【摘要】：肝臟是一個非常復(fù)雜的異質(zhì)性器官,肝實質(zhì)細(xì)胞要受到周圍至少七種以上基質(zhì)細(xì)胞(如肝星狀細(xì)胞、Kupffer細(xì)胞及竇狀內(nèi)皮細(xì)胞等)及其分泌的細(xì)胞外成分構(gòu)成的微環(huán)境(microenvironment)的支持,這些微環(huán)境成分主要包括可溶性細(xì)胞因子、不可溶性細(xì)胞外基質(zhì)(ECM)和細(xì)胞-細(xì)胞間相互作用。肝臟在正常發(fā)育的情況下,肝實質(zhì)細(xì)胞會受到其所處微環(huán)境嚴(yán)密而有序地調(diào)控,行使其正常的生理功能;微環(huán)境成分一旦改變或受到破壞,這些實質(zhì)細(xì)胞便會向異常方向發(fā)育,最終導(dǎo)致炎癥、纖維化甚至腫瘤的發(fā)生。本論文主要研究肝臟微環(huán)境中特異性表達(dá)在膽板間質(zhì)表面的一個重要蛋白——表皮形態(tài)發(fā)生素(EPM)在肝臟正常與異常發(fā)育中的作用及其調(diào)控機制。 一、Epimorphin調(diào)控肝干細(xì)胞向膽管上皮分化的分子機制 肝實質(zhì)細(xì)胞除了占絕對主體的肝上皮細(xì)胞外還包括膽管上皮細(xì)胞,這兩類細(xì)胞在發(fā)育上具有共同的前體細(xì)胞,即一直以來受到科學(xué)家廣泛關(guān)注的存在于成體肝臟而且仍然保持未分化狀態(tài)的少量肝干細(xì)胞。然而,迄今為止,人們對于肝干細(xì)胞確切的特征和生理學(xué)功能仍然缺乏深入了解。肝干細(xì)胞發(fā)育的命運離不開其所處的微環(huán)境,肝干細(xì)胞的微環(huán)境影響其增殖、分化和形態(tài)形成等生命現(xiàn)象。已有研究表明,肝基質(zhì)細(xì)胞中的肝星狀細(xì)胞(HSC)能夠特異性分泌一種叫做表皮形態(tài)發(fā)生素(EPM)的膜蛋白,該蛋白能夠調(diào)控多種組織上皮細(xì)胞腺管形態(tài)的發(fā)生,包括乳腺、胰腺、肺、膽囊、毛囊、皮膚、小腸等。EPM在肝損傷后修復(fù)后期表達(dá)上調(diào),并且參與肝干細(xì)胞的分化過程。我室近期的研究表明,非可溶性EPM(i-EPM)能夠通過介導(dǎo)細(xì)胞的粘著斑組裝和引導(dǎo)應(yīng)力纖維(SF)的排布,調(diào)節(jié)細(xì)胞大鼠肝干細(xì)胞(WB)有絲分裂方向,從生物力學(xué)角度證明了WB向膽管分化的新的機制。但是,EPM介導(dǎo)WB向膽管分化的相關(guān)分子機制并不清楚�；谝陨涎芯炕A(chǔ),我們第一部分的工作旨在尋找和驗證EPM蛋白調(diào)控WB細(xì)胞向膽管形態(tài)發(fā)生的分子機制。 我們首先構(gòu)建一個EPM誘導(dǎo)肝干細(xì)胞向膽管方向分化的模型:即將高表達(dá)外源性EPM蛋白的PT67細(xì)胞(PT67EPM)作為基質(zhì)細(xì)胞,和肝干細(xì)胞WB進(jìn)行接觸共培養(yǎng)。在共培養(yǎng)的誘導(dǎo)模型中,WB細(xì)胞能夠形成明顯管腔樣結(jié)構(gòu);RT-PCR和Western blot檢測結(jié)果表明,管腔結(jié)構(gòu)的的膽管相關(guān)表面標(biāo)記Yp,CK19,Cx43,GGT(IV),Aquaporin-1都有一定程度的上調(diào),尤其是膽管較為特異的表面標(biāo)記CK19和GGT(IV)的表達(dá)明顯上調(diào);值得關(guān)注的是,免疫熒光結(jié)果顯示高表達(dá)的CK19和GGT蛋白僅限于實驗組中具有拉伸結(jié)構(gòu)的WB細(xì)胞。以上結(jié)果證明EPM能夠促進(jìn)WB細(xì)胞向膽管方向分化。進(jìn)一步通過細(xì)胞免疫熒光的方法處理共培養(yǎng)細(xì)胞組,并在激光共聚焦顯微鏡(CLSM)下觀察細(xì)胞應(yīng)力纖維(SF)的分布情況,結(jié)果發(fā)現(xiàn)EPM可以引起WB細(xì)胞的應(yīng)力纖維的主要成分肌絲蛋白(F-actin)排列發(fā)生改變,同時發(fā)現(xiàn)與細(xì)胞形態(tài)變化及細(xì)胞骨架密切相關(guān)的小G蛋白RhoA(包括總RhoA蛋白和GTP-RhoA)明顯上調(diào),與此同時,Western blot的方法檢測結(jié)果表明EPM作用后FAK和ERK1/2磷酸化在EPM誘導(dǎo)過程中表達(dá)明顯上調(diào)。在此基礎(chǔ)上,我們我們構(gòu)建了RhoA失活的WB細(xì)胞株(WBRhoA-DN),發(fā)現(xiàn)RhoA的激活對于EPM促進(jìn)FAK和ERK1/2磷酸化以及肝干細(xì)胞向膽管分化過程所必需。進(jìn)一步雙熒光素酶報告系統(tǒng)和染色質(zhì)免疫共沉淀(ChIP)結(jié)果表明:EPM很可能通過C/EBPβ介導(dǎo)調(diào)節(jié)GGT IV型啟動子和GGT V型啟動子的活性,從而加強GGT啟動子IV的表達(dá)上調(diào),最終表現(xiàn)為促進(jìn)肝干細(xì)胞向膽管分化。以上研究表明EPM通過RhoA和FAK-ERK信號通路激活C/EBPβ并調(diào)節(jié)膽管上皮細(xì)胞特異性基因GGT IV的表達(dá),在肝臟正常發(fā)育中發(fā)揮著重要的作用。 二、Epimorphin對人肝細(xì)胞癌細(xì)胞浸潤和轉(zhuǎn)移的作用及其機制研究 近年來,越來越多的研究認(rèn)識到腫瘤與其微環(huán)境之間有著非常重要的對話(cross-talk);基質(zhì)細(xì)胞被募集到腫瘤周圍并被激活,從而促進(jìn)了腫瘤細(xì)胞的增殖、侵襲和轉(zhuǎn)移。肝臟從正常到異常轉(zhuǎn)變的過程中,基質(zhì)細(xì)胞尤其是肝星狀細(xì)胞(HSC)從靜息態(tài)轉(zhuǎn)變?yōu)榧せ顟B(tài),數(shù)量顯著增加,最終引起上皮細(xì)胞調(diào)控發(fā)生紊亂。HSC是肝癌微環(huán)境中重要的基質(zhì)細(xì)胞之一,它是肝細(xì)胞癌(HCC)細(xì)胞ECM的主要來源。HSC能夠通過旁分泌方式分泌很多重要的蛋白(如生長因子,信號分子和可溶性蛋白)來調(diào)控HCC的進(jìn)程,其中也就有可能包括我們非常關(guān)注的EPM。EPM發(fā)揮作用所依賴的FAK-ERK通路已被證明在腫瘤發(fā)生發(fā)展中扮演非常重要的角色,提示EPM很有可能參與微環(huán)境對HCC發(fā)生與發(fā)展的調(diào)控。目前關(guān)于EPM與腫瘤的關(guān)系,只有兩項獨立的研究報道:一項研究認(rèn)為外源性EPM的存在能夠促進(jìn)小鼠乳腺上皮細(xì)胞產(chǎn)生乳腺增生并誘發(fā)高發(fā)生率的乳腺癌;另外一項研究結(jié)果認(rèn)為EPM基因敲除能夠明顯地降低小鼠慢性結(jié)腸炎引起的結(jié)腸癌的發(fā)生。雖然EPM對于肝臟發(fā)育和肝再生的作用非常重要,然而,EPM在肝癌中的作用還未有過報道。因此,我們第二部分工作開展了EPM在肝癌中的作用及其信號通路的研究。 為了驗證EPM在HCC的生物學(xué)功能,我們首先構(gòu)建了穩(wěn)定表達(dá)外源性EPM的肝細(xì)胞癌細(xì)胞系,命名為97H-pIEPM和97L-pIEPM。通過MTT法,克隆形成實驗以及裸鼠皮下成瘤實驗分別檢測了其增殖能力,結(jié)果表明EPM對肝癌細(xì)胞的增殖能力沒有明顯影響。我們又通過Matrigel侵襲實驗和經(jīng)典的肝原位轉(zhuǎn)移模型(orthotopical liver implantation model)檢測了EPM對于肝癌細(xì)胞轉(zhuǎn)移能力的影響,體外和體內(nèi)實驗的所有結(jié)果一致表明EPM可以促進(jìn)肝癌細(xì)胞體內(nèi)浸潤和轉(zhuǎn)移能力。為了驗證EPM如何促進(jìn)HCC的侵襲能力,我們通過RT-PCR方法對與腫瘤侵襲密切相關(guān)的基質(zhì)金屬蛋白酶(MMPs)家族成員進(jìn)行了篩選,發(fā)現(xiàn)EPM存在的情況下肝癌細(xì)胞中MMP-9的表達(dá)上調(diào)。隨后通過Real-time PCR和Western blot方法從基因和蛋白水平進(jìn)行分析,證明了肝癌細(xì)胞中MMP-9的確是EPM的作用的一個靶點。為了進(jìn)一步研究EPM激活MMP-9的表達(dá)機制,我們通過Western blot方法進(jìn)一步發(fā)現(xiàn)EPM在促進(jìn)HCC細(xì)胞侵襲的過程中,FAK和ERK這兩個重要的信號通路蛋白的磷酸化水平明顯提高,對ERK和FAK分別進(jìn)行功能阻斷后,MMP-9的表達(dá)都明顯受到抑制,同時肝癌細(xì)胞的侵襲能力明顯下降,有力地說明MMP-9是受FAK-ERK信號通路正向調(diào)控而影響細(xì)胞侵襲的。 綜上所述,我們的研究表明:EPM在肝臟正常發(fā)育中通過RhoA-FAK- ERK-C/EBPβ信號通路調(diào)控肝干細(xì)胞向膽管分化。在肝癌發(fā)生中,激活的肝星狀細(xì)胞分泌的EPM能夠通過激活FAK-ERK-MMP-9信號通路促進(jìn)肝細(xì)胞癌細(xì)胞的浸潤和侵襲。我們的研究不僅為研究細(xì)胞外基質(zhì)ECM對于維持肝臟正常發(fā)育以及肝上皮形態(tài)的發(fā)生機制提供了新的理論支持,而且為研究肝細(xì)胞癌轉(zhuǎn)移的治療方案提供了一個新的理論參考。
[Abstract]:The liver is a very complex heterogeneous organ, and the liver parenchyma cells are supported by the support of at least seven or more stromal cells (such as hepatic stellate cells, Kupffer cells and sinus like endothelial cells) and their secreted extracellular components (microenvironment). These microenvironmental components mainly include soluble cytokines. The soluble extracellular matrix (ECM) and cell intercellular interaction. Liver parenchyma cells are regulated in a tight and orderly manner in the normal development of the liver, exercising their normal physiological functions. Once the microenvironmental components are changed or destroyed, these parenchymal cells will develop in the abnormal direction and eventually lead to inflammation. This paper mainly studies the role of epidermal morphogenetic (EPM) in the normal and abnormal development of the liver and its regulatory mechanism.
1. Epimorphin regulates the molecular mechanism of hepatic stem cells differentiating into bile duct epithelium.
In addition to the absolute main body of the hepatic epithelial cells, the hepatocytes also include the bile duct epithelial cells. These two types of cells have common precursor cells in development, that is, a small amount of liver stem cells that have been widely concerned by scientists in adult liver and still remain undifferentiated. The specific and physiological functions of the cells are still lacking in deep understanding. The fate of the liver stem cells can not be separated from its microenvironment, and the microenvironment of the liver stem cells affects its proliferation, differentiation and morphogenesis. It has been shown that the hepatic stellate cells (HSC) in the liver stromal cells can specifically secrete a kind of epidermis called the epidermis. The membrane protein of Morphin (EPM), which regulates the morphogenesis of a variety of tissue epithelial cells, includes mammary gland, pancreas, lung, gallbladder, hair follicle, skin, small intestine, and so on..EPM is up-regulated in the later period after liver injury and is involved in the differentiation of liver stem cells. Recent studies in my room have shown that non soluble EPM (i-EPM) can pass through. A new mechanism for the differentiation of WB into the bile duct is demonstrated from a biomechanical point of view. However, the molecular mechanism of the differentiation of the WB into the bile duct is not clear from the biomechanical angle. However, the first part of this study is based on the above research. The aim of the work is to find and verify the molecular mechanism of EPM protein regulating WB cell to bile duct morphogenesis.
We first constructed a model of EPM induced differentiation of hepatic stem cells into the bile duct: the PT67 cells (PT67EPM), which expressed exogenous EPM protein (PT67EPM), were used as matrix cells and co cultured with WB of liver stem cells. In the co culture induction model, WB cells could form a clear lumen like structure; RT-PCR and Western blot detection result table. The bile duct related surface markers Yp, CK19, Cx43, GGT (IV), and Aquaporin-1 were up regulated to a certain extent, especially the expression of the specific bile duct specific surface markers CK19 and GGT (IV). It is worth noting that the immunofluorescence results show that the high expression of CK19 and GGT proteins are limited to the tensile structure of WB in the experimental group. The above results showed that EPM could promote the differentiation of WB cells to the bile duct. The co cultured cell group was further treated by cell immunofluorescence, and the distribution of cell stress fiber (SF) was observed under the laser confocal microscope (CLSM). The results showed that EPM could cause the main component of myofilament protein (F) in the stress fiber of WB cells (F). -actin) changes in the arrangement of small G protein RhoA (including total RhoA protein and GTP-RhoA), which are closely related to cell morphologic changes and cytoskeleton. Meanwhile, the results of Western blot method detection showed that the phosphorylation of FAK and ERK1/2 was obviously up-regulated in EPM inducement after EPM action. On the basis of this, we and I We constructed the RhoA inactivated WB cell line (WBRhoA-DN). It was found that the activation of RhoA was necessary for EPM to promote FAK and ERK1/2 phosphorylation and to the differentiation of hepatic stem cells into the bile duct. The further double luciferase reporting system and chromatin immunoprecipitation (ChIP) results showed that EPM could be regulated by C/EBP beta mediated GGT IV type promoter. The activity of the type promoter enhances the up-regulated expression of the GGT promoter IV, which eventually promotes the differentiation of hepatic stem cells into the bile duct. The above study shows that EPM activates the C/EBP beta through the RhoA and FAK-ERK signaling pathways and regulates the expression of the specific gene GGT IV in the bile duct epithelial cells, which plays an important role in the normal development of the liver.
Two, the effect and mechanism of Epimorphin on invasion and metastasis of human hepatocellular carcinoma cells
In recent years, more and more studies have realized that there is a very important dialogue between the tumor and its microenvironment (cross-talk); the stromal cells are raised around the tumor and activated, thus promoting the proliferation, invasion and metastasis of the tumor cells. In the course of the liver from normal to abnormal, the stromal cells, especially the hepatic stellate cells (HSC), are quiet. The change of the interest state into the active state, the number of the.HSC is one of the important stromal cells in the microenvironment of liver cancer, which is one of the important stromal cells in the microenvironment of liver cancer. It is the main source of ECM in hepatocellular carcinoma (HCC) cells,.HSC can secrete a lot of important proteins (such as growth factors, signal molecules and soluble proteins) by paracrine. The process of controlling HCC, which is also likely to include the role of EPM.EPM, which we are very concerned with, has been shown to play a very important role in the development of cancer, suggesting that EPM is likely to participate in the regulation of the occurrence and development of HCC in microenvironment. There are only two independent studies on the relationship between EPM and cancer. A study suggests that the presence of exogenous EPM can promote mammary hyperplasia in mouse mammary glands and induce high incidence of breast cancer; another study found that EPM gene knockout could significantly reduce the occurrence of colon cancer in mice with chronic colitis. Although EPM is for liver development and liver regeneration It is very important, however, that the role of EPM in liver cancer has not been reported. Therefore, the second part of our work has carried out the study of the role of EPM in liver cancer and its signaling pathway.
In order to verify the biological function of EPM in HCC, we first constructed a hepatocellular carcinoma cell line that stably expressed exogenous EPM, which was named 97H-pIEPM and 97L-pIEPM. by MTT, clone formation and subcutaneous tumorigenesis in nude mice. The results showed that EPM had no significant effect on the proliferation of hepatoma cells. We also detected the effect of EPM on the metastatic capacity of hepatoma cells through the Matrigel invasion experiment and the classical orthotopical liver implantation model. All the results in vitro and in vivo showed that EPM could promote the invasion and metastasis of liver cancer cells. Ability to attack, we screened the members of the matrix metalloproteinase (MMPs) family closely related to tumor invasion by RT-PCR method. We found that the expression of MMP-9 in the hepatoma cells was up regulated under the presence of EPM. Then the Real-time PCR and Western blot methods were used to analyze the gene and egg white level, which proved MMP-9 in the liver cancer cells. It is indeed a target for the role of EPM. In order to further study the expression mechanism of EPM activation of MMP-9, we further found that the phosphorylation level of the two important signaling proteins of FAK and ERK increased significantly in the process of promoting the invasion of HCC cells by the Western blot method. The MMP-9, respectively, was blocked by ERK and FAK, respectively. The expression of MMP-9 was obviously inhibited and the invasion ability of hepatoma cells decreased significantly, which strongly indicated that the cell invasion was influenced by the positive regulation of FAK-ERK signaling pathway.
In summary, our study shows that EPM regulates the differentiation of hepatic stem cells into the bile duct through the RhoA-FAK- ERK-C/EBP beta signaling pathway in normal development of the liver. In the occurrence of liver cancer, the activation of the EPM secreted by hepatic stellate cells can promote the invasion and invasion of hepatocellular carcinoma cells by activating the FAK-ERK-MMP-9 signaling pathway. Our study not only The study of extracellular matrix ECM provides new theoretical support for the maintenance of normal liver development and the pathogenesis of liver epithelium, and provides a new theoretical reference for the study of the treatment of hepatocellular carcinoma metastasis.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2011
【分類號】：R363

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