Altered gene expression in breast cancer liver metastases
Altered gene expression in breast cancer liver metastases
复制标题
DOI：
10.1002/ijc.24131
复制
发表时间：
2009-04-01
影响因子：
6.4
通讯作者：
Clawson, Gary A.
中科院分区：
文献类型：
--
作者：
Erin, Nuray;Wang, Ning;Clawson, Gary A.
我们之前从4T1乳腺癌的心脏转移(命名为4THM)中开发了一种高度侵袭性的细胞系，该细胞系产生肝转移(命名为4TLM)。在这项研究中，基因阵列分析(GEA)比较了4TLM与4T1和4THM原发肿瘤的基因表达谱。GEA证明，4T1和4THM肿瘤在大约250个基因上存在差异。然而，超过1,000个基因在4TLM中的表达与原发肿瘤不同。16个基因在4THM肿瘤中的表达显著降低，在4TLM中的表达进一步降低。这些基因中的许多与乳腺癌有关，许多与细胞黏附和连接复合体有关。定量聚合酶链式反应、免疫印迹和免疫细胞化学(ICC)分析证实，在4TLM中，多种紧密和粘连连接蛋白的表达下调或消失；Claudin 4、Claudin 7和Gamma-calenin的表达下调。在蛋白水平上，ZO-1在4T1肿瘤中也有完整表达，但在4THM和4TLM肿瘤中不表达。在4T1肿瘤中，ICC表达在细胞膜上，而在4THM肿瘤中，则主要表达于核/核周围。免疫组化结果显示，肝转移灶周围的单核/巨噬细胞样细胞也表达Claudin 7，较大的4TLM肿瘤明显重新表达Claudin 7的RNA和蛋白。我们的结果表明，一些细胞黏附/连接蛋白的表达减少或异常，包括Claudin 4、7、ZO-1和Gamma-Catenin，与肝转移有关，微环境中的细胞黏附分子也发生了改变。(C)2008年Wiley-Liss，Inc.
We previously developed a highly aggressive cell line from heart metastases of 4T1 breast carcinoma (designated 4THM), which produced liver metastases (designated 4TLM). In this study, gene array analysis (GAEA) compared gene expression profiles in 4TLM with profiles in 4T1 and 4THM primary tumors. GAEA demonstrated that 4T1 and 4THM tumors differed in about 250 genes. Over 1,000 genes, however, were expressed differently in 4TLM compared with primary tumors. A cohort of 16 genes showed significantly decreased expression in 4THM tumors, which decreased even further in 4TLM. Many of these genes have been implicated in breast cancer, and many are involved in cell adhesion and junctional complexes. Expression of multiple tight and adherence junction proteins was either downregulated or disappeared in 4TLM; downregulation of claudin 4, claudin 7 and gamma-calenin was confirmed by quantitative polymerase chain reaction, immunoblot, and immunocytochemical (ICC) analyses. At the protein level, intact ZO-1 was also observed in 4T1 tumors, but was not expressed in 4THM or 4TLM tumors. ICC demonstrated expression of gamma-catenin at the plasma membrane with 4T1 tumors, whereas staining appeared to be nuclear/perinuclear in 4THM tumors. Claudin 7 staining was also seen in monocyte/pmacrophage-like cells in liver around metastatic lesions by ICC, and it appeared that larger 4TLM tumors apparently reexpressed claudin 7 RNA and protein. Our results demonstrate that decreased or abnormal expression of a number of cell adhesion/junctional proteins, including claudin 4, 7, ZO-1 and gamma-catenin, correlates with liver metastases, and that cell adhesion molecules in the microenvironment are also altered. (c) 2008 Wiley-Liss, Inc.