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磁流体热疗结合HSR1反义寡核苷酸抑制人脑膜瘤增殖和诱导细胞凋亡的体外实验研究
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摘要
目的:约90%的人脑膜瘤属于WHO I级,为生长缓慢的良性肿瘤。人脑膜瘤放疗及化疗效果欠佳,免疫疗法疗效不明确。目前,人脑膜瘤主要治疗方法是神经外科手术,但是手术后复发率仍可达到7-32%。肿瘤热疗在多种人类肿瘤治疗中的作用得到肯定,但在人脑膜瘤中尚未见系统研究报道。肿瘤热耐受的获得和细胞内多种HSPs的高表达有关。热刺激下,HSF1活化是调节多种HSPs转录的关键,而HSR1是调节HSF1三聚体活化的必要因素。HSR1 ASODN转染抑制HSF1活化,抑制多种HSPs表达,有可能改变人脑膜瘤细胞热敏感性。本研究应用了温水热疗和氧化铁磁流体热疗两种加热技术,结合了HSR1 ODN转染技术,通过对人脑膜瘤细胞热休克反应、增殖、凋亡等方面的研究,探讨应用MFH治疗脑膜瘤的可能性和优越性。
     方法:本实验首先建立人脑膜瘤细胞短期原代培养方法,应用免疫组织化学方法检测人脑膜瘤细胞HSF1、HSP27、HSP70和HSP90蛋白表达情况。在不同加热温度和时间下,应用免疫组织化学和western blot方法检测热刺激下HSF1、HSP27、HSP70和HSP90蛋白表达,应用MTT法检测人脑膜瘤细胞增殖抑制率。应用脂质体法和非脂质体转染载体系统——FuGENE HD转染法,将HSR1 ASODN和HSR1 SODN转染人脑膜瘤细胞。转染后分别进行温水加热实验和氧化铁磁流体加热实验,应用MTT法和多种凋亡检测方法,AO染色法、TUNNEL法和流式细胞双染法,检测人脑膜瘤细胞增殖抑制率和凋亡率以及检测HSF1、HSP27、HSP70和HSP90蛋白的变化。
     结果:成功进行了15例脑膜瘤短期原代培养,包括建立短期培养条件、传代方法、冻存和复苏方法和肿瘤细胞的鉴定,并发现人脑膜瘤细胞有HSF1蛋白表达,HSP27、HSP70和HSP90组成性表达水平低。在单纯温水加热(42-44℃,30-60min)和氧化铁磁流体加热(42-43℃,30min)的体外实验中,人脑膜瘤细胞HSF1表达没有明显增加,而是HSF1蛋白发生三聚体活化为主要改变方式,诱导HSP27、HSP70和HSP90在加热后24h内持续高表达,热刺激下细胞增殖没有受到影响,表明人脑膜瘤热敏感性低。单纯氧化铁磁流体44℃加热30min细胞增殖抑制率为12.62±0.78%,三次加热也不能增加这种抑制作用,而且其抑制细胞增殖的途径主要是以细胞破裂坏死为主,而未见到细胞凋亡的增加。应用脂质体法和FuGENE HD法转染HSR1 ODN至人脑膜瘤细胞内,没有影响肿瘤细胞增殖、HSF1蛋白和HSPs的表达,但是改变了人脑膜瘤细胞的热敏感性。其中,FuGENE HD转染法转染效率更高,对细胞毒性更小。体外HSR1 ASODN转染后进行加热实验中,氧化铁磁流体42.5℃加热30min和温水43℃加热30min抑制人脑膜瘤细胞HSF1蛋白活性,进而也阻断了HSP27、HSP70和HSP90的诱导表达,明显抑制人脑膜瘤细胞增殖,诱导大量细胞凋亡。
     结论:人脑膜瘤细胞热敏感性低,主要与热刺激下诱导型HSP27、HSP70和HSP90持续高表达有关。HSR1 ASODN转染抑制HSF1三聚体活化,抑制诱导型HSPs表达,改变了人脑膜瘤细胞热敏感性。体外实验中,氧化铁磁流体42.5℃加热30min结合HSR1 ASODN转染能通过抑制人脑膜瘤细胞HSF1蛋白活性,减少了诱导型HSPs表达后的保护修复和抗凋亡作用,增加人脑膜瘤细胞热敏性,实现了MFH明显抑制人脑膜瘤细胞生长,诱导大量细胞凋亡的治疗效果。氧化铁MFH结合HSR1反义转染基因治疗可能成为人脑膜瘤治疗的一种全新方法。
     创新之处:
     1.人脑膜瘤细胞热敏感性低,主要与热刺激下诱导型HSP27、HSP70和HSP90持续高表达有关。国内外尚未见报道。
     2.热刺激下,HSR1 ASODN转染抑制HSF1三聚体活化,抑制诱导型HSP27、HSP70和HSP90表达,改变了人脑膜瘤细胞热敏感性。国内外尚未见报道。
     3.单纯氧化铁磁流体44℃加热30min部分抑制人脑膜瘤细胞增殖能力。国内外尚未见报道。
     4.体外实验中,氧化铁磁流体42.5℃加热30min结合HSR1 ASODN转染能通过抑制人脑膜瘤细胞HSF1蛋白活性,阻断了HSP27、HSP70和HSP90的诱导表达,达到明显抑制肿瘤细胞增殖和诱导大量细胞凋亡的治疗效果。国内外尚未见报道。
Objective: About 90% of human meningioma belongs to WHO I grade, which is benign tumor and grow slowly. Effects of Radiotherapy and Chemotherapy are not effective and immunotherapy is not identified. At present, the popular therapy of human meningioma is neurosurgical operation. However, the recurrence rate after operation just reaches 7% to 32%.Although effect of tumor hyperthermia has been proved in many human tumor therapy, systematic study on hyperthermia of human meningioma is not clearly reported so far. The obtain of thermotolerance of tumor is related with high expression of variety of HSPs in tumor cells. Under heat stimulation, HSF1 protein activation is the key in transcription of HSPs, while HSR1 is the essential factor for HSF1 trimerization. Transfection of HSR1 ASODN suppressed HSF1 protein activation and expression of various HSPs, it has the possibility to change heat sensitivity of human meningioma.With the combination of HSR1 ODN transfection, two other techniques of warm water hyperthermia and ferric oxide MFH are also applied in the study. The aim of the research is to find the possibility and superiority of MFH in treatment of human meningioma by means of studying heat shock response, cell proliferation and cell apoptosis.
     Methods: Establishing the short-term primary cell culture method of human meningioma first, and then detects the expressions of HSF1 protein, HSP27, HSP70, HSP90 protein by immunohistochemistry (IHC) respectively.To detect the expression of HSF1, HSP27, HSP70 and HSP90 protein under different heat temperature and time by IHC or western blot,and the inhibition rate of tumor cell proliferation by MTT method.To transfect HSR1 ASODN and HSR1 SODN in human meningioma by liposome and FuGENE HD transfection system.The experiments of warm heat hyperthermia and ferric oxide magnetic fluid hyperthermia are conducted respectively right after cell transfection, so as to detect proliferation inhibition rate, apoptosis rate and the change of HSF1,HSP27,HSP70 and HSP90 protein by IHC,western blot,MTT method, various apoptosis detection methods, AO staining method, TUNNEL method and FCM double staining method.
     Result: Successfully established the short-term primary cell culture of 15 human meningioma cases, including the condition of short-term cell culture, and the methods of passage, Cryopreservation, cell revitalization, identification of tumor cell. It is also found that there exists expression of HSF1 protein in human meningioma, and the constructive expression in HSP27, HSP70 and HSP90 is low. The vitro experiment has proved that the expression of HSF1 protein in human meningioma did not increased, but HSF1 protein trimerization was activated under warm heat hyperthermia(42-44℃, 30-60min) or ferric oxide magnetic fluid hyperthermia(42-43℃,30min), which induced permanent and high expression of HSP27,HSP70 and HSP90 in 24 hours, while tumor cell proliferation was not effected by hyperthermia, which indicates that the heat sensitivity of human meningioma is low under this condition. When heated for 30min under 44℃, the cell proliferation inhibition rate of ferric oxide magnetic fluid in human meningioma was 12.62±0.78%. The inhibitory action could not be increased by this kind of hyperthermia in 3 times. The main channel for the proliferation inhibition was not in the form of increased cell apoptosis, but the cellular necrosis.Tumor cell proliferation and the expression of HSF1 protein and HSPs in human meningioma could not be affected by applying the method of FuGENE HD transfection in human meningioma, but heat sensitivity of tumor cell was changed. In addition, the effect of FuGENE HD transfection was higher in transfection and the cytotoxicity was much lower.In vitro test of hyperthermia after HSR1 ASODN transfection, ferric oxide MFH (42.5℃,30min) and warm water hyperthermia (43℃,30min) could inhibit activity of HSF1 protein, induce expression of HSP27,HSP70,HSP90, inhibit the ability of cell proliferation in human meningioma, and lead to cell apoptosis.
     Conclusion: Low heat sensitivity of human meningioma is mainly related to permanent and high expression of induced HSP27,HSP70 and HSP90 under heat stimulation.HSR1 ASODN transfection inhibits trimerization activation of HSF1 protein, and suppresses induced expression of HSPs, which leads to the change of heat sensitivity of human meningioma.In vitro test, ferric oxide MFH(42.5℃,30min) with the combination of HSR1 ASODN transfection could suppresse cell proliferation obviously, and induces cell apoptosis through inhabitation activity of HSF1 protein and induced expression of HSP27,HSP70,HSP90.MFH combined with HSR1 antisense transfection may become a brand-new treatment of human meningioma. Innovation:
     1.Low heat sensitivity of human meningioma is closely related to high expression of induced HSP27, HSP70 and HSP90 under heat stimulation. No reports concerned have been released so far both at home and abroad.
     2. Under heat stimulation, HSR1 ASODN transfection inhibits trimerization activation of HSF1 protein, and suppresses induced expression of HSPs, which leads to the change of heat sensitivity of human meningioma. No reports concerned have been released so far both at home and abroad.
     3. Ferric oxide magnetic fluid (44℃,30min) could inhibit the ability of cell proliferation in human meningioma. No reports concerned have been released so far both at home and abroad.
     4. In vitro test, ferric oxide MFH (42.5℃,30min) with the combination of HSR1 ASODN transfection could suppresse cell proliferation obviously, and induces cell apoptosis through inhibitation activity of HSF1 protein and induced expression of HSP27,HSP70,HSP90. No reports concerned have been released so far both at home and abroad.
引文
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