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)母細胞瘤(Glioblastoma multiforme,GBM,WHO IV級)具有低度分化,高度惡性,對放化療易發(fā)生耐受等特點。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)控功能對腫瘤細胞的發(fā)生發(fā)展至關(guān)重要。該分子的高度表達存在于人類多種惡性腫瘤之中,并且預(yù)示腫瘤細胞的惡性分化程度。我們前期研究發(fā)現(xiàn)DEC1在膠質(zhì)瘤中的表達與膠質(zhì)瘤的病理級別呈顯著的相關(guān)性,不但可以作為獨立的預(yù)后因素,而且能夠預(yù)示高級別膠質(zhì)瘤患者對烷化劑替莫唑胺(Temozolomide,TMZ)化療的反應(yīng)性。然而,DEC1的表達對替莫唑胺細胞毒性影響的具體分子機制卻不明確。核微球蛋白58(The nucleolar 58-kD microspherule protein,MSP58)是DEC1的相互作用分子,該分子同樣在人類多種腫瘤中存在高表達,是一個癌基因。DEC1發(fā)揮多種生物學(xué)功能都是通過與MSP58的相互作用而實現(xiàn)的。MLH1(Mut L homolog1,M u t L同源基因)是DNA錯配修復(fù)系統(tǒng)(Mis-match repair,MMR)的重要調(diào)控因子,該分子的表達缺失或功能缺陷能夠?qū)е履[瘤細胞對烷化劑細胞毒性產(chǎn)生耐受。轉(zhuǎn)錄調(diào)控因子DEC1能夠結(jié)合MLH1啟動子區(qū)域的E-box序列從而抑制MLH1的表達。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內(nèi)容。第一部分人腦膠質(zhì)瘤中msp58的表達及其對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的表達對膠質(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)后因素卻未見明確報道,并且作為與dec1癌基因功能密切相關(guān)的相互作用分子,msp58的表達情況對膠質(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msp58的表達情況,并且進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。腫瘤細胞增殖能力應(yīng)用核增殖抗原ki-67的免疫組化染色進行評估,并在msp58不同表達水平之間進行統(tǒng)計學(xué)分析。結(jié)果:msp58的表達水平與原發(fā)性膠質(zhì)瘤患者who級別(p0.001)和kps評分(p=0.003)均顯著相關(guān)。生存分析表明,msp58的表達水平越高、患者預(yù)后越差(p0.001)。多因素cox回歸模型結(jié)果顯示,msp58的表達水平可以作為原發(fā)性膠質(zhì)瘤患者獨立的預(yù)后因素。另外,隨msp58表達水平的不斷增高,膠質(zhì)瘤細胞的增殖能力也在不斷的增強(p0.01)。然而,在復(fù)發(fā)性gbm中,msp58的表達情況與tmz化療反應(yīng)性之間并沒有表現(xiàn)出顯著的統(tǒng)計學(xué)差異。結(jié)論:msp58的表達水平與膠質(zhì)瘤患者的who級別和增殖能力具有顯著的相關(guān)性,說明msp58在神經(jīng)膠質(zhì)細胞瘤腫瘤的發(fā)生和惡性進展中能夠發(fā)揮重要的作用。然而,msp58的表達水平在原發(fā)性和復(fù)發(fā)性膠質(zhì)瘤患者中未見顯著差異,說明tmz化療對膠質(zhì)瘤患者msp58的表達水平并無明確的影響。另外,msp58的表達與復(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)計學(xué)相關(guān)性,說明dec1影響tmz細胞毒性的具體分子機制可能并非是通過與msp58的相互作用而實現(xiàn)的。更重要的是,msp58表達水平與膠質(zhì)瘤患者總生存時間顯著相關(guān),說明msp58能夠作為一個輔助who分級系統(tǒng)的新型的預(yù)后標志,并且這一癌基因很有可能成為神經(jīng)膠質(zhì)細胞瘤患者靶向治療的重要靶點。第二部分人腦膠質(zhì)瘤中dec1的表達對替莫唑胺化療敏感性影響的分子機制目的:本課題前期研究發(fā)現(xiàn)發(fā)現(xiàn)dec1的表達對膠質(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制。mlh1作為mmr系統(tǒng)的關(guān)鍵分子,其突變或缺失的細胞系對tmz均具有抵抗性;然而,作為mlh1的轉(zhuǎn)錄調(diào)控因子,dec1能否通過抑制mlh1的表達水平從而影響tmz發(fā)揮細胞毒性卻有待驗證。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dec1和mlh1的表達情況;利用tdt介導(dǎo)dutp缺口末端標記法(tunel)評估腫瘤細胞的凋亡情況。然后,以人腦膠質(zhì)瘤u251和u87細胞為研究對象,通過構(gòu)建dec1特異性干涉片段慢病毒表達載體的方法,進一步的建立穩(wěn)定表達dec1-shrna的膠質(zhì)瘤細胞系。最后,在dec1不同表達背景的膠質(zhì)瘤細胞中分析tmz細胞毒性的表現(xiàn)差異,并且檢測相關(guān)蛋白分子的表達水平,以明確dec1對tmz化療反應(yīng)性影響的具體分子機制。結(jié)果:復(fù)發(fā)性gbm標本中dec1與mlh1的表達水平之間呈負相關(guān)(r=-0.55,p0.001),并且gbm腫瘤細胞的凋亡率隨mlh1的表達水平的增加而升高(r=0.29,p0.001)。另外,對dec1特異性干涉片段的測序鑒定結(jié)果表明成功的構(gòu)建了慢病毒表達載體psi-lv-dec1-shrna,并且熒光顯微鏡下證實獲得了穩(wěn)定表達dec1-shrna的膠質(zhì)瘤細胞株u251/u87-dec1-shrna。細胞毒性分析結(jié)果表明,膠質(zhì)瘤細胞dec1的表達被干涉后,mlh1的表達顯著上調(diào),腫瘤細胞對tmz的敏感性顯著增加;相反,在dec1過表達的情況下,膠質(zhì)瘤細胞mlh1的表達受到了明顯的抑制,并且對tmz的敏感性顯著下降。結(jié)論:mlh1的表達水平與復(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)性的分子機制正是通過對mlh1的轉(zhuǎn)錄調(diào)控而實現(xiàn)的。這些結(jié)論不但揭示了dec1在tmz化療耐受過程中發(fā)揮的重要作用,更在理論上豐富了TMZ治療GBM出現(xiàn)化療耐受的分子機制,為GBM的TMZ化療提供抗耐藥分子靶點,進一步為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)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R739.4

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

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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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