Expression of Intercellular Adhesion Molecule 1 by Hepatocellular Carcinoma Stem Cells and Circulating Tumor Cells
Expression of Intercellular Adhesion Molecule 1 by Hepatocellular Carcinoma Stem Cells and Circulating Tumor Cells
复制标题
肝细胞癌干细胞和循环肿瘤细胞表达细胞间粘附分子1
DOI：
10.1053/j.gastro.2013.01.046
复制
发表时间：
2013-05-01
期刊：
影响因子：
29.4
通讯作者：
Liu, Shanrong
中科院分区：
文献类型：
--
作者：
Liu, Shupeng;Li, Nan;Liu, Shanrong
背景与目的：细胞间粘附分子1（ICAM-1）被认为参与了肝细胞癌（HCC）细胞的转移。肿瘤干细胞促进肿瘤复发和转移。我们研究了ICAM-1是否是HCC干细胞的标志物。方法：采用球体形成实验和成瘤实验研究ICAM-1（+）细胞的干细胞特性。采用特异性靶向系统抑制ICAM-1的表达，并采用B型肝炎病毒转基因小鼠（M-TgHBV）研究ICAM-1的抑制是否能降低体内肿瘤的发病率和转移。我们使用实时聚合酶链反应和免疫印迹分析来评估ICAM-1和Nanog在肿瘤细胞系中的表达，并使用流式细胞术分析来研究ICAM-1在HCC和血液样品中的表达。研究结果：ICAM-1在HCC肿瘤细胞系中的少数细胞群上表达，以及在从患者和转基因小鼠分离的肿瘤组织和循环肿瘤细胞中表达。与ICAM-1（-）肿瘤细胞相比，ICAM-1（+）肿瘤细胞具有更强的成球能力和致瘤能力，干细胞相关基因的表达增加。特异性抑制ICAM-1可减少M-TgHBV小鼠的形成和转移。发现ICAM-1是来自患者和M-TgHBV小鼠的循环肿瘤细胞的标志物。HCC患者血液样本中CD 45（-）ICAM-1（+）细胞数量增加与临床结局较差相关。干细胞转录因子Nanog调控肝癌干细胞ICAM-1表达结论：ICAM-1是人类和小鼠肝癌干细胞的标志物; ICAM-1抑制剂可减缓小鼠肿瘤的形成和转移。ICAM-1的表达受干细胞转录因子Nanog的调控。
BACKGROUND & AIMS: Intercellular adhesion molecule 1 (ICAM-1) is believed to be involved in metastasis of hepatocellular carcinoma (HCC) cells. Cancer stem cells promote tumor relapse and metastasis. We investigated whether ICAM-1 is a marker of HCC stem cells. METHODS: Sphere formation and tumor formation assays were performed to investigate the stem cell properties of ICAM-1(+) cells in vitro and in vivo. A specific targeting system that inhibits ICAM-1 expression and hepatitis B virus transgenic mice (M-TgHBV) were used to investigate whether inhibition of ICAM-1 reduced tumor incidence and metastasis in vivo. We used real-time polymerase chain reaction and immunoblot analysis to assess ICAM-1 and Nanog expression in tumor cell lines, and flow cytometry analysis was used to investigate ICAM-1 expression in HCC and blood samples. RESULTS: ICAM-1 was expressed on a minor cell population in HCC tumor cell lines, as well as in tumor tissues and circulating tumor cells isolated from patients and transgenic mice. ICAM-1(+) tumor cells had greater sphere-forming and tumorigenic capacities and increased expression of stemness-related genes compared with ICAM-1(-) tumor cells. The specific inhibition of ICAM-1 reduced formation and metastasis in M-TgHBV mice. ICAM-1 was found to be a marker of circulating tumor cells from patients and M-TgHBV mice. Increased numbers of CD45(-)ICAM-1(+) cells in blood samples of patients with HCC correlated with worse clinical outcomes. The stem cell transcription factor Nanog regulated expression of ICAM-1 in HCC stem cells. CONCLUSIONS: ICAM-1 is a marker of HCC stem cells in humans and mice; ICAM-1 inhibitors slow tumor formation and metastasis in mice. ICAM-1 expression is regulated by the stem cell transcription factor Nanog.