本文選題：DEC1 + MSP58��； 參考：《第四軍醫(yī)大學(xué)》2016年博士論文

【摘要】：神經(jīng)膠質(zhì)瘤是人腦最常見(jiàn)的惡性腫瘤,占中樞神經(jīng)系統(tǒng)腫瘤的半數(shù)以上,并且預(yù)后極差。其中,多形性膠質(zhì)母細(xì)胞瘤(Glioblastoma multiforme,GBM,WHO IV級(jí))具有低度分化,高度惡性,對(duì)放化療易發(fā)生耐受等特點(diǎn)。癌基因胚胎軟骨發(fā)育基因1(Differentiated embryo chondrocyte expressed gene 1,DEC1)的轉(zhuǎn)錄調(diào)控功能對(duì)腫瘤細(xì)胞的發(fā)生發(fā)展至關(guān)重要。該分子的高度表達(dá)存在于人類(lèi)多種惡性腫瘤之中,并且預(yù)示腫瘤細(xì)胞的惡性分化程度。我們前期研究發(fā)現(xiàn)DEC1在膠質(zhì)瘤中的表達(dá)與膠質(zhì)瘤的病理級(jí)別呈顯著的相關(guān)性,不但可以作為獨(dú)立的預(yù)后因素,而且能夠預(yù)示高級(jí)別膠質(zhì)瘤患者對(duì)烷化劑替莫唑胺(Temozolomide,TMZ)化療的反應(yīng)性。然而,DEC1的表達(dá)對(duì)替莫唑胺細(xì)胞毒性影響的具體分子機(jī)制卻不明確。核微球蛋白58(The nucleolar 58-kD microspherule protein,MSP58)是DEC1的相互作用分子,該分子同樣在人類(lèi)多種腫瘤中存在高表達(dá),是一個(gè)癌基因。DEC1發(fā)揮多種生物學(xué)功能都是通過(guò)與MSP58的相互作用而實(shí)現(xiàn)的。MLH1(Mut L homolog1,M u t L同源基因)是DNA錯(cuò)配修復(fù)系統(tǒng)(Mis-match repair,MMR)的重要調(diào)控因子,該分子的表達(dá)缺失或功能缺陷能夠?qū)е履[瘤細(xì)胞對(duì)烷化劑細(xì)胞毒性產(chǎn)生耐受。轉(zhuǎn)錄調(diào)控因子DEC1能夠結(jié)合MLH1啟動(dòng)子區(qū)域的E-box序列從而抑制MLH1的表達(dá)。msp58和mlh1作為與dec1癌基因功能密切相關(guān)的蛋白分子,能否成為dec1影響tmz化療敏感性的關(guān)鍵所在,為本課題的主要研究?jī)?nèi)容。第一部分人腦膠質(zhì)瘤中msp58的表達(dá)及其對(duì)替莫唑胺化療敏感性的影響目的:本課題前期研究首次明確了msp58在人腦膠質(zhì)瘤中的癌基因作用,并且發(fā)現(xiàn)dec1的表達(dá)對(duì)膠質(zhì)瘤患者替莫唑胺化療反應(yīng)性具有重要影響。然而,msp58能否作為膠質(zhì)瘤患者的預(yù)后因素卻未見(jiàn)明確報(bào)道,并且作為與dec1癌基因功能密切相關(guān)的相互作用分子,msp58的表達(dá)情況對(duì)膠質(zhì)瘤患者替莫唑胺化療反應(yīng)性的影響也未知。方法:我們主要利用免疫組化的方法,在158例原發(fā)性膠質(zhì)瘤樣本和63例接受術(shù)后tmz化療、且腫瘤復(fù)發(fā)的復(fù)發(fā)性gbm樣本中,檢測(cè)msp58的表達(dá)情況,并且進(jìn)一步與患者臨床病理資料、預(yù)后、替莫唑胺化療反應(yīng)性等方面做相關(guān)性分析。腫瘤細(xì)胞增殖能力應(yīng)用核增殖抗原ki-67的免疫組化染色進(jìn)行評(píng)估,并在msp58不同表達(dá)水平之間進(jìn)行統(tǒng)計(jì)學(xué)分析。結(jié)果:msp58的表達(dá)水平與原發(fā)性膠質(zhì)瘤患者who級(jí)別(p0.001)和kps評(píng)分(p=0.003)均顯著相關(guān)。生存分析表明,msp58的表達(dá)水平越高、患者預(yù)后越差(p0.001)。多因素cox回歸模型結(jié)果顯示,msp58的表達(dá)水平可以作為原發(fā)性膠質(zhì)瘤患者獨(dú)立的預(yù)后因素。另外,隨msp58表達(dá)水平的不斷增高,膠質(zhì)瘤細(xì)胞的增殖能力也在不斷的增強(qiáng)(p0.01)。然而,在復(fù)發(fā)性gbm中,msp58的表達(dá)情況與tmz化療反應(yīng)性之間并沒(méi)有表現(xiàn)出顯著的統(tǒng)計(jì)學(xué)差異。結(jié)論:msp58的表達(dá)水平與膠質(zhì)瘤患者的who級(jí)別和增殖能力具有顯著的相關(guān)性,說(shuō)明msp58在神經(jīng)膠質(zhì)細(xì)胞瘤腫瘤的發(fā)生和惡性進(jìn)展中能夠發(fā)揮重要的作用。然而,msp58的表達(dá)水平在原發(fā)性和復(fù)發(fā)性膠質(zhì)瘤患者中未見(jiàn)顯著差異,說(shuō)明tmz化療對(duì)膠質(zhì)瘤患者msp58的表達(dá)水平并無(wú)明確的影響。另外,msp58的表達(dá)與復(fù)發(fā)性膠質(zhì)瘤患者tmz化療反應(yīng)性之間并未表現(xiàn)出顯著的統(tǒng)計(jì)學(xué)相關(guān)性,說(shuō)明dec1影響tmz細(xì)胞毒性的具體分子機(jī)制可能并非是通過(guò)與msp58的相互作用而實(shí)現(xiàn)的。更重要的是,msp58表達(dá)水平與膠質(zhì)瘤患者總生存時(shí)間顯著相關(guān),說(shuō)明msp58能夠作為一個(gè)輔助who分級(jí)系統(tǒng)的新型的預(yù)后標(biāo)志,并且這一癌基因很有可能成為神經(jīng)膠質(zhì)細(xì)胞瘤患者靶向治療的重要靶點(diǎn)。第二部分人腦膠質(zhì)瘤中dec1的表達(dá)對(duì)替莫唑胺化療敏感性影響的分子機(jī)制目的:本課題前期研究發(fā)現(xiàn)發(fā)現(xiàn)dec1的表達(dá)對(duì)膠質(zhì)瘤患者替莫唑胺化療反應(yīng)性具有重要影響。mmr是dna損傷修復(fù)、調(diào)控烷化劑化療耐受最主要的機(jī)制。mlh1作為mmr系統(tǒng)的關(guān)鍵分子,其突變或缺失的細(xì)胞系對(duì)tmz均具有抵抗性;然而,作為mlh1的轉(zhuǎn)錄調(diào)控因子,dec1能否通過(guò)抑制mlh1的表達(dá)水平從而影響tmz發(fā)揮細(xì)胞毒性卻有待驗(yàn)證。方法:首先,在63例接受術(shù)后tmz化療、且腫瘤復(fù)發(fā)的復(fù)發(fā)性gbm樣本中,我們利用免疫組化的方法檢測(cè)dec1和mlh1的表達(dá)情況;利用tdt介導(dǎo)dutp缺口末端標(biāo)記法(tunel)評(píng)估腫瘤細(xì)胞的凋亡情況。然后,以人腦膠質(zhì)瘤u251和u87細(xì)胞為研究對(duì)象,通過(guò)構(gòu)建dec1特異性干涉片段慢病毒表達(dá)載體的方法,進(jìn)一步的建立穩(wěn)定表達(dá)dec1-shrna的膠質(zhì)瘤細(xì)胞系。最后,在dec1不同表達(dá)背景的膠質(zhì)瘤細(xì)胞中分析tmz細(xì)胞毒性的表現(xiàn)差異,并且檢測(cè)相關(guān)蛋白分子的表達(dá)水平,以明確dec1對(duì)tmz化療反應(yīng)性影響的具體分子機(jī)制。結(jié)果:復(fù)發(fā)性gbm標(biāo)本中dec1與mlh1的表達(dá)水平之間呈負(fù)相關(guān)(r=-0.55,p0.001),并且gbm腫瘤細(xì)胞的凋亡率隨mlh1的表達(dá)水平的增加而升高(r=0.29,p0.001)。另外,對(duì)dec1特異性干涉片段的測(cè)序鑒定結(jié)果表明成功的構(gòu)建了慢病毒表達(dá)載體psi-lv-dec1-shrna,并且熒光顯微鏡下證實(shí)獲得了穩(wěn)定表達(dá)dec1-shrna的膠質(zhì)瘤細(xì)胞株u251/u87-dec1-shrna。細(xì)胞毒性分析結(jié)果表明,膠質(zhì)瘤細(xì)胞dec1的表達(dá)被干涉后,mlh1的表達(dá)顯著上調(diào),腫瘤細(xì)胞對(duì)tmz的敏感性顯著增加;相反,在dec1過(guò)表達(dá)的情況下,膠質(zhì)瘤細(xì)胞mlh1的表達(dá)受到了明顯的抑制,并且對(duì)tmz的敏感性顯著下降。結(jié)論:mlh1的表達(dá)水平與復(fù)發(fā)性gbm患者tmz的化療耐受性密切相關(guān)。作為mlh1的轉(zhuǎn)錄調(diào)控基因,dec1影響gbm患者tmz化療反應(yīng)性的分子機(jī)制正是通過(guò)對(duì)mlh1的轉(zhuǎn)錄調(diào)控而實(shí)現(xiàn)的。這些結(jié)論不但揭示了dec1在tmz化療耐受過(guò)程中發(fā)揮的重要作用,更在理論上豐富了TMZ治療GBM出現(xiàn)化療耐受的分子機(jī)制,為GBM的TMZ化療提供抗耐藥分子靶點(diǎn),進(jìn)一步為GBM化療提供新的治療策略。
[Abstract]:Neuroglioma is the most common malignant tumor of the human brain, which accounts for more than half of the central nervous system tumors and has a poor prognosis. Among them, Glioblastoma multiforme, GBM, WHO IV are highly differentiated, highly malignant, and easy to tolerate chemotherapy and chemotherapy. The oncogene embryo cartilage development gene 1 (Differentia) The transcriptional regulation function of Ted embryo chondrocyte expressed gene 1, DEC1) is essential for the development of tumor cells. The high expression of this molecule exists in a variety of human malignant tumors and indicates the malignant differentiation of tumor cells. Our previous study found that the expression of DEC1 in glioma and the pathological grade of glioma. There is a significant correlation, not only as an independent prognostic factor, but also to predict the responsiveness of patients with high grade glioma to Temozolomide (TMZ). However, the specific molecular mechanism of the cytotoxic effect of DEC1 on the cytotoxicity of temozolomide is not clear. Nuclear microglobulin 58 (The nucleolar 58-kD microsphe Rule protein, MSP58) is the interaction molecule of DEC1, which is also highly expressed in a variety of human tumors. It is an important tone of the.MLH1 (Mut L homolog1, M U), which is an oncogene.DEC1 playing a variety of biological functions. The deletion or functional defects of the molecule can lead to the tolerance of the tumor cells to the cytotoxicity of alkylating agents. The transcriptional regulator DEC1 can combine the E-box sequence of the MLH1 promoter region to inhibit the expression of MLH1,.Msp58 and MLH1 as a protein molecule closely related to the function of the DEC1 oncogene, and whether DEC1 affects TMZ The key part of the treatment sensitivity is the main research content of this subject. Part 1 the expression of MSP58 in human glioma and its effect on the chemosensitivity of temozolomide: the first study of this subject was first to clarify the oncogene role of MSP58 in human glioma, and to present the expression of DEC1 for the timozolamine in the patients with glioma. Therapeutic responsiveness has an important impact. However, the prognostic factors of MSP58 as a glioma have not been clearly reported, and as a interacting molecule closely related to the function of the DEC1 oncogene, the expression of MSP58 has no effect on the chemotherapeutic reactivity of temozolomide in glioma patients. Methods the expression of MSP58 was detected in 158 cases of primary glioma samples and 63 patients receiving postoperative TMZ chemotherapy and recurrence of tumor recurrence, and the correlation analysis was done with the patient's clinicopathological data, prognosis, and the reactivity of temozolomide in chemotherapy. The proliferation ability of tumor cells was immune to the use of nuclear proliferation antigen Ki-67. The results were statistically significant correlation between the expression level of MSP58 and the WHO level (p0.001) and KPS score (p=0.003) of the patients with primary glioma. The survival analysis showed that the higher the expression level of MSP58 was, the worse the prognosis of the patients (p0.001). The results of the multiple factor Cox regression model showed that the results of the MSP58 were significant. The expression level of MSP58 can be used as an independent prognostic factor in patients with primary glioma. In addition, the proliferation ability of glioma cells is constantly enhanced with the increasing level of MSP58 expression (P0.01). However, there is no significant statistical difference between the expression of MSP58 and the response of TMZ in recurrent GBM. Conclusion: the expression level of MSP58 has a significant correlation with the WHO level and proliferation ability of glioma patients, indicating that MSP58 plays an important role in the occurrence and malignant progression of glioblastoma tumor. However, the expression level of MSP58 is not significantly different in the patients with primary and recurrent gelatoma, indicating the TMZ chemotherapy. There is no definite effect on the expression level of MSP58 in patients with glioma. In addition, there is no significant statistical correlation between the expression of MSP58 and the response to TMZ chemotherapy in patients with recurrent glioma, indicating that the specific molecular mechanism that DEC1 affects the toxicity of TMZ cells may not be achieved through the interaction with MSP58. More importantly, it is The expression level of MSP58 is significantly associated with the total survival time of the patients with glioma, indicating that MSP58 can be a new prognostic marker for a adjuvant who grading system, and this oncogene is very likely to be an important target for targeting treatment of glioblastoma patients. The expression of DEC1 in second human gliomas is treated with temozolomide chemotherapy The molecular mechanism of sensitivity influence: the previous study found that the expression of DEC1 has an important effect on the reactivity of timozolamine in the patients with glioma..mmr is the DNA damage repair, and the most important mechanism for regulating the tolerance of alkylating agents,.Mlh1, is the key molecule of the MMR system, and the mutation or missing cell lines are all against TMZ. Resistance; however, as a transcriptional regulator of MLH1, whether DEC1 can affect the cytotoxicity of TMZ by inhibiting the expression level of MLH1 remains to be verified. First, in 63 cases of postoperative TMZ chemotherapy and recurrent GBM samples, we used immunohistochemical method to detect the expression of DEC1 and MLH1; DUTP nick end labeling (TUNEL) is used to evaluate the apoptosis of tumor cells. Then, the human glioma U251 and U87 cells are used as the research object. By constructing the DEC1 specific interference fragment Lentivirus Expression Vector, the glioma cell lines that express dec1-shrna are further established. Finally, the colloid expressing the background in DEC1 is different. The difference in the expression of TMZ cytotoxicity was analyzed in the tumor cells and the expression level of the related protein molecules was detected to determine the specific molecular mechanism of the effect of DEC1 on TMZ chemotherapy reactivity. Results: there was a negative correlation between the expression level of DEC1 and MLH1 in the recurrent GBM specimens (r=-0.55, p0.001), and the apoptosis rate of the GBM tumor cells was expressed with the expression of MLH1. In addition, r=0.29, p0.001. In addition, the sequencing of DEC1 specific interference fragments showed that the Lentivirus Expression Vector psi-lv-dec1-shrna was successfully constructed, and the cytotoxicity analysis of the glioma cell line u87-dec1-shrna. was confirmed by the fluorescence microscope, and the results of the cytotoxicity analysis of the glioma cell line of the glioma cell line showed that the glioma was glioma. After the expression of DEC1 was interfered, the expression of MLH1 was significantly up-regulated and the sensitivity of the tumor cells to TMZ increased significantly. On the contrary, the expression of MLH1 in the glioma cells was significantly inhibited and the sensitivity to TMZ decreased significantly in the case of DEC1 overexpression. Conclusion: the expression level of MLH1 is closely related to the tolerance of TMZ in recurrent GBM patients. As a transcriptional regulation gene of MLH1, the molecular mechanism that DEC1 affects the responsiveness of TMZ chemotherapy in GBM patients is achieved through the transcription regulation of MLH1. These conclusions not only reveal the important role of DEC1 in the TMZ chemotherapy tolerance, but also theoretically enrich the molecular mechanism of the chemotherapy tolerance in TMZ treatment GBM, for GBM. TMZ chemotherapy provides a target for anti drug resistance, and further provides a new therapeutic strategy for GBM chemotherapy.

【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R739.4

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5 孫濤;董瑩;張矛;;替莫唑胺聯(lián)合放射治療在非小細(xì)胞肺癌腦轉(zhuǎn)移患者治療中的作用研究[A];第13屆全國(guó)肺癌學(xué)術(shù)大會(huì)論文匯編[C];2013年

6 田新華;林曉寧;林錦超;魏峰;莊再旺;任磊;陳鍔;孫瑾;;腦靶向載替莫唑胺聚氰基丙烯酸正丁酯納米粒體內(nèi)外實(shí)驗(yàn)研究[A];中華醫(yī)學(xué)會(huì)神經(jīng)外科學(xué)分會(huì)第九次學(xué)術(shù)會(huì)議論文匯編[C];2010年

7 許建萍;張湘茹;李峻嶺;王宏羽;王燕;郝學(xué)志;石遠(yuǎn)凱;;替莫唑胺聯(lián)合伊立替康治療復(fù)發(fā)性非小細(xì)胞肺癌腦轉(zhuǎn)移的療效和毒副作用分析[A];中國(guó)腫瘤內(nèi)科進(jìn)展 中國(guó)腫瘤醫(yī)師教育（2014）[C];2014年

8 宋諸臣;楊磊;魏金芝;叢智榮;彭春雷;;替莫唑胺聯(lián)合美羅華治療復(fù)發(fā)中樞神經(jīng)系統(tǒng)淋巴瘤(附1例報(bào)告)[A];2009醫(yī)學(xué)前沿論壇暨第十一屆全國(guó)腫瘤藥理與化療學(xué)術(shù)會(huì)議論文集[C];2009年

9 陳鵬;傅偉明;張宏;石鍵;;替莫唑胺治療術(shù)后殘留惡性腦膠質(zhì)瘤的療效[A];2009年浙江省神經(jīng)外科學(xué)術(shù)年會(huì)論文匯編[C];2009年

10 孫爽;李鴻彬;;替莫唑胺對(duì)腦轉(zhuǎn)移腫瘤的治療研究報(bào)告[A];2010年中國(guó)藥學(xué)大會(huì)暨第十屆中國(guó)藥師周論文集[C];2010年

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1 徐道;抗腦瘤老藥替莫唑胺煥發(fā)生機(jī)[N];醫(yī)藥經(jīng)濟(jì)報(bào);2010年

2 ;替莫唑胺新適應(yīng)癥獲批[N];醫(yī)藥經(jīng)濟(jì)報(bào);2005年

3 國(guó)訊;英國(guó)提示替莫唑胺的肝臟損害風(fēng)險(xiǎn)[N];中國(guó)醫(yī)藥報(bào);2014年

4 劉民;替莫唑胺可長(zhǎng)期治療神經(jīng)膠質(zhì)瘤[N];中國(guó)醫(yī)藥報(bào);2004年

5 董江萍;FDA增加替莫唑胺的骨髓抑制警告[N];中國(guó)醫(yī)藥報(bào);2008年

6 雷諾島;徹底擊斃毀滅性疾病[N];醫(yī)藥經(jīng)濟(jì)報(bào);2011年

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1 劉彥廷;長(zhǎng)鏈非編碼RNA RP11-838N2.4通過(guò)miR-10a調(diào)控腦膠質(zhì)瘤替莫唑胺耐藥性的機(jī)制研究[D];南方醫(yī)科大學(xué);2016年

2 樊天禹;膠質(zhì)母細(xì)胞瘤中抑制EZH2的表達(dá)改善替莫唑胺化療敏感性的研究[D];南方醫(yī)科大學(xué);2016年

3 李曉明;人腦膠質(zhì)瘤中DEC1的表達(dá)對(duì)烷化劑替莫唑胺化療敏感性影響的分子機(jī)制[D];第四軍醫(yī)大學(xué);2016年

4 林靖;泛素連接酶Fbw7在人腦膠質(zhì)瘤增殖、侵襲、遷移以及對(duì)替莫唑胺敏感性中的作用研究[D];第二軍醫(yī)大學(xué);2016年

5 林洪;白藜蘆醇誘導(dǎo)惡性膠質(zhì)瘤細(xì)胞凋亡并增強(qiáng)替莫唑胺藥物敏感性作用的分子機(jī)制[D];第四軍醫(yī)大學(xué);2011年

6 宋振華;survivin在替莫唑胺誘導(dǎo)的膠質(zhì)瘤細(xì)胞凋亡及老化中的作用研究[D];南方醫(yī)科大學(xué);2014年

7 崔勇;RNA干擾AKT2對(duì)腦膠質(zhì)瘤替莫唑胺化療敏感性的影響及相關(guān)機(jī)制研究[D];第二軍醫(yī)大學(xué);2014年

8 朱巍巍;替莫唑胺誘導(dǎo)的人腦膠質(zhì)瘤耐藥細(xì)胞株的建立及其繼發(fā)性耐藥相關(guān)基因的篩查[D];蘇州大學(xué);2011年

9 程全;替莫唑胺通過(guò)調(diào)控miR-223/PAX6抑制膠質(zhì)瘤細(xì)胞增殖的研究[D];中南大學(xué);2014年

10 劉岳;BCL-2與人腦膠質(zhì)細(xì)胞瘤生物學(xué)特性及替莫唑胺敏感性的關(guān)系[D];武漢大學(xué);2014年

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1 趙海濤;替莫唑胺聯(lián)合全腦放療治療復(fù)發(fā)/難治性原發(fā)中樞神經(jīng)系統(tǒng)淋巴瘤的臨床研究[D];濟(jì)南大學(xué);2015年

2 王勇;替莫唑胺為主的化療聯(lián)合放療治療原發(fā)中樞神經(jīng)系統(tǒng)淋巴瘤的臨床研究[D];濟(jì)南大學(xué);2013年

3 王能江;原發(fā)性腦膠質(zhì)瘤術(shù)后替莫唑胺化療的臨床觀察[D];華中科技大學(xué);2007年

4 李梅;替莫唑胺靜脈乳的制備及質(zhì)量研究[D];山東大學(xué);2013年

5 王蘭;抗腫瘤藥替莫唑胺一氧化氮供體型衍生物的合成與表征[D];天津大學(xué);2007年

6 潘強(qiáng);替莫唑胺耐藥的惡性膠質(zhì)瘤細(xì)胞系耐藥特性演變的研究[D];天津醫(yī)科大學(xué);2010年

7 卓龍泉;放療聯(lián)合替莫唑胺化療治療非小細(xì)胞肺癌腦轉(zhuǎn)移的療效評(píng)價(jià)[D];吉林大學(xué);2013年

8 湯浩;乙胺嘧啶協(xié)同替莫唑胺聯(lián)合用藥對(duì)小鼠垂體促性腺激素腺瘤細(xì)胞的影響[D];北京協(xié)和醫(yī)學(xué)院;2011年

9 唐東方;替莫唑胺衍生物治療人腦膠質(zhì)瘤的實(shí)驗(yàn)研究[D];蘇州大學(xué);2012年

10 溫宏宇;惡性腦膠質(zhì)瘤術(shù)后放療聯(lián)合替莫唑胺療效分析[D];大連醫(yī)科大學(xué);2012年

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