【摘要】： 侵襲和轉(zhuǎn)移是導(dǎo)致各種惡性腫瘤患者死亡的主要原因,并受多種基因的調(diào)控。近年來(lái),已相繼克隆出許多與腫瘤轉(zhuǎn)移直接相關(guān)的“腫瘤轉(zhuǎn)移相關(guān)基因”,其中有Yasushi Toh等從鼠和人類乳腺癌轉(zhuǎn)移細(xì)胞系中篩選克隆出腫瘤候選基因MTA1 (metastasis associated gene 1,腫瘤轉(zhuǎn)移相關(guān)基因1)。腫瘤轉(zhuǎn)移相關(guān)基因(MTA)是一個(gè)基因家族,現(xiàn)已確認(rèn)3類(MTA1, MTA2, MTA3)及6個(gè)亞型(MTA1, MTA1s, MTA1-ZG29p, MTA2, MTA3, MTA3L),其中MTA1, MTA2, MTA3均被認(rèn)為是細(xì)胞核小體重構(gòu)和脫乙酰基(NuRD)復(fù)合物的組成部分,它們通過(guò)影響染色質(zhì)的狀態(tài)來(lái)調(diào)整DNA復(fù)制,調(diào)控組蛋白乙�；癄顟B(tài)從而發(fā)揮生物學(xué)功能。 研究表明,MTA1與人類許多惡性腫瘤的侵襲轉(zhuǎn)移過(guò)程緊密相關(guān),在乳腺癌、卵巢癌、胃腸腫瘤、前列腺癌和食管癌等腫瘤細(xì)胞中都呈過(guò)表達(dá)。MTA1在NuRD復(fù)合物中與組蛋白去乙�；�1 (HDAC1)結(jié)合緊密,與組蛋白去乙�；烧嚓P(guān),作為組蛋白去乙�；傅妮o助激動(dòng)因子抑制轉(zhuǎn)錄,成為轉(zhuǎn)錄過(guò)程中一個(gè)輔助抑制因子。Mazumdar等報(bào)道,雌激素受體(ER)陽(yáng)性的乳腺細(xì)胞中hereglutin /HER2信號(hào)傳導(dǎo)通路的激活可刺激MTA1的表達(dá),MTA1結(jié)合于ER的AF2 (ER的一個(gè)配體結(jié)合位點(diǎn)),同時(shí)MTA1與HDAC2結(jié)合,使HDAC2募集于含ER反應(yīng)元件的啟動(dòng)子附近,進(jìn)而組蛋白去乙�；黾�,使雌激素受體作用元件激活的基因轉(zhuǎn)錄受阻,使乳腺癌發(fā)展成更具侵襲特性的惡性表型。MTA1作為組蛋白修飾物,在不同腫瘤的侵襲和轉(zhuǎn)移過(guò)程中都發(fā)揮了不同程度的促進(jìn)作用。 目前,國(guó)內(nèi)外對(duì)MTA1的研究大部分著眼于其在腫瘤轉(zhuǎn)移過(guò)程的作用機(jī)理,而其生理功能的研究甚少。研究表明,MTA1不僅在腫瘤細(xì)胞中過(guò)表達(dá),在哺乳動(dòng)物正常細(xì)胞組織中也有表達(dá),尤其是睪丸與胸腺組織,提示MTA1可能在這兩種組織發(fā)育過(guò)程中起到了更為重要的作用。為了更好的理解這一組蛋白修飾物的生理作用,我們前期觀察了MTA1在人、鼠睪丸發(fā)育過(guò)程中的表達(dá),揭示了它在精子發(fā)生減數(shù)分裂階段起了基因修飾的關(guān)鍵作用。 眾所周之,精子在附睪內(nèi)移行并逐漸成熟的過(guò)程是其獲得運(yùn)動(dòng)能力和受精能力的保證,而這一過(guò)程同樣受到雄激素的調(diào)控。鑒于MTA1在精子發(fā)生過(guò)程中的重要作用,我們研究它在附睪中不同部位不同細(xì)胞類型的表達(dá)定位,分析它在精子成熟、運(yùn)輸和儲(chǔ)存過(guò)程的作用,并深入探討了雄激素對(duì)MTA1的調(diào)控作用機(jī)制,進(jìn)一步明確它在生殖系統(tǒng)中表達(dá)的生理意義。本實(shí)驗(yàn)分為四部分: 第一部分:MTA1在正常成年小鼠組織中的表達(dá) 第二部分:MTA1在正常小鼠附睪中的表達(dá)與定位 第三部分:MTA1在小鼠生后不同發(fā)育階段附睪中的表達(dá) 第四部分:建立去勢(shì)模型分析雄激素對(duì)MTA1的調(diào)控作用 本實(shí)驗(yàn)觀察了MTA1在正常成年小鼠各組織中的表達(dá)譜,結(jié)果顯示MTA1廣泛表達(dá)于小鼠各類組織器官,提示MTA1在多系統(tǒng)多器官的生理功能調(diào)節(jié)中發(fā)揮了重要的基因修飾作用。同時(shí),我們揭示這一新的分子在附睪上皮細(xì)胞中的區(qū)段特異性表達(dá)特點(diǎn)。MTA1主要定位于附睪上皮細(xì)胞胞核,可能通過(guò)組蛋白乙�；揎椬饔脤�(duì)附睪上皮細(xì)胞重吸收、分泌及內(nèi)吞過(guò)程起到一定調(diào)控作用,間接維持精子成熟的內(nèi)環(huán)境穩(wěn)定。小鼠生后附睪發(fā)育過(guò)程中,MTA1的表達(dá)隨雄激素分泌水平呈趨勢(shì)性變化,并參與附睪成熟過(guò)程。建立去勢(shì)模型并給予DHT,觀察小鼠附睪中MTA1的表達(dá)差異,提示雄激素對(duì)MTA1表達(dá)可能有正性調(diào)控作用,為后續(xù)研究其信號(hào)傳導(dǎo)機(jī)制提供依據(jù)。
[Abstract]:Invasion and metastasis are the main causes of death in various malignant tumors and are regulated by a variety of genes. In recent years, many "tumor metastasis related genes" which have been cloned directly related to tumor metastasis have been cloned, including Yasushi Toh and so on from mouse and human mammary cancer metastatic cell lines to clone and clone the tumor candidate gene MTA1 (me Tastasis associated gene 1, tumor metastasis related gene 1). The tumor metastasis related gene (MTA) is a gene family, which has been identified as 3 categories (MTA1, MTA2, MTA3) and 6 subtypes (MTA1, MTA1s, MTA1-ZG29p, MTA2, MTA3), which are considered to be the components of the cell nuclear reconfiguration and the deacetylation complex. They regulate DNA replication by regulating the state of chromatin, regulate histone acetylation, and exert biological functions.
The study shows that MTA1 is closely related to the invasion and metastasis of many human malignant tumors. In breast cancer, ovarian cancer, gastrointestinal tumor, prostate cancer and esophageal cancer,.MTA1 is closely associated with histone deacetylase 1 (HDAC1) in the NuRD complex, and is positively related to histone deacetylation, as histone The adjuvant agonist of acetylase inhibits transcription and becomes a supplementary inhibitory factor.Mazumdar in the transcription process. The activation of the hereglutin /HER2 signaling pathway in the estrogen receptor (ER) positive breast cells stimulates the expression of MTA1, and MTA1 is combined with AF2 of ER (a ligand binding site of ER), while MTA1 and HDAC2 are combined, HDAC2 is raised near the promoter of the ER reaction element, and then the histone deacetylation is increased and the gene transcription activated by the estrogen receptor action element is blocked, and the breast cancer is developed into a more invasive, malignant phenotype,.MTA1, as a histone modifier, and to varying degrees in the invasion and metastasis of different tumors. Promoting effect.
At present, most studies on MTA1 are focused on the mechanism of its role in the process of tumor metastasis, and the study of its physiological functions is very small. The study shows that MTA1 is not only overexpressed in tumor cells, but also expressed in normal mammalian cells, especially in the testis and thymus gland, suggesting that MTA1 may have developed in these two tissues. In order to better understand the physiological role of this histone modifier, we have observed the expression of MTA1 during the development of human and rat testicles, and revealed that it plays a key role in gene modification during the meiosis stage of spermatogenesis.
The process of sperm migration and maturation in the epididymis is the guarantee of its ability to gain exercise and fertilization, and this process is also regulated by androgens. In view of the important role of MTA1 in the process of spermatogenesis, we study its location in different parts of the epididymis and the analysis of it in spermatozoa. The role of maturation, transportation and storage process and the mechanism of androgens' regulation on MTA1 are discussed and the physiological significance of its expression in the reproductive system is further clarified. This experiment is divided into four parts:
Part one: expression of MTA1 in normal adult mice
The second part: the expression and localization of MTA1 in normal mouse epididymis.
The third part: the expression of MTA1 in epididymis at different developmental stages in mice.
The fourth part: establishment of castration model to analyze androgen regulating effect on MTA1.
In this experiment, the expression of MTA1 in the tissues of normal adult mice was observed. The results showed that MTA1 was widely expressed in various tissues and organs of mice, suggesting that MTA1 played an important gene modification in the physiological function regulation of multiple systems and multiple organs. .MTA1 is mainly located in the nucleus of epididymal epithelial cells, which may play a regulatory role in the reabsorption of epididymal epithelial cells through the histone acetylation modification, and indirectly maintain the internal stability of the sperm maturation. The expression of MTA1 in the development process of the epididymis of mice is trend to the level of androgen secretion. Change, and participate in the epididymal maturation process. Establish a castration model and give DHT to observe the difference in the expression of MTA1 in the epididymis of mice, suggesting that androgen has a positive regulatory effect on the expression of MTA1, which provides a basis for the follow-up study of the signal transduction mechanism.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2009
【分類號(hào)】：R346

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