本文選題：乳腺癌 + 生長激素��； 參考：《中國科學(xué)技術(shù)大學(xué)》2015年博士論文

【摘要】：第一部分：人生長激素不僅在乳腺發(fā)育過程發(fā)揮重要作用,也有證據(jù)顯示 自分泌的人生長激素促進(jìn)乳腺上皮細(xì)胞的惡性轉(zhuǎn)化。之前我們報道生長激素通 過促進(jìn)乳腺細(xì)胞上皮間充質(zhì)轉(zhuǎn)變(EMT)增強(qiáng)細(xì)胞的侵襲能力,但具體機(jī)制并 未詳細(xì)探討。這里,利用芯片技術(shù),我們發(fā)現(xiàn)在乳腺癌細(xì)胞MCF7中自分泌的 人生長激素調(diào)節(jié)一系列的微小RNA(miRNA)的表達(dá)水平。其中,受生長激素 上調(diào)的miR-183-96-182簇介導(dǎo)了生長激素促進(jìn)乳腺細(xì)胞上皮間充質(zhì)轉(zhuǎn)變的過 程。在體外和體內(nèi)實(shí)驗(yàn)中,過表達(dá)miR-183-96-182簇顯著增強(qiáng)上皮樣的MCF-7 細(xì)胞的遷移能力,同時伴隨有細(xì)胞骨架的重排以及EMT相關(guān)蛋白表達(dá)水平的改 變。進(jìn)一步的研究證實(shí)miR-183-96-182簇是通過乳腺癌轉(zhuǎn)移抑制蛋白1相似蛋 白基因(BRMS1L)調(diào)節(jié)細(xì)胞的EMT過程。同時,生長激素受體(GHR)受到 miR-96和miR-182的直接調(diào)節(jié),證實(shí)了生長激素-miR-183-96-182簇之間的負(fù) 反饋調(diào)節(jié)機(jī)制。而且我們還發(fā)現(xiàn)受生長激素激活的信號轉(zhuǎn)導(dǎo)及轉(zhuǎn)錄激活因子 STAT3和STAT5轉(zhuǎn)錄因子可以結(jié)合到miR-96-183-183簇啟動子區(qū)激活 miR-183-96-182的轉(zhuǎn)錄。miR-183-96-182簇與BRMS1L的表達(dá)水平在乳腺癌病 人樣本中與淋巴結(jié)轉(zhuǎn)移指標(biāo)相關(guān)。研究揭示了人生長激素通過miR-183-96-182 簇調(diào)節(jié)乳腺癌轉(zhuǎn)移的具體分子機(jī)制。第二部分：腫瘤組織的基因組研究可以為個體化的醫(yī)療方案以及治療反應(yīng) 提供豐富的參考信息,但對特定基因組突變背后的機(jī)制研究是整合基因組信息 和臨床決策的關(guān)鍵。這里,我們報道人類三號染色體斷臂上的MIR135A1基因 在30%左右的乳腺癌病人中均存在拷貝丟失的現(xiàn)象,并且該類乳腺癌病人的預(yù) 后相比其他病人明顯較差。同時,MIR135A1基因的成熟產(chǎn)物,.miR-135a的表 達(dá)水平也被發(fā)現(xiàn)在乳腺癌腫瘤組織中明顯較良性組織低。在體內(nèi)和體外實(shí)驗(yàn)中, 我們都證實(shí)了低的miR-135a表達(dá)水平與細(xì)胞的高惡性度以及轉(zhuǎn)移潛力密切相 關(guān)。在腫瘤組織中,miR-135a的水平與雌激素受體alpha(ERa)呈明顯的正相 關(guān)。進(jìn)一步的研究證實(shí)MIR135A1基因的啟動子區(qū)存在ERa響應(yīng)元件(ERE), 在雌激素刺激下可以轉(zhuǎn)錄出更高水平的miR-135a。實(shí)驗(yàn)中還發(fā)現(xiàn)較低的 miR-135a水平可以削弱ERa陽性的細(xì)胞生長過程中對雌激素的依賴。在體外長 期對細(xì)胞使用抗雌激素治療藥物他莫昔芬(tamoxifen)引起miR-135a不可逆的 下調(diào)。在體內(nèi)體外實(shí)驗(yàn)中我們都證實(shí)了miR-135a的下調(diào)是獲得他莫昔芬抗性的 充分必要條件。對miR-135a的下游信號通路的研究顯示,miR-135a不僅可以 通過靶點(diǎn)ERa(ESR1),雌激素受體alpha相關(guān)蛋白A(ESRRA)和核受體輔激活蛋白1(NCOA1)負(fù)反饋調(diào)節(jié)雌激素信號通路,而且抑制ERK和AKT信號通路上游基因PIM2, MRASLCP1的表達(dá)。這些研究揭示了miR-135a與乳腺癌發(fā)生發(fā)展中扮演重要角色的信號網(wǎng)絡(luò)ERa-ERK-AKT之間的平衡機(jī)制,而MIR135A1基因的缺失或者長期的抗雌激素治療破壞了該平衡從而導(dǎo)致乳腺癌的發(fā)展以及對他莫昔芬治療的抗性產(chǎn)生。
[Abstract]:Part I : Human growth hormone plays an important role not only in the development of mammary gland , but also in evidence .

Self - secreted human growth hormone promotes malignant transformation of mammary epithelial cells . We report growth hormone .

Overpromoting mesenchymal transition ( EMT ) in the mammary gland cells enhances the invasion ability of cells , but specific mechanisms and

Not discussed in detail . Here , using chip technology , we have found that self - secreted in breast cancer cell MCF7

Human growth hormone regulates the level of expression of a series of miRNA .

Up - regulated miR - 183 - 96 - 182 cluster mediated growth hormone to promote mesenchymal transition of mammary gland cells

Cheng . Over - expression of miR - 183 - 96 - 182 clusters in vitro and in vivo experiments significantly enhanced epithelial - like MCF - 7

The migration ability of the cells is accompanied by the rearrangement of the cytoskeletal framework and the alteration of the expression level of EMT - related protein .

Further studies confirm that miR - 183 - 96 - 182 clusters are similar to those obtained by breast cancer metastasis suppressor protein 1

White gene ( BRMS1L ) regulates EMT process of cells . At the same time , the growth hormone receptor ( GHR ) is affected

Direct modulation of miR - 96 and miR - 182 confirms the negative between growth hormone - miR - 183 - 96 - 182 clusters

Feedback regulatory mechanisms . And we also found signal transduction and transcriptional activation factors activated by growth hormone

STAT5 Transcription Factor binds to the miR - 96 - 183 - 183 cluster promoter region activation

Transcription of miR - 183 - 96 - 182 . Expression level of miR - 183 - 96 - 182 cluster and BRMS1L in breast cancer

The study revealed that human growth hormone was passed through miR - 183 - 96 - 182 .

Cluster regulates the specific molecular mechanism of breast cancer metastasis . Part 2 : The gene group of tumor tissue can be a personalized medical regimen and therapeutic response .

Provides rich reference information , but the mechanism behind a particular genome mutation is to integrate genome information

and the key to clinical decision - making . Here , we report the gene of the human chromosome 3 on the genome of the gene .

There is a loss of copy in breast cancer patients around 30 % , and the pre - treatment of this type of breast cancer patient

At the same time , the mature product of the mir135A1 gene , the expression of miR -

the level was also found to be significantly lower in breast cancer tumor tissues than in benign tissues , in vivo and in vitro experiments ,

We all confirmed that the low expression level of miR - 135 was closely related to the high malignancy of the cell and the metastatic potential .

In the tumor tissues , the level of miR - A is positively correlated with the estrogen receptor alpha ( ERa ) .

Further studies confirm the presence of an ERa response element ( ERE ) in the promoter region of the mir135A1 gene ,

Higher levels of miR - 135 can be transcribed under estrogen stimulation . The experiments also find low

The level of miR - 135 can weaken the dependence of ERa - positive cells on estrogen during growth , and is long in vitro

The use of an anti - estrogen therapy drug tamoxifen for the cells in the period of time causes an irreversible miR -

Down - regulation . In in vitro experiments in vivo , we all confirmed that the down regulation of miR - 135 was tamoxifen resistant .

It is sufficient and necessary . Research on the downstream signaling pathway of miR -

Estrogen receptor alpha - associated protein A ( ESRRA ) and nuclear receptor sub - activator protein 1 ( NCOA1 ) negative feedback regulate estrogen signaling pathway through target ERa ( ESR1 ) , estrogen receptor alpha - associated protein A ( ESRRA ) , and nuclear receptor secondary activator protein 1 ( NCOA1 ) . These studies revealed a balance mechanism between ERK and ERa - ERK - 1 , a signaling network that plays an important role in the development of breast cancer , and the absence or long - term anti - estrogen treatment of either the mir135A1 gene disrupted the balance leading to the development of breast cancer and the resistance to tamoxifen therapy .
【學(xué)位授予單位】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R737.9

【共引文獻(xiàn)】

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