Yu Yanlin, Khan Javed, Khanna Chand, Helman Lee, Meltzer Paul S, Merlino Glenn
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Med. 2004 Feb;10(2):175-81. doi: 10.1038/nm966. Epub 2004 Jan 4.
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.
患有转移性横纹肌肉瘤（RMS）的患者，RMS是儿童最常见的软组织肉瘤，其临床预后非常差。这在很大程度上是由于我们对决定转移潜能的分子事件了解有限。我们对源自肝细胞生长因子/散射因子（HGF/SF）转基因的Ink4a/Arf缺陷小鼠的RMS细胞系进行了cDNA微阵列分析，以鉴定一组在高转移性和低转移性细胞之间表达有显著差异的基因。随后的体内功能研究表明，肌动蛋白丝-质膜连接蛋白埃兹蛋白（由Vil2编码）和含同源结构域的转录因子Six-1（无眼相关同源盒-1同源物）在决定RMS细胞的转移命运中起重要作用。VIL2和SIX1在人类RMS组织中的表达增强，与临床分期显著相关。将埃兹蛋白和Six-1鉴定为RMS转移的关键调节因子，为这种儿科癌症提供了新的机制和治疗见解。
