋白表达水平。采用CCK-8、FACS分析各组细胞活力及凋亡情况。激光共聚焦显微镜下观察RL-4RH细胞在敲低SFXN2后的自噬通量。裸鼠实验分为RL组(接种RL肿瘤细胞)、RL-4RH组(接种RL-4RH肿瘤细胞)和RL-4RH+shSFXN2组(接种转染shSFXN2的RL-4RH肿瘤细胞),各组动物给予利妥昔单抗干预后,采用免疫组织化学染色分析各组肿瘤组织Ki67和SFXN2表达情况。 结果与shNC/RL组相比,shSFXN2/RL组SFXN2蛋白表达水平、细胞活力降低(P＜0.05),细胞凋亡率增加(P＜0.05)；与Vector/OCI-LY1组相比,SFXN2/OCI-LY1组SFXN2蛋白表达水平、细胞活力升高(P＜0.05)。与shNC/RL-4RH组相比,shSFXN2/RL-4RH组自噬体数量减少(P＜0.05),自噬空泡、自溶体数量增加(P＜0.05)。与shSFXN2/RL-4RH组相比,CQ+shSFXN2/RL-4RH组自噬体数量增加(P＜0.05),自溶体数量减少(P＜0.05)。与RL组相比,RL-4RH组荷瘤小鼠肿瘤体积增加(P＜0.05),肿瘤组织中SFXN2、Ki67表达水平上调(P＜0.05)；RL-4RH+shSFXN2组逆转了RL-4RH组荷瘤小鼠中的利妥昔单抗耐药性效应(P＜0.05)。 结论SFXN2敲低可能通过诱导线粒体自噬的过度激活,逆转利妥昔单抗耐药性。 |
| 英文摘要: |
| AimTo explore the mechanism of rituximab resistance in diffuse large B-cell lymphoma (DLBCL) through mitochondrial autophagy mediated by sideroflexin 2 (SFXN2). MethodsThe DLBCL cell lines (OCI-LY1 and RL) and rituximab resistant cell lines (RL-4RH) were divided into Vector/OCI-LY1 group, SFXN2/OCI-LY1 group, short hairpin SFXN2 (shSFXN2)/RL group and its negative control (shNC)/RL group, shNC/RL-4RH group, shSFXN2/RL-4RH group, mitochondrial autophagy inhibitor Chloroquine (CQ)/RL-4RH group, and CQ+shSFXN2/RL-4RH group in this study. The expression level of SFXN2 protein in each group was compared. CCK-8 and FACS were used to analyze cell viability and apoptosis in each group. Autophagy flux of RL-4RH cells after knocking down SFXN2 was observed under laser confocal microscopy. The nude mice were divided into RL group (inoculated with RL tumor cells), RL-4RH group (inoculated with RL-4RH tumor cells), and RL-4RH+shSFXN2 group (inoculated with shSFXN2 transfected RL-4RH tumor cells). After intervention with rituximab, the expression of Ki67 and SFXN2 in tumor tissues of each group was analyzed by immunohistochemical staining. ResultsCompared with the shNC/RL group, the shSFXN2/RL group showed a decrease in SFXN2 protein expression level and cell viability (P＜0.05), but an increase in cell apoptosis rate (P＜0.05). Compared with the Vector/OCI-LY1 group, the SFXN2 protein expression level and cell viability were increased in the SFXN2/OCI-LY1 group (P＜0.05). Compared with the shNC/RL-4RH group, the shSFXN2/RL-4RH group showed a decrease in autophagosomes (P＜0.05), but an increase in the number of autophagic vacuoles and autolysosomes (P＜0.05). Compared with the shSFXN2/RL-4RH group, the CQ+shSFXN2/RL-4RH group showed an increase in autophagosomes (P＜0.05) but a decrease in the number of autolysosomes (P＜0.05). Compared with the RL group, the RL-4RH group showed an increase in tumor volume in tumor bearing mice (P＜0.05), and upregulation of SFXN2 and Ki67 expression in tumor tissue (P＜0.05); Knockdown of SFXN2 reversed the rituximab resistance effect in RL-4RH tumor bearing mice (P＜0.05). ConclusionKnockdown of SFXN2 may reverse rituximab resistance by inducing excessive activation of mitochondrial autophagy. |
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