發(fā)布時間：2018-04-20 13:25

  本文選題：褪黑素 + GSCs�。� 參考：《山東大學(xué)》2017年博士論文

【摘要】：膠質(zhì)細胞瘤是一種顱內(nèi)原發(fā)性腫瘤,其發(fā)病率高,占所有顱內(nèi)腫瘤的50%以上。由于膠質(zhì)瘤呈浸潤性生長,侵襲性強,所以手術(shù)難以完全切除,治療效果差,往往預(yù)后不良。WHO將膠質(zhì)瘤分為4級,級別越高則惡性程度就越高。其中級別最高的膠質(zhì)母細胞瘤(GBM)為WHO Ⅳ級,該腫瘤發(fā)病率高,約占到所有顱內(nèi)腫瘤的15%。在膠質(zhì)母細胞瘤盡可能手術(shù)切除的前提下,再輔以標(biāo)準(zhǔn)的放化療,病人的中位生存期仍然不超過15個月。近年來的研究表明,膠質(zhì)瘤,特別是惡性程度最高的膠質(zhì)母細胞瘤中含有一種細胞亞群,這種細胞亞群擁有部分正常干細胞的特性,被稱為膠質(zhì)瘤干細胞(glioblastoma stem-like cells,GSCs)。GSCs起到了極強的促進膠質(zhì)母細胞瘤增殖的作用,同時GSCs在促進腫瘤向顱內(nèi)周圍腦組織浸潤、擴散的過程中起到了關(guān)鍵作用。目前手術(shù)綜合放化療并不能有效的殺滅GSCs,這導(dǎo)致腫瘤往往會較快復(fù)發(fā),預(yù)后不良,所以亟需探索能夠有效殺滅GSCs的治療手段。褪黑素是一種由松果體分泌的激素。長期以來,褪黑素一直被認為是一種調(diào)節(jié)生物節(jié)律的激素,而近年來越來越多的研究證明,褪黑素對多種腫瘤均具有抑制作用,其中便包括膠質(zhì)瘤。然而褪黑素對GSCs的作用還少有研究,其機制也尚不明確。EZH2具有組蛋白甲基化轉(zhuǎn)移酶作用,是多梳蛋白復(fù)合體2的組分之一。在包括膠質(zhì)瘤、乳腺癌、胃癌、結(jié)腸癌在內(nèi)的多種腫瘤中,均發(fā)現(xiàn)了 EZH2的異常升高。并且EZH2的表達量越高,腫瘤往往惡性程度越高,預(yù)后越發(fā)不良,而抑制EZH2的表達能夠延緩腫瘤的發(fā)生和發(fā)展。同時已經(jīng)有確切證據(jù)表明,EZH2是GSCs的干性指標(biāo)之一。NOTCH受體的過表達也存在于包括膠質(zhì)瘤在內(nèi)的多種惡性腫瘤中。EZH2-NOTCH1信號軸已經(jīng)被證明存在于胰腺癌中,而EZH2-NOTCH1信號軸是否也存在于GSCs中,同時是否參與了褪黑素對GSCs的作用還尚沒有報道。本實驗主要研究了褪黑素對GSCs的作用及具體的作用機制。目的:1、研究褪黑素對GSCs增殖、自我更新及干性的作用;2、研究EZH2-NOTCH1信號軸在褪黑素起效過程中發(fā)揮的具體作用;3、研究EZH2對NOTCH1調(diào)控中的具體作用機制。方法:第一部分:褪黑素對GSCs增殖、自我更新及干性的影響1、U251和T98細胞系中GSCs的培養(yǎng)及驗證1.1在干細胞富集培養(yǎng)基(無血清,加入B27,bFGF和EGF因子)培養(yǎng)U251和T98G細胞系,培養(yǎng)至少三周,建立GSCU251和GSCT98G細胞模型。1.2 qRT-PCR檢測GSCs干細胞標(biāo)記物CD133和SOX2的含量,驗證GSCU251和GSCT98G細胞模型是否建立成功。2、檢測不同濃度褪黑素對GSCs的生存、增殖能力的影響2.1配制含有不同濃度褪黑素(0.1-1000μM)的培養(yǎng)基,培養(yǎng)GSCU251和GSCT98G。2.2 CCK-8實驗檢測不同濃度褪黑素對GSCU251和GSCT98G增殖能力的影響。3、檢測褪黑素其對GSCs自我更新能力的影響通過成球?qū)嶒灆z測不同濃度褪黑素對GSCU251和GSCT98G自我更新能力的影響。4、檢測褪黑素對GSCs干性的影響qRT-PCR和Western Blot檢測褪黑素對GSCU251和GSCT98G中干性標(biāo)記物CD133和SOX2表達的影響。第二部分:EZH2在褪黑素對GSCs的抑制過程中的作用探究1、檢測褪黑素對GSCs中EZH2表達的影響。qRT-PCR和Western Blot檢測褪黑素對GSCs中EZH2表達的影響。2、EZH2敲除GSCU251模型的建立2.1通過EZH2 shRNA轉(zhuǎn)染GSCU251,建立EZH2敲除GSCU251模型。2.2 Western Blot檢測EZH2敲除GSCU251模型建立是否成功。3、檢測EZH2敲除后GSCU251的增殖能力、自我更新能力及干性的變化敲除GSCU251中的EZH2后,CCK-8實驗檢測GSCU251的生長、增殖能力變化;成球?qū)嶒灆z測GSCU251的自我更新能力變化;qRT-PCR檢測GSCU251中CD133分子表達的變化。4、EZH2過表達GSCU251模型的建立4.1通過GV230-EZH2質(zhì)粒轉(zhuǎn)染GSCU251,中建立EZH2過表達GSU251模型。4.2 Western Blot檢測EZH2過表達GSCU251模型建立是否成功。5、檢測EZH2過表達后GSCU251的增殖能力、自我更新能力及干性的變化GSCU251中的EZH2過表達后,CCK-8實驗檢測GSCU251的生長、增殖能力變化;成球試驗檢測GSCU251的自我更新能力變化;qRT-PCR檢測GSCU251中CD133分子表達的變化。6、檢測褪黑素加入后,對照組和EZH2過表達組GSCU251的增殖能力、自我更新能力及干性的變化6.1在對照組GSCU251中加入褪黑素進行培養(yǎng),CCK-8、成球?qū)嶒灆z測GSCU251的增殖能力、自我更新能力變化;qRT-PCR檢測GSCU251中CD133分子表達的變化。6.2在EZH2過表達組GSCU251中加入褪黑素進行培養(yǎng),CCK-8、成球?qū)嶒灆z測GSCU251的增殖能力、自我更新能力變化;qRT-PCR檢測GSCU251中CD133分子表達的變化。第三部分:NOTCH1在EZH2起效過程中的作用及機制1、檢測褪黑素對GSCs中NOTCH1表達的影響1.1 qRT-PCR檢測褪黑素干預(yù)后GSCU251和GSCT98G中NOTCH1及下游因子CCND1,CCNE2和HES1等的mRNA表達量變化。1.2 Western Blot 檢測褪黑素干預(yù)后 GSCU251 和 GSCT98G 中 NICD1(NOTCH1的胞內(nèi)功能區(qū)域)和HES1的蛋白表達量變化。2、檢測EZH2對NOTCH1的調(diào)控作用2.1通過雙熒光素酶報告實驗檢測EZH2敲除和過表達GSCU251中NOTCH1轉(zhuǎn)錄活性的變化。2.2 Western Blot檢測EZH2敲除和過表達GSCU251中NICD1和HES1的蛋白表達量變化。2.3染色質(zhì)免疫共沉淀實驗檢測GSCU251中NOTCH1的啟動子位置EZH2、H3K27me3和SUZ12的聚集情況。第四部分:EZH2-NOTCH1信號軸在臨床樣本中的初步探究1、檢測膠質(zhì)母細胞瘤樣本和正常腦組織樣本中EZH2和NICD1表達的相關(guān)性1.1選取67例膠質(zhì)母細胞瘤樣本和12例正常腦組織樣本進行EZH2和NICD1指標(biāo)的免疫組化染色。1.2統(tǒng)計學(xué)分析膠質(zhì)母細胞瘤樣本中EZH2和N1CD1的表達相關(guān)性。結(jié)果:第一部分:褪黑素對GSCs增殖、自我更新及干性的影響1、U251和T98細胞系中GSCs的培養(yǎng)及驗證通過干細胞富集培養(yǎng)基培養(yǎng)U251和T98G細胞系三周后,建立GSCU251和GSCT98G細胞模型。通過qRT-PCR檢測,我們發(fā)現(xiàn),與普通U251和T98G細胞系相比,GSCU251和GSCT98G細胞模型的干細胞標(biāo)記物CD133和SOX2的含量明顯升高。2、檢測不同濃度褪黑素對GSCs的生存、增殖能力的影響不同濃度褪黑素處理GSC251和GSCT98G后,CCK-8實驗結(jié)果顯示,100μM和1mM的褪黑素對GSCs的生長產(chǎn)生了抑制作用。3、檢測褪黑素其對GSCs自我更新能力的影響不同濃度褪黑素處理GSCU251和GSCT98G后,成球?qū)嶒灲Y(jié)果顯示,100μM和1mM的褪黑素對GSCs的自我更新產(chǎn)生了抑制作用。4、檢測褪黑素對GSCs干性的影響qRT-PCR和Western Blot檢測結(jié)果表明,1mM的褪黑素對GSCU251和GSCT98G中干性標(biāo)記物CD133和SOX2表達有明顯的抑制作用。第二部分:EZH2在褪黑素對GSCs的抑制過程中的作用探究1、檢測褪黑素對GSCs中EZH2表達的影響。qRT-PCR和Western Blot檢測結(jié)果表明,褪黑素的干預(yù)顯著降低了 GSCU251和GSCT98G中EZH2的表達量。2、EZH2敲除GSCU25,模型的建立通過EZH2 shRNA轉(zhuǎn)染GSCU251,建立EZH2敲除GSCU251模型后,Western Blot實驗表明,EZH2敲除GSC251模型中的EZH2蛋白表達量明顯降低。3、檢測EZH2敲除后GSCU251的增殖能力、自我更新能力及干性的變化敲除GSCU251中的EZH2后,CCK-8實驗表明,GSCU251的生長、增殖能力顯著降低;成球?qū)嶒灡砻?GSCU251的自我更新能力顯著降低;qRT-PCR檢測顯示,GSCU251中CD133分子表達量顯著下降。4、EZH2過表達GSCU251模型的建立通過GV230-EZH2轉(zhuǎn)染GSCU251,建立EZH2過表達GSCU251模型后,Western Blot實驗表明,EZH2過表達GSCU251模型中的EZH2蛋白表達量明顯升高。5、檢測EZH2過表達后GSCU251的增殖能力、自我更新能力及干性的變化GSCU251中的EZH2過表達后,CCK-8實驗表明,GSCU251的生長、增殖能力顯著增強;成球?qū)嶒灡砻?GSCU251的自我更新能力顯著增強;qRT-PCR檢測顯示,GSCU251中CD133分子表達量顯著升高。6、檢測褪黑素加入后,對照組和EZH2過表達組GSCU251的增殖能力、自我更新能力及干性的變化6.1對照組GSCU251中加入褪黑素進行培養(yǎng)后,CCK-8、成球?qū)嶒灲Y(jié)果顯示,GSCU251的增殖能力、自我更新能力顯著下降;qRT-PCR檢測表明,GSCU251中CD133的表達量明顯降低。6.2 EZH2過表達組GSCU251中加入褪黑素進行培養(yǎng)后,CCK-8、成球?qū)嶒灲Y(jié)果顯示,GSCU251的增殖能力、自我更新能力顯著下降;qRT-PCR檢測表明,GSCU251中CD133的表達量明顯降低。第三部分:NOTCH1在EZH2起效過程中的作用及機制1、檢測褪黑素對GSCs中NOTCH1表達的影響1.1 qRT-PCR檢測結(jié)果顯示,褪黑素干預(yù)后GSCU251和GSCT98G中NOTCH1及下游因子CCND1,CCNE2和HES1等的mRNA表達量顯著下降。1.2 Western Blot檢測結(jié)果也表明,褪黑素干預(yù)后GSCU251和GSCT98G中NICD1和HES1的蛋白表達量顯著下降。2、檢測EZH2對NOTCH1的調(diào)控作用2.1通過雙熒光素酶報告實驗,我們發(fā)現(xiàn),GSCU251中的EZH2敲除和過表后,NOTCH1轉(zhuǎn)錄活性隨之減弱和增強。2.2 Western Blot結(jié)果表明,GSCU251中EZH2敲除和過表達后,NICD1和HES1的蛋白表達量也隨之升高和降低。2.3染色質(zhì)免疫共沉淀實驗檢測發(fā)現(xiàn),GSCU251中NOTCH1的啟動子位置可以檢測到EZH2的顯著聚集,而并未檢測到H3K27me3和SUZ12的聚集。同時,褪黑素的干預(yù)顯著降低了 EZH2在NOTCH1的啟動子區(qū)域的聚集。第四部分:EZH2-NOTCH1信號軸在臨床樣本中的初步探究1、檢測膠質(zhì)母細胞瘤樣本和正常腦組織樣本中EZH2和NICD1表達的相關(guān)性1.1免疫組化染色結(jié)果顯示,73%的EZH2高表達膠質(zhì)母細胞瘤樣本中也存在著NICD1的高表達。1.2統(tǒng)計學(xué)分析發(fā)現(xiàn),膠質(zhì)母細胞瘤樣本中EZH2和NICD1的表達存在高度的正相關(guān)。結(jié)論:1、特定濃度的褪黑素對GSCs增殖、自我更新能力具有顯著地抑制作用,并能顯著降低GSCs的干性。2、通過機制實驗,我們發(fā)現(xiàn),褪黑素通過抑制EZH2-NOTCH1信號軸發(fā)揮了抑制GSCs的作用。3、EZH2-NOTCH1信號軸中,EZH2通過直接結(jié)合NOTCH1的啟動子區(qū)域調(diào)控NOTCH1的表達。
[Abstract]:Glioma is a primary intracranial tumor with high incidence of all intracranial tumors, accounting for more than 50% of all intracranial tumors. Because glioma is infiltrative and aggressive, the operation is difficult to complete resection, and the treatment is poor. Often the prognosis is bad.WHO divides the glioma into 4 grade, the higher the grade, the higher the malignant degree. The highest grade of glioma is the glioma. Mother cell tumor (GBM) is WHO IV, and the tumor has a high incidence of 15%. in all intracranial tumors under the premise of surgical removal of glioblastoma, supplemented by standard radiotherapy and chemotherapy, and the patient's median survival is still not more than 15 months. Recent studies have shown that gliomas, especially the highest malignant glioblastoma, have been shown. The tumor contains a cell subgroup, which has some characteristics of normal stem cells and is called glioblastoma stem-like cells (GSCs).GSCs, which plays a very strong role in promoting the proliferation of glioblastoma, and GSCs plays a key role in promoting the infiltration and diffusion of the tumor to the brain tissue around the cranium. At present, combined chemotherapy and chemotherapy can not effectively kill GSCs, which causes the tumor to relapse quickly and have poor prognosis, so it is urgent to explore the treatment that can effectively kill GSCs. Melatonin is a hormone secreted by the pineal body. More and more studies have shown that melatonin has an inhibitory effect on a variety of tumors, including glioma. However, the role of melatonin in GSCs is still less studied. Its mechanism is not yet clear that.EZH2 has a histone methyltransferase, which is one of the components of the multi comb protein complex 2. It includes glioma, breast cancer, and gastric cancer. The higher the expression of EZH2, the higher the expression of EZH2, the higher the expression of the tumor, the higher the malignancy, the worse the prognosis, and the inhibition of the expression of EZH2 can delay the occurrence and development of the tumor. At the same time, there is a definite evidence that EZH2 is one of the dry indexes of GSCs, the overexpression of.NOTCH receptor is also The.EZH2-NOTCH1 signal axis in a variety of malignant tumors, including gliomas, has been shown to exist in pancreatic cancer, and whether the EZH2-NOTCH1 signal axis is also in GSCs, and whether melatonin has been involved in the effect of melatonin on GSCs has not yet been reported. This experiment mainly studied the effect of melatonin on GSCs and the specific mechanism of action. Objective: 1, to study the effect of melatonin on GSCs proliferation, self renewal and dry action; 2, to study the specific role of EZH2-NOTCH1 signal axis in the process of melatonin, and 3, to study the specific mechanism of EZH2 in the regulation of NOTCH1. Methods: the first part: the effects of melatonin on GSCs proliferation, self renewal and dry effect 1, GSC in U251 and T98 cell lines. Culture and verification of s 1.1 in the culture medium of stem cell enrichment (serum free, B27, bFGF and EGF factor) culture U251 and T98G cell lines, culture for at least three weeks, and establish GSCU251 and GSCT98G cell model.1.2 qRT-PCR to detect GSCs stem cell marker CD133 and content. Effects of melatonin on the survival and proliferative ability of GSCs 2.1 prepared medium containing different concentrations of melatonin (0.1-1000 M), culture GSCU251 and GSCT98G.2.2 CCK-8 to detect the effect of melatonin on the proliferation of GSCU251 and GSCT98G at different concentrations. The effects of melatonin on the self-renewal ability of GSCs were tested by a ball test. The effects of melatonin on the self-renewal capacity of GSCU251 and GSCT98G.4,.4, the effect of melatonin on GSCs's dry property, qRT-PCR and Western Blot were used to detect the effects of melatonin on CD133 and SOX2 expression of dry markers in GSCU251 and GSCT98G. Part second: the role of EZH2 in the inhibition process of melatonin 1, detection of melatonin The influence of.QRT-PCR and Western Blot on the expression of EZH2 in GSCs,.QRT-PCR and Western Blot were used to detect the effect of melatonin on the expression of EZH2 in GSCs. After the ability, self renewal ability and dry change to knock out EZH2 in GSCU251, CCK-8 test detected the growth of GSCU251 and the change of proliferation ability; the ball test detected the change of self renewal ability of GSCU251; qRT-PCR detected the change of CD133 molecule expression in GSCU251, and the establishment of GSCU251 model of EZH2 over expression 4.1 was transfected through GV230-EZH2 plasmids. 51, we established EZH2 overexpressed GSU251 model.4.2 Western Blot to detect EZH2 over expression GSCU251 model to establish a successful.5, detect the proliferation ability of GSCU251 after EZH2 overexpression, self renewal ability and the EZH2 over expression in the dry change GSCU251. Changes in self renewal ability; qRT-PCR detection of the changes in the expression of CD133 in GSCU251,.6, after the addition of melatonin, the proliferation ability of GSCU251 in the control group and EZH2 overexpression group, the ability of self renewal and the change of dry nature 6.1 were added in the control group GSCU251 with melatonin to be cultured, CCK-8, and the ball test to detect the proliferating ability of GSCU251, and the self more Changes in new capacity; qRT-PCR detection of the changes in the expression of CD133 molecules in GSCU251,.6.2 added melatonin in EZH2 overexpression group GSCU251 to culture, CCK-8, test of CCK-8, test of GSCU251's proliferation ability, change of self-renewal ability, and qRT-PCR detection CD133 molecule expression in GSCU251. The third part: the role of NOTCH1 in the initiation process. And mechanism 1, detection of the effect of melatonin on the expression of NOTCH1 in GSCs 1.1 qRT-PCR detection of NOTCH1 and NOTCH1 and downstream factors CCND1, CCNE2, HES1 and other mRNA expressions in GSCU251 and GSCT98G after the intervention of melatonin Quantitative change.2 and detection of EZH2's regulatory role on NOTCH1 2.1 detection of EZH2 knockout and overexpressed GSCU251 NOTCH1 transcriptional activity by double luciferase reporter assay.2.2 Western Blot detection of.2.2 Western Blot detection EZH2 knockout and overexpression GSCU251 NICD1 and protein expression changes The aggregation of promoter location EZH2, H3K27me3 and SUZ12. Part fourth: preliminary inquiry into the EZH2-NOTCH1 signal axis in clinical samples 1, the correlation of the expression of EZH2 and NICD1 in glioblastoma samples and normal brain tissue samples 1.1 selected 67 cases of glioblastoma samples and 12 normal brain tissue samples for EZH2 and NICD1 indicators Immunohistochemical staining.1.2 analysis of the expression of EZH2 and N1CD1 in glioblastoma samples. Results: the first part: the effect of melatonin on GSCs proliferation, self renewal and dry effect 1, the culture and validation of GSCs in the U251 and T98 cell lines, and the establishment of GSCU251 and the development of U251 and T98G cell lines by stem cell enrichment medium for three weeks. GSCT98G cell model. Through qRT-PCR detection, we found that the content of CD133 and SOX2 in the stem cell markers of GSCU251 and GSCT98G cell models significantly increased.2 compared with the common U251 and T98G cell lines, and the effects of melatonin on the survival of GSCs and the proliferation ability of different concentrations were different from that of GSC251 and GSCT98G after the concentration of melatonin. The results showed that melatonin, 100 M and 1mM, inhibited the growth of GSCs, and the effects of melatonin on the self-renewal capacity of GSCs were detected by melatonin. The effects of melatonin on GSCU251 and GSCT98G in different concentrations were observed. The results showed that melatonin of 100 mu and 1mM produced a more inhibitory effect on the self of GSCs, and the detection of melatonin to GSCs dried. The results of qRT-PCR and Western Blot detection showed that melatonin in 1mM had an obvious inhibitory effect on the expression of CD133 and SOX2 in GSCU251 and GSCT98G. The second part: EZH2 in the inhibitory process of melatonin to GSCs 1, the effect of melatonin on EZH2 expression in GSCs and the detection results The results showed that the intervention of melatonin significantly reduced the expression of EZH2 in GSCU251 and GSCT98G, and EZH2 knocked out GSCU25. The establishment of the model was established through EZH2 shRNA to GSCU251, and EZH2 knocking GSCU251 model was established. After the ability, self renewal ability and the dry change to knock out EZH2 in GSCU251, the CCK-8 experiment showed that the growth of GSCU251 and the proliferation ability significantly decreased, and the ball test showed that the self-renewal ability of GSCU251 decreased significantly; qRT-PCR detection showed that the expression of CD133 molecules in GSCU251 decreased significantly and the GSCU251 model of EZH2 overexpression was established through GV2. After transfecting GSCU251 with 30-EZH2 and establishing EZH2 overexpressed GSCU251 model, Western Blot experiment showed that the expression of EZH2 protein in EZH2 overexpressed GSCU251 model was significantly higher than that of.5. The colonization ability was significantly enhanced, and the self-renewal ability of GSCU251 was significantly enhanced by the ball formation test; qRT-PCR detection showed that the expression of CD133 molecules in GSCU251 increased significantly by.6. After the detection of melatonin, the proliferation ability of GSCU251 in the control group and EZH2 overexpressed group, the self-renewal ability and the changes of dry nature were added to the 6.1 control group GSCU251 to add melatonin into the GSCU251. After the culture, CCK-8, the results of the ball formation test showed that the proliferation ability of GSCU251 and self renewal ability decreased significantly, and qRT-PCR detection showed that the expression of CD133 in GSCU251 was obviously reduced by.6.2 EZH2 overexpression group GSCU251 added melatonin in the culture, CCK-8, and the result showed that the proliferation ability and self-renewal ability of GSCU251 were significant. The qRT-PCR detection showed that the expression of CD133 in GSCU251 was obviously reduced. Third part: the role and mechanism of NOTCH1 in the process of EZH2, the effect of melatonin on the expression of NOTCH1 in GSCs 1.1 qRT-PCR detection results showed that after the intervention of melatonin and GSCT98G NOTCH1 and downstream factors CCND1, etc. The.1.2 Western Blot detection results also showed that the protein expression of NICD1 and HES1 in GSCU251 and GSCT98G decreased significantly after the intervention of melatonin, and the regulatory role of EZH2 on NOTCH1 was 2.1 through the double Luciferase Report experiment, we found that the transcriptional activity of EZH2 knocking and passing the table was weakened and enhanced. 2 Western Blot results showed that after EZH2 knockout and overexpression in GSCU251, the protein expression of NICD1 and HES1 also increased and decreased the.2.3 chromatin immunoprecipitation test, and found that the promoter location of NOTCH1 in GSCU251 could detect the significant aggregation of EZH2, but did not detect the accumulation of H3K27me3 and SUZ12. Meanwhile, the dry of melatonin. Pre significantly reduced the aggregation of EZH2 in the promoter region of NOTCH1. Fourth part: preliminary inquiry into EZH2-NOTCH1 signal axis in clinical samples 1, correlation of EZH2 and NICD1 expression in glioblastoma samples and normal brain tissue samples 1.1 immuno histochemical staining results showed that 73% of EZH2 high expression glioblastoma samples were also found NICD1 high expression.1.2 statistical analysis found that there was a high positive correlation between the expression of EZH2 and NICD1 in the samples of glioblastoma. Conclusion: 1, the specific concentration of melatonin has a significant inhibitory effect on GSCs proliferation and self-renewal capacity, and can significantly reduce the dry.2 of GSCs. Through mechanism experiments, we found that melatonin passes through the mechanism. Inhibition of EZH2-NOTCH1 signal axis plays a role in inhibiting GSCs..3, in EZH2-NOTCH1 signal axis, EZH2 regulates NOTCH1 expression by directly combining NOTCH1 promoter region.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R739.41

【參考文獻】

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1 Ahmad R.Safa;Mohammad Reza Saadatzadeh;Aaron A.Cohen-Gadol;Karen E.Pollok;Khadijeh Bijangi-Vishehsaraei;;Emerging targets for glioblastoma stem cell therapy[J];The Journal of Biomedical Research;2016年01期

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本文編號：1777958