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与婆罗门相关的基因1在人类风湿性成纤维细胞样滑膜细胞MH7A中以p53依赖性方式诱导细胞凋亡。

Brahma-related gene 1 induces apoptosis in a p53-dependent manner in human rheumatoid fibroblast-like synoviocyte MH7A.

作者信息

Hou Hongli, Xing Weipeng, Li Wuyin

机构信息

Luoyang Orthopedic-traumatological Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, China.

出版信息

Medicine (Baltimore). 2016 Dec;95(51):e5241. doi: 10.1097/MD.0000000000005241.

Abstract

Blocked apoptosis and aggressive inflammatory responses occur in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA) patients. Although Brahma-related gene 1 (BRG1) is considered as a tumor suppressor, few research covers its role in RA. This study aims to reveal effects and potential mechanisms of BRG1 in human FLS cell line MH7A.BRG1 expression in MH7A cells was altered by transfection of overexpression vectors or short hairpin RNAs (shRNAs). Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry after transfection. Factors involved in inflammation and apoptosis were quantified by qPCR and Western blot. The interaction between BRG1 and p53 was assessed by immunoprecipitation (IP).Results showed that BRG1 overexpression significantly suppressed MH7A cell viability and induced apoptosis (P < 0.01), and its knockdown had opposite effects. BRG1 reduced mRNA levels of matrix metallopeptidase 3, TIMP metallopeptidase inhibitor 2, cyclooxygenase 2, and interleukin 6, implying its suppressive effects on inflammation. BRG1 interacted with and promoted p53 (P < 0.05). B-cell chronic lymphocytic leukemia/lymphoma 2 was suppressed (P < 0.05), while cytochrome c, caspase 3 (CASP3) and CASP9 were activated (P < 0.01) by BRG1. However, the regulation on these factors was abrogated by p53 knockdown (P < 0.01).These findings suggest that BRG1 may induce apoptosis and suppress inflammation in MH7A cells. Potential functional mechanisms involve the regulation of apoptotic factors by BRG1, which may depend on the recruitment and promotion of p53. This study provides the essential proof for applying BRG1 to the molecular therapy of RA.

摘要

类风湿关节炎(RA)患者的成纤维样滑膜细胞(FLS)中存在凋亡受阻和强烈的炎症反应。尽管与婆罗门相关基因1(BRG1)被认为是一种肿瘤抑制因子,但很少有研究涉及其在RA中的作用。本研究旨在揭示BRG1在人FLS细胞系MH7A中的作用及潜在机制。通过转染过表达载体或短发夹RNA(shRNA)改变MH7A细胞中BRG1的表达。转染后,采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐(MTT)法和流式细胞术检测细胞活力和凋亡情况。通过qPCR和蛋白质免疫印迹法对参与炎症和凋亡的因子进行定量分析。通过免疫沉淀(IP)评估BRG1与p53之间的相互作用。结果显示,BRG1过表达显著抑制MH7A细胞活力并诱导凋亡(P<0.01),而其敲低则产生相反的效果。BRG1降低了基质金属肽酶3、金属蛋白酶组织抑制剂2、环氧化酶2和白细胞介素6的mRNA水平,表明其对炎症具有抑制作用。BRG1与p53相互作用并促进p53表达(P<0.05)。BRG1抑制了B细胞慢性淋巴细胞白血病/淋巴瘤2的表达(P<0.05),同时激活了细胞色素c、半胱天冬酶3(CASP3)和半胱天冬酶9(P<0.01)。然而,p53敲低消除了BRG1对这些因子的调控作用(P<0.01)。这些发现表明,BRG1可能诱导MH7A细胞凋亡并抑制炎症。潜在的功能机制包括BRG1对凋亡因子的调控,这可能依赖于对p53的募集和促进作用。本研究为将BRG1应用于RA的分子治疗提供了重要依据。

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