【摘要】：惡性腫瘤生長速度快,具有侵襲浸潤能力,且常有遠(yuǎn)處轉(zhuǎn)移。腫瘤轉(zhuǎn)移是指腫瘤細(xì)胞從原發(fā)部位脫離,經(jīng)血管、淋巴道或體腔等途徑,最終到達(dá)機(jī)體其他部位繼續(xù)生長增殖的過程。腫瘤轉(zhuǎn)移是罹患惡性腫瘤的患者高死亡率的罪魁禍?zhǔn)?因此人們一直致力于腫瘤轉(zhuǎn)移機(jī)制的研究。細(xì)胞上皮樣表型與間質(zhì)樣表型之間的轉(zhuǎn)化過程與很多生理病理過程密切相關(guān),如胚胎發(fā)育、腫瘤轉(zhuǎn)移等。腫瘤細(xì)胞經(jīng)歷上皮-間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition,EMT)時,細(xì)胞間粘附連接性降低,極性逐漸喪失轉(zhuǎn)變?yōu)殚g質(zhì)樣狀態(tài),細(xì)胞更具移動能力,有利于腫瘤早期侵襲轉(zhuǎn)移。在腫瘤轉(zhuǎn)移的晚期,腫瘤細(xì)胞經(jīng)歷間質(zhì)-上皮轉(zhuǎn)化(mesenchymal-epithelial transition,MET),重塑上皮樣表型,促進(jìn)轉(zhuǎn)移灶形成。可以認(rèn)為,EMT和MET在腫瘤轉(zhuǎn)移的不同階段發(fā)揮各自不同的作用。細(xì)胞表型轉(zhuǎn)化的一個重要標(biāo)志是細(xì)胞粘附分子E-鈣粘素(E-cadherin)表達(dá)水平的變化,該分子被視為上皮表型的標(biāo)志物。此外,一些間質(zhì)樣表型的標(biāo)志蛋白,如波形蛋白(Vimentin)、N-鈣粘素(N-cadherin)、α-平滑肌肌動蛋白(α-smooth muscle actin,α-SMA)表達(dá)水平的變化也可以反映細(xì)胞是否發(fā)生細(xì)胞表型的轉(zhuǎn)變。作為Toll樣受體炎癥信號通路的關(guān)鍵銜接蛋白,髓樣分化因子88(Myeloid differentiation factor 88或Myeloid differentiation primary response 88,簡稱My D88)發(fā)揮著重要的信號轉(zhuǎn)導(dǎo)作用。已有很多研究證實My D88在多種腫瘤組織中表達(dá)升高,并通過炎癥反應(yīng)途徑促進(jìn)腫瘤發(fā)生發(fā)展。最近的研究發(fā)現(xiàn),除了通過Toll樣受體介導(dǎo)的炎癥反應(yīng)通路促進(jìn)腫瘤發(fā)展外,My D88還可以通過非炎癥途徑調(diào)控腫瘤的發(fā)展。我們前期通過對110例肝細(xì)胞肝癌組織進(jìn)行免疫組織化學(xué)染色,發(fā)現(xiàn)My D88在癌組織中的表達(dá)高于相應(yīng)的癌旁組織,而My D88的高表達(dá)和肝細(xì)胞肝癌患者的不良預(yù)后密切相關(guān);此外,前期研究結(jié)果顯示My D88高表達(dá)可以促進(jìn)腫瘤的生長與轉(zhuǎn)移。因此,探討腫瘤細(xì)胞中My D88高表達(dá)如何通過非炎癥途徑促進(jìn)腫瘤轉(zhuǎn)移是本項研究需要解決的重點問題。骨橋蛋白(osteopontin,OPN)通常被認(rèn)為是一種分泌型磷酸化糖蛋白,研究者們也確實發(fā)現(xiàn)分泌到細(xì)胞外的OPN生物活性十分多樣。有趣的是,人們后來發(fā)現(xiàn)OPN并不只是一種分泌型蛋白,在細(xì)胞核、細(xì)胞膜等均發(fā)現(xiàn)OPN的表達(dá)分布,并參與了細(xì)胞的功能調(diào)節(jié)。近年來,OPN在腫瘤發(fā)生發(fā)展過程中發(fā)揮的作用日益引起人們關(guān)注。在肝癌、乳腺癌、胃癌和肺癌等多種癌組織中均發(fā)現(xiàn)OPN表達(dá)增加,并且在一些腫瘤轉(zhuǎn)移病人血液中亦出現(xiàn)高水平表達(dá)。OPN促進(jìn)腫瘤轉(zhuǎn)移可能是通過參與調(diào)節(jié)上皮間質(zhì)表型轉(zhuǎn)變而實現(xiàn)的。因此,在腫瘤轉(zhuǎn)移研究方面,對OPN的研究前景廣闊。本課題旨在研究My D88與OPN兩種分子在腫瘤細(xì)胞中的表達(dá),探討兩種分子對腫瘤細(xì)胞表型轉(zhuǎn)化及腫瘤轉(zhuǎn)移的作用與機(jī)制,并對其臨床意義加以闡釋。在前半部分,我們首先利用過表達(dá)慢病毒和sh RNA慢病毒改變My D88的表達(dá)水平,通過檢測細(xì)胞表型轉(zhuǎn)化相關(guān)標(biāo)志蛋白在蛋白質(zhì)水平和細(xì)胞內(nèi)定位的變化,以及對EMT相關(guān)轉(zhuǎn)錄因子的檢測,研究My D88在上皮、間質(zhì)表型轉(zhuǎn)化中的調(diào)控作用,并在肝癌臨床標(biāo)本中加以驗證。之后通過體外實驗檢測腫瘤干細(xì)胞相關(guān)標(biāo)志分子和體內(nèi)成瘤實驗發(fā)現(xiàn),My D88的高表達(dá)不但誘導(dǎo)發(fā)生EMT,對腫瘤細(xì)胞干性特征的表達(dá)也非常關(guān)鍵。之后我們探討My D88促進(jìn)EMT的內(nèi)在機(jī)制。通過激酶活性檢測、免疫共沉淀實驗、細(xì)胞表型標(biāo)志蛋白檢測和體內(nèi)腫瘤轉(zhuǎn)移等實驗,發(fā)現(xiàn)My D88通過與PI3-K的p85調(diào)節(jié)亞基直接結(jié)合,激活PI3-K/Akt/GSK-3β/Snail信號通路,促進(jìn)EMT和腫瘤轉(zhuǎn)移。最后,我們檢測了肝癌細(xì)胞株和肝癌臨床標(biāo)本中My D88和p-Akt的表達(dá)情況,對其相關(guān)性和兩者對腫瘤患者預(yù)后的影響進(jìn)行了統(tǒng)計學(xué)分析,提示My D88表達(dá)水平和Akt磷酸化水平升高促進(jìn)肝癌轉(zhuǎn)移,并且綜合分析My D88和p-AKT對肝癌預(yù)后判斷具有更好價值。在后半部分,我們主要檢測OPN在腫瘤細(xì)胞中的表達(dá)分布,研究不同表達(dá)形式的OPN對細(xì)胞表型轉(zhuǎn)化的作用,并對轉(zhuǎn)移灶中OPN轉(zhuǎn)入細(xì)胞核表達(dá)的機(jī)制進(jìn)行探討。我們首先檢測多種腫瘤細(xì)胞中OPN的表達(dá)定位,發(fā)現(xiàn)在腫瘤細(xì)胞除了表達(dá)經(jīng)典的分泌型OPN,還表達(dá)僅分布于細(xì)胞核的OPN。緊接著,利用sh RNA慢病毒和過表達(dá)慢病毒調(diào)控OPN的表達(dá)水平,通過檢測細(xì)胞表型轉(zhuǎn)化相關(guān)標(biāo)志分子在蛋白質(zhì)水平和細(xì)胞內(nèi)定位的變化,以及細(xì)胞表型轉(zhuǎn)化相關(guān)轉(zhuǎn)錄因子的變化,研究不同形式OPN對細(xì)胞表型轉(zhuǎn)化的作用。我們發(fā)現(xiàn)分泌型OPN和細(xì)胞核型OPN作用不同:分泌型OPN促進(jìn)腫瘤細(xì)胞發(fā)生EMT,而細(xì)胞核型OPN誘導(dǎo)MET發(fā)生。我們前期發(fā)現(xiàn)細(xì)胞核型OPN誘導(dǎo)MET發(fā)生的過程中,AKT1/mi R-429/ZEB軸起關(guān)鍵作用。在此我們繼續(xù)探討細(xì)胞核型OPN調(diào)控AKT1表達(dá)的機(jī)制。通過雙熒光素酶報告基因?qū)嶒灐⒚庖邿晒怆p染色、免疫共沉淀等實驗,發(fā)現(xiàn)細(xì)胞核型OPN直接結(jié)合HIF2α,阻斷HIF2α在轉(zhuǎn)錄水平對AKT1的表達(dá)抑制,這種作用使得mi R-429表達(dá)上調(diào),從而可以作用于ZEB誘導(dǎo)細(xì)胞發(fā)生MET。我們前期通過動物體內(nèi)實驗和檢測肝癌臨床標(biāo)本發(fā)現(xiàn),在原發(fā)灶中OPN主要表達(dá)在細(xì)胞質(zhì),誘導(dǎo)EMT促進(jìn)腫瘤轉(zhuǎn)移擴(kuò)散;在轉(zhuǎn)移灶中OPN轉(zhuǎn)入細(xì)胞核中表達(dá)并誘導(dǎo)MET,促進(jìn)癌細(xì)胞定植形成轉(zhuǎn)移灶。之后,我們探討了轉(zhuǎn)移灶中誘發(fā)OPN轉(zhuǎn)入細(xì)胞核內(nèi)的機(jī)制。通過皮下腫瘤轉(zhuǎn)移實驗,收集不同時期肺組織用于抗體芯片檢測,我們發(fā)現(xiàn)Leptin、FGFa和VEGF三種變化明顯的細(xì)胞因子。刺激細(xì)胞并檢測OPN定位變化,篩選出誘發(fā)OPN轉(zhuǎn)入細(xì)胞核分布的細(xì)胞因子VEGF。之后通過檢測OPN修飾水平的改變、激酶抑制、抗體中和等實驗,我們證明VEGF通過KDR/PLCγ/PKC路徑促使OPN轉(zhuǎn)入細(xì)胞核,進(jìn)而誘導(dǎo)MET和轉(zhuǎn)移灶形成。本課題通過對My D88與OPN兩種分子的研究,闡述了細(xì)胞表型轉(zhuǎn)化(EMT和MET)促進(jìn)腫瘤轉(zhuǎn)移的新機(jī)制。我們證明了My D88可以在不依賴Toll受體的情況下,直接與PI3-K的p85亞基結(jié)合,啟動下游信號通路,誘導(dǎo)細(xì)胞發(fā)生EMT,促進(jìn)腫瘤生長和轉(zhuǎn)移;我們揭示了腫瘤細(xì)胞中細(xì)胞核型OPN的表達(dá)分布、不同表達(dá)形式的OPN對細(xì)胞表型轉(zhuǎn)化的調(diào)控作用,并發(fā)現(xiàn)轉(zhuǎn)移灶微環(huán)境中細(xì)胞因子的變化促使OPN轉(zhuǎn)入細(xì)胞核表達(dá),通過誘發(fā)MET促進(jìn)腫瘤細(xì)胞定植和形成轉(zhuǎn)移灶。這些研究或可為腫瘤轉(zhuǎn)移的研究提供全新的依據(jù)。
[Abstract]:Malignant tumor grows fast, has invasion and invasion ability, and often has distant metastasis. Tumor metastasis refers to the process of tumor cells from the original site, through the blood vessels, lymphatic channels or body cavity, and finally to the other parts of the body to continue to grow and proliferate. Tumor metastasis is the culprit of high mortality in patients with malignant tumor. The transformation process between the epithelioid and interstitial like phenotype is closely related to many physiological and pathological processes, such as embryo development, tumor metastasis, and so on. When the tumor cells undergo epithelial mesenchymal transition (epithelial-mesenchymal transition, EMT), the intercellular adhesion connectivity is reduced and the polarity is reduced. In the late stage of tumor metastasis, the tumor cells undergo interstitial epithelial transformation (mesenchymal-epithelial transition, MET), reshape the epithelioid phenotype and promote metastatic foci in the late stage of tumor metastasis. It can be considered that EMT and MET are occurring at different stages of tumor metastasis. One of the important markers of cell phenotypic transformation is the change in the expression level of cell adhesion molecule E- cadherin (E-cadherin), which is considered as a marker of epithelial phenotype. In addition, some markers of interstitial like phenotypes, such as vimentin (Vimentin), N- cadherin (N-cadherin), and alpha smooth muscle actin (alpha -smoo) The changes in the expression level of th muscle actin, alpha -SMA also reflect cell phenotype transformation. As the key cohesive protein of the inflammatory signaling pathway of the Toll like receptor, the myeloid differentiation factor 88 (Myeloid differentiation factor 88 or Myeloid differentiation primary response 88, for short), plays an important signal turn. Guidance. Many studies have shown that My D88 is elevated in a variety of tumor tissues and promotes the development of tumors through an inflammatory response pathway. Recent studies have found that My D88 can also regulate tumor development through non inflammatory pathways through the Toll like receptor mediated inflammatory pathway. After immunohistochemical staining of 110 hepatocellular carcinoma tissues, it was found that the expression of My D88 in the cancer tissues was higher than that of the corresponding para cancerous tissue, and the high expression of My D88 was closely related to the poor prognosis of the liver cancer patients. In addition, the earlier results showed that the high expression of My D88 could promote the growth and metastasis of the tumor. Therefore, the study of the high expression of My D88 can promote the growth and metastasis of the tumor. The high expression of My D88 in tumor cells how to promote tumor metastasis through non inflammatory pathways is the key problem to be solved in this study. Osteopontin (OPN) is generally considered to be a secretory phosphorylated glycoprotein, and researchers do find that the biological activity of OPN secreted out of cells is very diverse. To find that OPN is not only a secretory protein, the expression distribution of OPN is found in the cell nucleus and cell membrane, and the function regulation of the cells is involved. In recent years, the role of OPN in the development of tumor has attracted more and more attention. The expression of OPN is increased in many kinds of cancer tissues such as liver cancer, breast cancer, gastric cancer and lung cancer. There is also a high level of expression of.OPN in the blood of some patients with tumor metastasis, which may be achieved by regulating the phenotype of epithelial mesenchymal transition. Therefore, the study of tumor metastasis has a broad prospect for the study of OPN. The purpose of this study is to study the expression of two molecules of My D88 and OPN in tumor cells, and explore two In the first half, we use the expression of lentivirus and sh RNA lentivirus to change the expression level of My D88 by detecting the changes in the protein level and intracellular localization of the egg white by the cell phenotype transformation. And the detection of EMT related transcription factors, study the regulatory role of My D88 in epithelial and interstitial phenotypic transformation, and verify it in the clinical specimens of liver cancer. After the detection of tumor stem cell related markers and in vivo tumorigenesis experiments in vitro, the high expression of My D88 not only induces the occurrence of EMT, but also the dry character of the tumor cells. The expression is also crucial. Then we explore the intrinsic mechanism of My D88 to promote EMT. Through the experiments of kinase activity detection, immunoprecipitation experiment, cell phenotype marker protein detection and tumor metastasis in vivo, we found that My D88 activates PI3-K /Akt/GSK-3 beta /Snail signaling pathway through the p85 regulated subunit of PI3-K, and promotes EMT and tumor turn. Finally, we detected the expression of My D88 and p-Akt in the liver cancer cell lines and the clinical specimens of liver cancer, and analyzed the correlation and the effect of the two on the prognosis of the tumor patients. It was suggested that the expression level of My D88 and the increase of Akt phosphorylation level promoted the metastasis of liver cancer, and the prognosis of the liver cancer was judged by My D88 and p-AKT. It is of better value. In the second half, we mainly examine the expression distribution of OPN in tumor cells, study the effect of different expressions of OPN on cell phenotype transformation, and discuss the mechanism of OPN transfer to the nuclear expression in the metastases. We first detected the expression of OPN in various tumor cells, and found that the tumor cells were found to be removed from the tumor cells. The expression of the classical secretory OPN, and the expression of the OPN. only distributed in the nucleus, using the SH RNA lentivirus and the overexpression of lentivirus to regulate the expression level of OPN, the changes in the protein level and intracellular localization of the cell phenotype transformation markers and the changes of the related transcription factors of the cell phenotype transformation are studied. The effect of different forms of OPN on cell phenotype transformation. We have found that secretory OPN and cell nuclear type OPN are different: secretory OPN promotes EMT, and cell nuclear OPN induces MET. We found that AKT1/mi R-429 /ZEB axis plays a key role in the process of cell nuclear OPN induced MET. The mechanism of AKT1 expression by cytoplasmic OPN regulation. Through double luciferase reporter gene experiment, immunofluorescence double staining and immunoprecipitation experiments, it was found that the cell nuclear OPN was directly combined with HIF2 alpha, blocking the inhibition of the expression of HIF2 alpha at the transcriptional level of AKT1. This effect made the MI R-429 table up regulation, which could be used to induce MET in ZEB induced MET. We found that OPN was mainly expressed in the cytoplasm and induced EMT to promote the metastasis and diffusion of tumor in the primary foci, and OPN was transferred into the nucleus to express and induce MET in the metastatic foci, and promote the metastasis of cancer cells to form the metastasis. After that, we explored the induction of OPN into the nucleus in the metastases. Internal mechanism. Through the subcutaneous tumor metastasis experiment, we collect different period lung tissues for antibody chip detection. We found three kinds of cytokine that have obvious changes in Leptin, FGFa and VEGF, stimulate the cell and detect the change of OPN location, and screen the change of the OPN modification level after screening the cytokine VEGF. that induces the transfer of OPN to the nucleus distribution. Kinase inhibition, antibody neutralization and other experiments, we have demonstrated that VEGF induces OPN into the nucleus through the KDR/PLC gamma /PKC pathway, and then induces the formation of MET and metastatic foci. This topic illustrates the new mechanism of cell phenotype transformation (EMT and MET) to promote tumor metastasis through the study of two molecules of My D88 and OPN. In the case of the receptor, it combines with the p85 subunit of PI3-K directly to initiate the downstream signal pathway, induce the cell to develop EMT, promote the growth and metastasis of the tumor; we reveal the expression distribution of the cell nuclear OPN in the tumor cells, the regulation of the different expressions of OPN on the cell phenotype transformation, and the change of the cytokines in the microenvironment of the metastases. It promotes the transfer of OPN into the nuclear expression, and promotes tumor cell colonization and metastasis by inducing MET. These studies may provide a new basis for the study of tumor metastasis.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R73-37

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