肝细胞癌细胞系的细胞角蛋白异常表达及层粘连蛋白对细胞角蛋白19表达的诱导
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摘要
正常成人肝组织中肝细胞和胆管上皮细胞的细胞角蛋白（cytokeratin，CK）组
型不同，前者仅由CK8和CK18组成，称为“肝细胞型”CK，胆管上皮细胞除了含
有这两种CK以外，还有CK7和CK19，称为“胆管型”CK。过去认为这种差别可在
各种病理条件下甚至能在它们形成的肿瘤中得到保持，并作为各自细胞谱系的标志而
用于肝脏肿瘤的鉴别诊断中。近年来发现，肝细胞的CK组型在某些生理和病理状态下
也可发生改变，出现CK19单独或伴有CK7的表达，称为肝细胞CK的异常表达。近
年来发表的数据提示，肝细胞CK异常表达可能与层粘连蛋白（Laminin，LN）等细胞
外基质成分的异常沉积有关。
为了进一步探讨肝细胞癌中CK的异常表达及其可能机制，我们进行了以下探讨：
（1）应用能特异识别CK8、18、7、19、LN及LN受体的特异性抗体对6株肝细胞癌细
胞系的CK、LN和LN受体的表达进行免疫细胞化学观察；（2）应用激光共聚焦显微镜
技术对肝细胞癌细胞系的CK19和LN表达情况进行观察；（3）通过免疫印迹反应对肝
细胞癌细胞系的CK18、7、19的表达进行了检测；（4）应用LN诱导肝细胞癌细胞系中
CK19的表达；（5）应用抗LN多克隆抗体阻断LN对肝细胞癌细胞系CK19表达的诱导
作用。结果发现，6株肝细胞癌细胞系CK8和CK18表达全部为阳性；CK7也全部为
阳性，但强度不同；其中4株细胞系CK19为阳性，其余2株为阴性；LN免疫组化
结果与CK19的结果一致，CK19和LN阳性物质共定位于同一癌细胞的细胞质中，所
有LN明确阳性的细胞都为CK19免疫反应阳性；所有6株细胞系都表达LN受体。当
第四军医大学硕士学位论文
接种于加有LN的培养液中时，原来CK19阴性的肝细胞癌细胞系出现CK19的表达，
阳性程度与剂量具有一定程度的相关性。上述LN对CK19表达的诱导作用可以被LN
抗体阻断。
本研究进一步证实了肝细胞癌细胞系的CK表达确实不同于正常肝细胞，常出现
CK7和CK19的异常表达；发现CK19和LN表达于相同的细胞系及细胞亚群，二者常
共存于同一细胞中；LN对肝细胞癌细胞系CK19的异常表达确实具有诱导作用，这种
作用能够被LN抗体所阻断。我们的观察明确了LN异常沉积在肝细胞CK异常表达表
型的发生和维持中的关键作用，对深入了解肝细胞的分化及癌变机制，指导肝脏肿瘤
的鉴别诊断都有重要意义。
In normal adult liver, the cytokeratin (CK) expression pattern in hepatocytes is different from that in ductal biliary cells. Intermidiate filament (IF) cytoskeleton of hepatocytes consists of only CK8 and CK18 ("hepatocyte type" CKs), while the bile ductal and ductular cells contain CK7 and CK19 ("bile duct type" CKs) hi addition to CKS and CK18. It was believed that the difference between these two types of liver cells in their CK patterns could be maintained under all pathological conditions, even after neoplastic transformation. Therefore, it appears that CKs can serve as important "lineage markers" in differential diagnosis of liver neoplasms. However, accumulating data indicates that CK pattern in hepatocytes can change under some pathological conditions. Expression of CK19, with or without CK7, can be observed in hepatocyte in diseased human livers, which is called abnormal CK expression. According to the data from our and other laboratories, abnormal deposition of extracellular matrix components, particularly laminin (LN) may play an important role in this process.
In the present study, five approaches were used to clarify relationship between expression of CK19 and LN in six hepatocellular cell lines growing in vitro. (l)An immunocytochemical assay conducted demonstrate CKS, CK18, CK7, CK19, LN and LN receptor in hepatocellular carcinoma cell lines; (2) expression of CK19 and LN in hepatocellular carcinoma cell lines were cojocalized using a confocal laser scanning microscopy technique; (3) expression of CK18, CK7 and CK19 were also detected via Western blotting in heaptocellular carcinoma
cell lines; (4) expression of CK19 was induced by administration of purified LN protein into the culture medium in two hepatocelular carcinoma cell lines formerly negative for CK19; (5) polyclonal antibodies against LN can block the induction effect of LN on the expression of CK19 in hepatocellular carcinoma cell lines.
It was found that CK8 and CK18 were expressed in all of the six cell lines examined. CK7 was also observed in all of them, but its level being different. CK19 was positive in four, and negative in two cell lines, which was correlative well to LN-immunoreactivity. The positive products of both molecules were demonstrated to be present in the same cells as demonstrated via laser confocal scanning microscopy. LN receptor was expressed in all of the six cell lines. With the LN protein added in culture medium, two hepatocellular carcinoma cell lines, formerly negative for CK19, began to express CK19. The reaction is dose-dependent. Polyclonal antibodies against LN that added in the cell culture medium could block the induction effect of LN.
Our data have demonstrated that abnormal expression of CK7 and CK19 occurred frequently in HCC cell lines, providing cell models for further understanding the mechanism of the abnormal CK19 expression in hepatocytic cells. Our previous reports have suggested that CK19 expression in liver parenchyma cells is associated with abnormal LN deposition. The concept has been verified in this study by the following findings: (1) the correlative expression and colocalization of CK19 and LN in HCC cell lines expressing LN receptors; (2) the induction of CK19 in two cell lines formerly negative for both CK19 and LN by adding a certain amount of LN directly into the culture medium; and (3) the successful blockage of CK19 expression in two cells lines by a medium containing LN antibodies. These data are helpful for the further understanding of hepatocyte differentiation and hepatocarcinogenesis, and are important for differential diagnosis of liver neoplasms.
型不同，前者仅由CK8和CK18组成，称为“肝细胞型”CK，胆管上皮细胞除了含
有这两种CK以外，还有CK7和CK19，称为“胆管型”CK。过去认为这种差别可在
各种病理条件下甚至能在它们形成的肿瘤中得到保持，并作为各自细胞谱系的标志而
用于肝脏肿瘤的鉴别诊断中。近年来发现，肝细胞的CK组型在某些生理和病理状态下
也可发生改变，出现CK19单独或伴有CK7的表达，称为肝细胞CK的异常表达。近
年来发表的数据提示，肝细胞CK异常表达可能与层粘连蛋白（Laminin，LN）等细胞
外基质成分的异常沉积有关。
为了进一步探讨肝细胞癌中CK的异常表达及其可能机制，我们进行了以下探讨：
（1）应用能特异识别CK8、18、7、19、LN及LN受体的特异性抗体对6株肝细胞癌细
胞系的CK、LN和LN受体的表达进行免疫细胞化学观察；（2）应用激光共聚焦显微镜
技术对肝细胞癌细胞系的CK19和LN表达情况进行观察；（3）通过免疫印迹反应对肝
细胞癌细胞系的CK18、7、19的表达进行了检测；（4）应用LN诱导肝细胞癌细胞系中
CK19的表达；（5）应用抗LN多克隆抗体阻断LN对肝细胞癌细胞系CK19表达的诱导
作用。结果发现，6株肝细胞癌细胞系CK8和CK18表达全部为阳性；CK7也全部为
阳性，但强度不同；其中4株细胞系CK19为阳性，其余2株为阴性；LN免疫组化
结果与CK19的结果一致，CK19和LN阳性物质共定位于同一癌细胞的细胞质中，所
有LN明确阳性的细胞都为CK19免疫反应阳性；所有6株细胞系都表达LN受体。当
第四军医大学硕士学位论文
接种于加有LN的培养液中时，原来CK19阴性的肝细胞癌细胞系出现CK19的表达，
阳性程度与剂量具有一定程度的相关性。上述LN对CK19表达的诱导作用可以被LN
抗体阻断。
本研究进一步证实了肝细胞癌细胞系的CK表达确实不同于正常肝细胞，常出现
CK7和CK19的异常表达；发现CK19和LN表达于相同的细胞系及细胞亚群，二者常
共存于同一细胞中；LN对肝细胞癌细胞系CK19的异常表达确实具有诱导作用，这种
作用能够被LN抗体所阻断。我们的观察明确了LN异常沉积在肝细胞CK异常表达表
型的发生和维持中的关键作用，对深入了解肝细胞的分化及癌变机制，指导肝脏肿瘤
的鉴别诊断都有重要意义。
In normal adult liver, the cytokeratin (CK) expression pattern in hepatocytes is different from that in ductal biliary cells. Intermidiate filament (IF) cytoskeleton of hepatocytes consists of only CK8 and CK18 ("hepatocyte type" CKs), while the bile ductal and ductular cells contain CK7 and CK19 ("bile duct type" CKs) hi addition to CKS and CK18. It was believed that the difference between these two types of liver cells in their CK patterns could be maintained under all pathological conditions, even after neoplastic transformation. Therefore, it appears that CKs can serve as important "lineage markers" in differential diagnosis of liver neoplasms. However, accumulating data indicates that CK pattern in hepatocytes can change under some pathological conditions. Expression of CK19, with or without CK7, can be observed in hepatocyte in diseased human livers, which is called abnormal CK expression. According to the data from our and other laboratories, abnormal deposition of extracellular matrix components, particularly laminin (LN) may play an important role in this process.
In the present study, five approaches were used to clarify relationship between expression of CK19 and LN in six hepatocellular cell lines growing in vitro. (l)An immunocytochemical assay conducted demonstrate CKS, CK18, CK7, CK19, LN and LN receptor in hepatocellular carcinoma cell lines; (2) expression of CK19 and LN in hepatocellular carcinoma cell lines were cojocalized using a confocal laser scanning microscopy technique; (3) expression of CK18, CK7 and CK19 were also detected via Western blotting in heaptocellular carcinoma
cell lines; (4) expression of CK19 was induced by administration of purified LN protein into the culture medium in two hepatocelular carcinoma cell lines formerly negative for CK19; (5) polyclonal antibodies against LN can block the induction effect of LN on the expression of CK19 in hepatocellular carcinoma cell lines.
It was found that CK8 and CK18 were expressed in all of the six cell lines examined. CK7 was also observed in all of them, but its level being different. CK19 was positive in four, and negative in two cell lines, which was correlative well to LN-immunoreactivity. The positive products of both molecules were demonstrated to be present in the same cells as demonstrated via laser confocal scanning microscopy. LN receptor was expressed in all of the six cell lines. With the LN protein added in culture medium, two hepatocellular carcinoma cell lines, formerly negative for CK19, began to express CK19. The reaction is dose-dependent. Polyclonal antibodies against LN that added in the cell culture medium could block the induction effect of LN.
Our data have demonstrated that abnormal expression of CK7 and CK19 occurred frequently in HCC cell lines, providing cell models for further understanding the mechanism of the abnormal CK19 expression in hepatocytic cells. Our previous reports have suggested that CK19 expression in liver parenchyma cells is associated with abnormal LN deposition. The concept has been verified in this study by the following findings: (1) the correlative expression and colocalization of CK19 and LN in HCC cell lines expressing LN receptors; (2) the induction of CK19 in two cell lines formerly negative for both CK19 and LN by adding a certain amount of LN directly into the culture medium; and (3) the successful blockage of CK19 expression in two cells lines by a medium containing LN antibodies. These data are helpful for the further understanding of hepatocyte differentiation and hepatocarcinogenesis, and are important for differential diagnosis of liver neoplasms.
引文
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