Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators

被引:384
作者
Yu, YL
Khan, J
Khanna, C
Helman, L
Meltzer, PS
Merlino, G [1 ]
机构
[1] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA
[2] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA
[3] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1038/nm966
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:175 / 181
页数:7
相关论文
共 46 条
[1]   Molecular classification of cutaneous malignant melanoma by gene expression profiling [J].
Bittner, M ;
Meitzer, P ;
Chen, Y ;
Jiang, Y ;
Seftor, E ;
Hendrix, M ;
Radmacher, M ;
Simon, R ;
Yakhini, Z ;
Ben-Dor, A ;
Sampas, N ;
Dougherty, E ;
Wang, E ;
Marincola, F ;
Gooden, C ;
Lueders, J ;
Glatfelter, A ;
Pollock, P ;
Carpten, J ;
Gillanders, E ;
Leja, D ;
Dietrich, K ;
Beaudry, C ;
Berens, M ;
Alberts, D ;
Sondak, V ;
Hayward, N ;
Trent, J .
NATURE, 2000, 406 (6795) :536-540
[2]   ERM proteins and merlin: Integrators at the cell cortex [J].
Bretscher, A ;
Edwards, K ;
Fehon, RG .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2002, 3 (08) :586-599
[3]   A system for stable expression of short interfering RNAs in mammalian cells [J].
Brummelkamp, TR ;
Bernards, R ;
Agami, R .
SCIENCE, 2002, 296 (5567) :550-553
[4]  
CHEN Y, 1997, BIOMED OPTICS, V2, P364
[5]   Ratio statistics of gene expression levels and applications to microarray data analysis [J].
Chen, YD ;
Kamat, V ;
Dougherty, ER ;
Bittner, ML ;
Meltzer, PS ;
Trent, JM .
BIOINFORMATICS, 2002, 18 (09) :1207-1215
[6]   Genomic analysis of metastasis reveals an essential role for RhoC [J].
Clark, EA ;
Golub, TR ;
Lander, ES ;
Hynes, RO .
NATURE, 2000, 406 (6795) :532-535
[7]   Ezrin is an effector of hepatocyte growth factor-mediated migration and morphogenesis in epithelial cells [J].
Crepaldi, T ;
Gautreau, A ;
Comoglio, PM ;
Louvard, D ;
Arpin, M .
JOURNAL OF CELL BIOLOGY, 1997, 138 (02) :423-434
[8]  
Dagher R, 1999, Oncologist, V4, P34
[9]   Dual stimulation of Ras/Mitogen-activated protein kinase and RhoA by cell adhesion to fibronectin supports growth factor-stimulated cell cycle progression [J].
Danen, EHJ ;
Sonneveld, P ;
Sonnenberg, A ;
Yamada, KM .
JOURNAL OF CELL BIOLOGY, 2000, 151 (07) :1413-1422
[10]   Rho GTPases in cell biology [J].
Etienne-Manneville, S ;
Hall, A .
NATURE, 2002, 420 (6916) :629-635