Expression of stem cell factor and its receptor c-Kit during the development of intrahepatic cholangiocarcinoma
Expression of stem cell factor and its receptor c-Kit during the development of intrahepatic cholangiocarcinoma
复制标题
DOI：
10.1038/labinvest.2009.15
复制
发表时间：
2009-05-01
影响因子：
5
通讯作者：
Ramadori, Giuliano
中科院分区：
文献类型：
--
作者：
Mansuroglu, Tuemen;Ramadori, Pierluigi;Ramadori, Giuliano
干细胞因子（SCF）及其受体c-Kit是重要的信号转导系统，具有增殖和抗凋亡的功能。除了调节造血干细胞增殖和肝再生外，它还涉及人类恶性肿瘤的调节。然而，在胆管癌发生过程中，肝中的SCF-c-Kit基因系统的细胞表达至今尚未研究。在正常大鼠肝脏、分离的正常大鼠肝细胞和硫代乙酰胺诱导的肝内胆管癌（CC）大鼠模型中检测了SCF和c-Kit基因的蛋白质和mRNA表达水平。正常肝脏的免疫组化分析显示，SCF表达于肝动脉壁和位于沿着窦状隙的一些细胞中，尽管它不存在于肝细胞和胆管上皮细胞中。分离的正常肝细胞群的mRNA分析显示，SCF-和c-Kit-mRNA在窦内皮细胞和枯否细胞中共表达，而传代培养的肝肌成纤维细胞（MFs）仅表达SCF。在正常肝细胞中检测到低水平的SCF-和c-Kit-mRNA表达。CC组织的免疫组化分析显示SCF在增殖的胆管细胞（CK-19（+））、巨噬细胞（艾德-1（+））和肿瘤微环境的MF（α-平滑肌肌动蛋白，α-SMA（+））中呈阳性。在再生结节的肝细胞和CC增生的胆管上可检测到c-Kit阳性。与正常肝组织相比，来自CC组织的SCF-mRNA上调高达20倍，而c-Kit-mRNA上调高达5倍。这些数据表明，几个细胞群可能成为能够表达SCF和/或c-Kit在胆管癌发生。因此，SCF-c-Kit系统可能有助于肿瘤的发展，例如，通过诱导肝细胞和胆管细胞的增殖，并作为CC细胞的存活因子。
Stem cell factor (SCF) and its receptor, c-Kit, constitute an important signal transduction system with proliferative and anti-apoptotic functions. Besides regulating hemopoietic stem cell proliferation and liver regeneration, it has been implicated in the regulation of human malignancies. However, the cellular expression of the SCF-c-Kit gene system in the liver during cholangiocarcinogenesis has not been studied to date. The protein-and mRNA-expression levels of SCF and c-Kit genes were examined in normal rat liver, in isolated normal rat liver cells and in a thioacetamide-induced rat model of intrahepatic cholangiocarcinoma (CC). Immunohistochemical analysis of the normal liver showed that SCF is expressed in the wall of the hepatic artery and in some cells, which were located along the sinusoids, although it was absent from hepatocytes and biliary epithelial cells. The mRNA analysis of isolated normal liver cell populations revealed a co-expression of SCF- and c-Kit-mRNA in sinusoidal endothelial cells and in Kupffer cells, whereas passaged and cultured liver myofibroblasts (MFs) expressed only SCF. Low levels of the SCF-and c-Kit-mRNA expression could be detected in isolated hepatocytes of the normal liver. Immunohistochemical analysis of the CC tissue showed SCF positivity in proliferating biliary cells (CK-19(+)), in macrophages (ED-1(+)) and in MFs (alpha-smooth-muscle-actin, alpha-SMA(+)) of the tumoral microenvironment. c-Kit-positivity could be detected on hepatocytes of the regenerating nodules and on the proliferating bile ducts of CC. Compared with the normal liver tissue, SCF-mRNA from the CC tissue was upregulated up to 20-fold, whereas c-Kit-mRNA was upregulated up to fivefold. These data indicate that several cell populations may become able to express SCF and/or c-Kit during cholangiocarcinogenesis. Therefore, the SCF-c-Kit system may contribute to tumor development, for instance, by inducing proliferation of hepatocytes and of biliary cells and by acting as a surviving factor for CC cells.