本文選題：神經(jīng)膠質(zhì)瘤 + 曲古菌素A��； 參考：《吉林大學(xué)》2014年碩士論文

【摘要】：神經(jīng)膠質(zhì)瘤作為目前臨床上的高發(fā)性腦部腫瘤，由于死亡率高，復(fù)發(fā)率高的特點(diǎn)，嚴(yán)重威脅著人類的健康。但是由于其發(fā)病部位的特殊性，常規(guī)的手術(shù)治療被極大的限制，在治療時(shí)得不到很好的效果。而目前常規(guī)的抗腫瘤藥在治療神經(jīng)膠質(zhì)瘤時(shí)，雖然可以對(duì)腫瘤細(xì)胞有一定的殺傷效果，但也對(duì)正常的神經(jīng)組織和細(xì)胞產(chǎn)生較大的損傷，并且在預(yù)后過(guò)程中，神經(jīng)膠質(zhì)瘤細(xì)胞能夠產(chǎn)生極強(qiáng)的耐藥性，從而限制了常規(guī)的抗腫瘤藥在神經(jīng)膠質(zhì)瘤治療中的使用。因此，尋找治療神經(jīng)膠質(zhì)瘤的新靶點(diǎn)以及開(kāi)發(fā)治療神經(jīng)膠質(zhì)瘤的新藥物具有極大的臨床參考價(jià)值和實(shí)用意義。 Survivin作為目前已發(fā)現(xiàn)的最強(qiáng)抑制凋亡蛋白之一，可以通過(guò)直接抑制凋亡終端效應(yīng)蛋白Caspase-3，達(dá)到抑制凋亡，促進(jìn)增殖的作用，對(duì)腫瘤的發(fā)生發(fā)展有十分重要的意義。已有研究報(bào)道，Survivin在神經(jīng)膠質(zhì)瘤中有較高表達(dá)，與此同時(shí)在正常的神經(jīng)組織和細(xì)胞中Survivin的表達(dá)較低。這種在腫瘤和正常組織中表達(dá)的特異性使其極有可能成為神經(jīng)膠質(zhì)瘤治療領(lǐng)域的新靶點(diǎn)。但目前，對(duì)于神經(jīng)膠質(zhì)瘤中Survivin的調(diào)控機(jī)制尚不明確。 曲古菌素A（TSA）作為組蛋白去乙酰化酶抑制劑中的代表，可以通過(guò)抑制腫瘤細(xì)胞中過(guò)高表達(dá)的去乙�；傅幕钚�，調(diào)節(jié)腫瘤中去乙酰化水平，調(diào)節(jié)相關(guān)基因的轉(zhuǎn)錄達(dá)到有效殺傷腫瘤細(xì)胞的作用。在抗腫瘤的同時(shí)，TSA還具有廣譜、高效，低毒的特點(diǎn)。已有研究表明，TSA在有效殺傷腫瘤細(xì)胞的同時(shí)，對(duì)神經(jīng)組織和細(xì)胞有一定的保護(hù)作用。TSA這種對(duì)腫瘤和正常組織凋亡調(diào)控的特異性可能與Survivin在腫瘤和正常組織中表達(dá)的特異性存在一定的相關(guān)性。 實(shí)驗(yàn)?zāi)康模?本實(shí)驗(yàn)擬研究TSA對(duì)神經(jīng)膠質(zhì)瘤細(xì)胞凋亡作用的影響，并進(jìn)一步的探討TSA通過(guò)調(diào)控Survivin介導(dǎo)神經(jīng)膠質(zhì)瘤凋亡的相關(guān)機(jī)制。 實(shí)驗(yàn)方法： 分別對(duì)PC12細(xì)胞系及C6細(xì)胞系進(jìn)行培養(yǎng)，通過(guò)CCK-8實(shí)驗(yàn)檢測(cè)TSA在不同劑量濃度下對(duì)PC12細(xì)胞及C6細(xì)胞存活率的影響，確定TSA是否對(duì)神經(jīng)膠質(zhì)瘤細(xì)胞殺傷的同時(shí)對(duì)正常神經(jīng)細(xì)胞無(wú)損傷并確定TSA的最佳工作濃度；采用細(xì)胞形態(tài)學(xué)實(shí)驗(yàn)和流式細(xì)胞術(shù)，觀察TSA給藥前后，PC12細(xì)胞及C6細(xì)胞形態(tài)的變化以及凋亡率的變化，進(jìn)一步確定TSA對(duì)PC12細(xì)胞及C6細(xì)胞凋亡的影響；HDACs活性試劑盒檢測(cè)TSA給藥前后，第Ⅰ類HDAC活性的變化；免疫熒光染色觀察，在TSA給藥前以及TSA給藥后使第Ⅰ類HDAC活性發(fā)生變化時(shí)，PC12細(xì)胞及C6細(xì)胞中Survivin及被其直接抑制的Caspase-3表達(dá)的變化，研究TSA對(duì)神經(jīng)膠質(zhì)瘤細(xì)胞及正常神經(jīng)細(xì)胞中Survivin表達(dá)的影響以及神經(jīng)膠質(zhì)瘤細(xì)胞細(xì)胞中第Ⅰ類HDAC活性與Survivin表達(dá)的關(guān)系；采用Western blot法觀察不同劑量TSA作用下，神經(jīng)膠質(zhì)瘤細(xì)胞及正常神經(jīng)細(xì)胞中Survivin和Caspase-3的表達(dá)變化，通過(guò)上述指標(biāo)來(lái)評(píng)價(jià)TSA對(duì)Survivin的調(diào)控作用以及TSA通過(guò)調(diào)控Survivin對(duì)神經(jīng)膠質(zhì)瘤細(xì)胞凋亡的介導(dǎo)作用。并選用丙戊酸鈉為工具藥，使用HDACs活性試劑盒和western blot法進(jìn)一步驗(yàn)證實(shí)驗(yàn)的結(jié)論。 實(shí)驗(yàn)結(jié)果： 1. CCK-8實(shí)驗(yàn)結(jié)果顯示：與Control組相比較，C6細(xì)胞TSA100nM組存活率為：81.33%±4.15；200nM組的存活率為：65.33%±2.15；400nM組存活率為：37.14%±2.66。與Control組相比較， PC12細(xì)胞TSA100nM組、200nM組存活率無(wú)明顯差異，在400nM時(shí)，存活率為84.67%±4.33。 2.細(xì)胞形態(tài)學(xué)實(shí)驗(yàn)結(jié)果顯示：與Control組比較，發(fā)現(xiàn)PC12的密度無(wú)明顯變化，細(xì)胞形態(tài)也無(wú)明顯改變；而C6細(xì)胞200nM給藥組與Control組比較，細(xì)胞密度明顯減少，細(xì)胞間距變大，細(xì)胞輪廓不清。 3.流式細(xì)胞術(shù)實(shí)驗(yàn)結(jié)果表明： TSA在200nM濃度下，PC12細(xì)胞的凋亡率（5.42%±0.23）與Control組的凋亡率（3.37%±0.36）相比較，無(wú)明顯差異。而在200nM濃度下C6細(xì)胞的凋亡有明顯增加，其結(jié)果與毒性試驗(yàn)的結(jié)果相一致，200nM組凋亡率為：30.11%±1.97，Control組的凋亡率為3.12%±1.31，存在明顯差異（P＜0.01）。 4.第Ⅰ類HDAC活性檢測(cè)實(shí)驗(yàn)結(jié)果表明：C6細(xì)胞的Control組中HDAC1、HDAC2、HDAC3、HDAC8活性，與PC12細(xì)胞的Control組比較，均有顯著性差異（P＜0.01），活性明顯高于PC12細(xì)胞的Control組；而在C6細(xì)胞200nMTSA給藥處理24h后，與C6細(xì)胞Control組相比較，HDAC1、HDAC2、HDAC3、HDAC8的活性均有明顯下降（P＜0.01），且下降的比例巨大。而PC12細(xì)胞200nM給藥組與PC12細(xì)胞Control組比較，HDAC1、HDAC2、HDAC3、HDAC8的活性無(wú)明顯變化。 5.免疫熒光染色結(jié)果顯示：C6細(xì)胞Control組Survivin的熒光強(qiáng)度明顯高于C6細(xì)胞給藥組。而PC12細(xì)胞Control組Survivin的熒光強(qiáng)度與PC12細(xì)胞給藥組無(wú)明顯差別。同時(shí)，C6細(xì)胞Control組Survivin的熒光強(qiáng)度也明顯高于PC12細(xì)胞Control組Survivin的熒光強(qiáng)度；而在TSA給藥后，C6細(xì)胞中的Caspase-3活性的熒光強(qiáng)度明顯高于C6細(xì)胞Control組。而PC12細(xì)胞Control組Caspase-3的熒光強(qiáng)度與PC12細(xì)胞給藥組無(wú)明顯差別。 6. Western blot實(shí)驗(yàn)結(jié)果顯示：TSA給藥劑量為100nM、200nM、400nM。Survivin在C6細(xì)胞中的表達(dá)隨著TSA劑量的增加，呈現(xiàn)逐步下降的趨勢(shì)，而PC12細(xì)胞中的Survivin無(wú)明顯變化；C6細(xì)胞中Caspase-3的表達(dá)隨著TSA劑量的增加而增加，在100nM和200nM給藥時(shí)，PC12細(xì)胞中的Caspase-3與PC12細(xì)胞Control組比較無(wú)明顯差異，在400nM劑量時(shí)有明顯上升（P＜0.01）。 7.在驗(yàn)證性實(shí)驗(yàn)中，選用丙戊酸鈉為工具藥，采用HDAC活性檢測(cè)實(shí)驗(yàn)和Western blot實(shí)驗(yàn)，實(shí)驗(yàn)結(jié)果顯示與TSA的相關(guān)實(shí)驗(yàn)結(jié)果基本一致。 實(shí)驗(yàn)結(jié)論： 1.在一定劑量范圍內(nèi)，TSA可以有效殺傷神經(jīng)膠質(zhì)瘤細(xì)胞而對(duì)正常神經(jīng)細(xì)胞無(wú)損傷； 2.神經(jīng)膠質(zhì)瘤中第Ⅰ類HDACs的活性明顯高于正常神經(jīng)細(xì)胞，TSA可以有效降低神經(jīng)膠質(zhì)瘤細(xì)胞第Ⅰ類HDACs的活性； 3.神經(jīng)膠質(zhì)瘤中Survivin的表達(dá)明顯高于正常神經(jīng)細(xì)胞，抑制Survivin蛋白水平的表達(dá)是TSA殺傷神經(jīng)膠質(zhì)瘤細(xì)胞的機(jī)制之一； 4. TSA可能通過(guò)降低神經(jīng)膠質(zhì)瘤中第Ⅰ類HDACs的活性，，改變神經(jīng)膠質(zhì)瘤中組蛋白去乙�；乃�，調(diào)控Survivin的表達(dá)，進(jìn)而促進(jìn)Caspase-3的活性增加，達(dá)到促進(jìn)神經(jīng)膠質(zhì)瘤細(xì)胞凋亡的作用。
[Abstract]:As a clinical high incidence brain tumor, neuroglioma is a serious threat to human health because of its high mortality and high recurrence rate. However, conventional surgical treatment has been greatly restricted because of its specific location. While the tumor cells can have a certain killing effect on the tumor cells, it also produces greater damage to normal nerve tissue and cells, and in the process of prognosis, the neuroglioma cells can produce very strong resistance, which restricts the use of conventional antitumor drugs in the treatment of glioma. The new targets of glioma and the development of new drugs for glioma are of great clinical value and practical significance.
As one of the strongest inhibitory apoptotic proteins that have been found at present, Survivin can inhibit apoptosis and promote proliferation by inhibiting apoptotic terminal effect protein Caspase-3 directly, and it is of great significance for the development of tumor. It has been reported that Survivin has high expression in glioma and is at the same time in normal. The expression of Survivin in neural tissue and cells is low. The specificity expressed in tumors and normal tissues makes it possible to be a new target in the field of neuroglioma treatment. However, the regulation mechanism of Survivin in glioma is not yet clear.
As a representative of histone deacetylase inhibitors, curacicotin A (TSA) can regulate the level of deacetylation in tumor by inhibiting the activity of exorbitant deacetylase in tumor cells, regulating the transcription of related genes to effectively kill tumor cells. At the same time, TSA also has broad spectrum, high efficiency and low toxicity. Some studies have shown that TSA has a certain protective effect on the tissue and cells of the tumor cells while it is effective in killing tumor cells. The specificity of.TSA on the regulation of tumor and normal tissue apoptosis may be related to the specificity of Survivin expression in the tumor and normal tissues.
Objective:
This study aims to investigate the effect of TSA on the apoptosis of glioma cells, and to further explore the mechanism of TSA mediated apoptosis of glioma by regulating Survivin.
Experimental methods:
The PC12 cell line and the C6 cell line were cultured, and the effects of TSA on the survival rate of PC12 cells and C6 cells at different doses were tested by CCK-8. It was determined whether TSA had no damage to glioma cells and no damage to normal neurons and determined the optimum working concentration of TSA, and the cell morphology experiment and flow formula were used. The changes in the morphology and apoptosis rate of PC12 cells and C6 cells before and after TSA were observed, and the effect of TSA on the apoptosis of PC12 cells and C6 cells was further determined. The HDACs activity kit was used to detect the changes of class I HDAC activity before and after TSA administration, immunofluorescence staining, and the first class HDA before and after TSA administration and TSA. The effects of TSA on the expression of Survivin in glioma cells and normal neurons, as well as the relationship between the expression of Survivin in glioma cells and normal neurons, and the relationship between the activity of class I HDAC and the expression of Survivin in glioma cells, as well as the changes in the expression of Survivin in PC12 and C6 cells and the expression of Caspase-3 in C6 cells, and the relationship between the activity of class I HDAC and the expression of Survivin in glioma cells, were observed by Western blot. The expression of Survivin and Caspase-3 in glioma cells and normal nerve cells under the same dose of TSA was used to evaluate the regulatory role of TSA on Survivin and the mediating effect of TSA on the apoptosis of glioma cells by regulating Survivin. The use of sodium valproate as a tool, the use of HDACs active kits and we The stern blot method further verified the conclusion of the experiment.
Experimental results:
1. CCK-8 experimental results showed that compared with group Control, the survival rate of C6 cell TSA100nM group was 81.33% + 4.15, and the survival rate of 200nM group was 65.33% + 2.15, and the survival rate of group 400nM was compared with that of Control group, PC12 cell TSA100nM group, 200nM group survival rate had no obvious difference, and the survival rate was 84.67% + at 400nM.
The experimental results of 2. cell morphology showed that compared with the Control group, the density of PC12 was not obviously changed, and the cell morphology did not change obviously, but the cell density of the 200nM administration group of C6 cells decreased obviously, the cell spacing became larger, and the cell profile was not clear.
The results of 3. flow cytometry showed that the apoptosis rate (5.42% + 0.23) of PC12 cells (5.42% + 0.23) was not significantly different from that of Control group (3.37% + 0.36) at the concentration of TSA, but the apoptosis of C6 cells increased significantly at 200nM concentration, and the result was consistent with the results of toxicity test. The apoptosis rate of 200nM group was 30.11% + 1.97, Control. The apoptosis rate of the group was 3.12% + 1.31, and there was a significant difference (P < 0.01).
4. the test results of class I HDAC activity test showed that the activity of HDAC1, HDAC2, HDAC3 and HDAC8 in the Control group of C6 cells was significantly different from the Control group of PC12 cells (P < 0.01), and the activity was significantly higher than that of PC12 cells. 3, the activity of HDAC8 decreased significantly (P < 0.01), and the proportion of the decrease was huge, but the activity of HDAC1, HDAC2, HDAC3 and HDAC8 was not significantly changed in the 200nM administration group of PC12 cells and the Control group of PC12 cells.
5. the results of immunofluorescence staining showed that the fluorescence intensity of Survivin in the Control group of C6 cells was significantly higher than that in the C6 cell administration group, but the fluorescence intensity of Survivin in the Control group of PC12 cells was not significantly different from that of the PC12 cell administration group. Meanwhile, the fluorescence intensity of Survivin in the C6 cell Control group was significantly higher than that of the PC12 cells. After TSA administration, the fluorescence intensity of Caspase-3 activity in C6 cells was significantly higher than that in the Control group of C6 cells, but the fluorescence intensity of Caspase-3 in the Control group of PC12 cells was not significantly different from that in the PC12 cell group.
The results of 6. Western blot showed that the dosage of TSA was 100nM, the expression of 200nM and 400nM.Survivin in C6 cells was gradually decreasing with the increase of TSA dose, while Survivin in PC12 cells did not change obviously, and the expression of Caspase-3 in C6 cells increased with the increase of dosage. There was no significant difference in Caspase-3 between cells and PC12 cells in Control group, but increased significantly at 400nM dose (P < 0.01).
7. in the confirmatory experiment, the sodium valproate was used as the tool, the HDAC activity test and the Western blot experiment were used. The experimental results showed that the related experimental results of TSA were basically the same.
Experimental conclusions:
1. in a certain dose range, TSA can effectively kill glioma cells without damage to normal neurons.
2. the activity of type HDACs of glioma is significantly higher than that of normal nerve cells. TSA can effectively reduce the activity of type HDACs of glioma cells.
3. the expression of Survivin in neuroglioma is obviously higher than that of normal nerve cells, and the inhibition of the expression of Survivin protein is one of the mechanisms of TSA killing neuroglioma cells.
4. TSA may reduce the activity of class I HDACs in glioma, change the level of histone deacetylation in glioma, regulate the expression of Survivin, and then promote the increase of Caspase-3 activity, so as to promote the apoptosis of glioma cells.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R739.41

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