Epimorphin在正常与异常肝细胞发育中的作用及其调控机制的研究
发布时间：2018-07-24 19:18
【摘要】：肝脏是一个非常复杂的异质性器官,肝实质细胞要受到周围至少七种以上基质细胞(如肝星状细胞、Kupffer细胞及窦状内皮细胞等)及其分泌的细胞外成分构成的微环境(microenvironment)的支持,这些微环境成分主要包括可溶性细胞因子、不可溶性细胞外基质(ECM)和细胞-细胞间相互作用。肝脏在正常发育的情况下,肝实质细胞会受到其所处微环境严密而有序地调控,行使其正常的生理功能;微环境成分一旦改变或受到破坏,这些实质细胞便会向异常方向发育,最终导致炎症、纤维化甚至肿瘤的发生。本论文主要研究肝脏微环境中特异性表达在胆板间质表面的一个重要蛋白——表皮形态发生素(EPM)在肝脏正常与异常发育中的作用及其调控机制。 一、Epimorphin调控肝干细胞向胆管上皮分化的分子机制 肝实质细胞除了占绝对主体的肝上皮细胞外还包括胆管上皮细胞,这两类细胞在发育上具有共同的前体细胞,即一直以来受到科学家广泛关注的存在于成体肝脏而且仍然保持未分化状态的少量肝干细胞。然而,迄今为止,人们对于肝干细胞确切的特征和生理学功能仍然缺乏深入了解。肝干细胞发育的命运离不开其所处的微环境,肝干细胞的微环境影响其增殖、分化和形态形成等生命现象。已有研究表明,肝基质细胞中的肝星状细胞(HSC)能够特异性分泌一种叫做表皮形态发生素(EPM)的膜蛋白,该蛋白能够调控多种组织上皮细胞腺管形态的发生,包括乳腺、胰腺、肺、胆囊、毛囊、皮肤、小肠等。EPM在肝损伤后修复后期表达上调,并且参与肝干细胞的分化过程。我室近期的研究表明,非可溶性EPM(i-EPM)能够通过介导细胞的粘着斑组装和引导应力纤维(SF)的排布,调节细胞大鼠肝干细胞(WB)有丝分裂方向,从生物力学角度证明了WB向胆管分化的新的机制。但是,EPM介导WB向胆管分化的相关分子机制并不清楚。基于以上研究基础,我们第一部分的工作旨在寻找和验证EPM蛋白调控WB细胞向胆管形态发生的分子机制。 我们首先构建一个EPM诱导肝干细胞向胆管方向分化的模型:即将高表达外源性EPM蛋白的PT67细胞(PT67EPM)作为基质细胞,和肝干细胞WB进行接触共培养。在共培养的诱导模型中,WB细胞能够形成明显管腔样结构;RT-PCR和Western blot检测结果表明,管腔结构的的胆管相关表面标记Yp,CK19,Cx43,GGT(IV),Aquaporin-1都有一定程度的上调,尤其是胆管较为特异的表面标记CK19和GGT(IV)的表达明显上调;值得关注的是,免疫荧光结果显示高表达的CK19和GGT蛋白仅限于实验组中具有拉伸结构的WB细胞。以上结果证明EPM能够促进WB细胞向胆管方向分化。进一步通过细胞免疫荧光的方法处理共培养细胞组,并在激光共聚焦显微镜(CLSM)下观察细胞应力纤维(SF)的分布情况,结果发现EPM可以引起WB细胞的应力纤维的主要成分肌丝蛋白(F-actin)排列发生改变,同时发现与细胞形态变化及细胞骨架密切相关的小G蛋白RhoA(包括总RhoA蛋白和GTP-RhoA)明显上调,与此同时,Western blot的方法检测结果表明EPM作用后FAK和ERK1/2磷酸化在EPM诱导过程中表达明显上调。在此基础上,我们我们构建了RhoA失活的WB细胞株(WBRhoA-DN),发现RhoA的激活对于EPM促进FAK和ERK1/2磷酸化以及肝干细胞向胆管分化过程所必需。进一步双荧光素酶报告系统和染色质免疫共沉淀(ChIP)结果表明:EPM很可能通过C/EBPβ介导调节GGT IV型启动子和GGT V型启动子的活性,从而加强GGT启动子IV的表达上调,最终表现为促进肝干细胞向胆管分化。以上研究表明EPM通过RhoA和FAK-ERK信号通路激活C/EBPβ并调节胆管上皮细胞特异性基因GGT IV的表达,在肝脏正常发育中发挥着重要的作用。 二、Epimorphin对人肝细胞癌细胞浸润和转移的作用及其机制研究 近年来,越来越多的研究认识到肿瘤与其微环境之间有着非常重要的对话(cross-talk);基质细胞被募集到肿瘤周围并被激活,从而促进了肿瘤细胞的增殖、侵袭和转移。肝脏从正常到异常转变的过程中,基质细胞尤其是肝星状细胞(HSC)从静息态转变为激活态,数量显著增加,最终引起上皮细胞调控发生紊乱。HSC是肝癌微环境中重要的基质细胞之一,它是肝细胞癌(HCC)细胞ECM的主要来源。HSC能够通过旁分泌方式分泌很多重要的蛋白(如生长因子,信号分子和可溶性蛋白)来调控HCC的进程,其中也就有可能包括我们非常关注的EPM。EPM发挥作用所依赖的FAK-ERK通路已被证明在肿瘤发生发展中扮演非常重要的角色,提示EPM很有可能参与微环境对HCC发生与发展的调控。目前关于EPM与肿瘤的关系,只有两项独立的研究报道:一项研究认为外源性EPM的存在能够促进小鼠乳腺上皮细胞产生乳腺增生并诱发高发生率的乳腺癌;另外一项研究结果认为EPM基因敲除能够明显地降低小鼠慢性结肠炎引起的结肠癌的发生。虽然EPM对于肝脏发育和肝再生的作用非常重要,然而,EPM在肝癌中的作用还未有过报道。因此,我们第二部分工作开展了EPM在肝癌中的作用及其信号通路的研究。 为了验证EPM在HCC的生物学功能,我们首先构建了稳定表达外源性EPM的肝细胞癌细胞系,命名为97H-pIEPM和97L-pIEPM。通过MTT法,克隆形成实验以及裸鼠皮下成瘤实验分别检测了其增殖能力,结果表明EPM对肝癌细胞的增殖能力没有明显影响。我们又通过Matrigel侵袭实验和经典的肝原位转移模型(orthotopical liver implantation model)检测了EPM对于肝癌细胞转移能力的影响,体外和体内实验的所有结果一致表明EPM可以促进肝癌细胞体内浸润和转移能力。为了验证EPM如何促进HCC的侵袭能力,我们通过RT-PCR方法对与肿瘤侵袭密切相关的基质金属蛋白酶(MMPs)家族成员进行了筛选,发现EPM存在的情况下肝癌细胞中MMP-9的表达上调。随后通过Real-time PCR和Western blot方法从基因和蛋白水平进行分析,证明了肝癌细胞中MMP-9的确是EPM的作用的一个靶点。为了进一步研究EPM激活MMP-9的表达机制,我们通过Western blot方法进一步发现EPM在促进HCC细胞侵袭的过程中,FAK和ERK这两个重要的信号通路蛋白的磷酸化水平明显提高,对ERK和FAK分别进行功能阻断后,MMP-9的表达都明显受到抑制,同时肝癌细胞的侵袭能力明显下降,有力地说明MMP-9是受FAK-ERK信号通路正向调控而影响细胞侵袭的。 综上所述,我们的研究表明:EPM在肝脏正常发育中通过RhoA-FAK- ERK-C/EBPβ信号通路调控肝干细胞向胆管分化。在肝癌发生中,激活的肝星状细胞分泌的EPM能够通过激活FAK-ERK-MMP-9信号通路促进肝细胞癌细胞的浸润和侵袭。我们的研究不仅为研究细胞外基质ECM对于维持肝脏正常发育以及肝上皮形态的发生机制提供了新的理论支持,而且为研究肝细胞癌转移的治疗方案提供了一个新的理论参考。
[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.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R363
本文编号：2142388
[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.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R363
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