Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators
Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators
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DOI：
10.1038/nm966
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发表时间：
2004-02-01
期刊：
影响因子：
82.9
通讯作者：
Merlino, G
中科院分区：
文献类型：
--
作者：
Yu, YL;Khan, J;Merlino, G
转移性横纹肌肉瘤（RMS）是儿童最常见的软组织肉瘤，临床预后非常差。这在很大程度上是由于我们对决定转移潜力的分子事件的基本知识。我们使用cDNA微阵列分析RMS细胞系，来自Ink 4a/Arf缺陷小鼠肝细胞生长因子/分散因子（HGF/SF）转基因，以确定一组基因的表达是显着不同的高转移性和低转移性细胞。随后的体内功能研究表明，肌动蛋白介导的质膜接头ezrin（由Vil 2编码）和含同源结构域的转录因子Six-1（sine oculis相关的同源框-1同源物）在确定RMS细胞的转移命运中具有重要作用。VIL 2和SIX 1在人RMS组织中的表达增强，与临床分期显著相关。ezrin和Six-1作为RMS转移的关键调节因子的鉴定为这种儿科癌症提供了新的机制和治疗见解。
Patients presenting with metastatic rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, have a very poor clinical prognosis. This is due, in large part, to our rudimentary knowledge of the molecular events that dictate metastatic potential. We used cDNA microarray analysis of RMS cell lines, derived from Ink4a/Arf-deficient mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF), to identify a set of genes whose expression was significantly different between highly and poorly metastatic cells. Subsequent in vivo functional studies revealed that the actin filament-plasma membrane linker ezrin (encoded by Vil2) and the homeodomain-containing transcription factor Six-1 (sine oculis-related homeobox-1 homolog) had essential roles in determining the metastatic fate of RMS cells. VIL2 and SIX1 expression was enhanced in human RMS tissue, significantly correlating with clinical stage. The identification of ezrin and Six-1 as critical regulators of metastasis in RMS provides new mechanistic and therapeutic insights into this pediatric cancer.