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

Abstract

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.

Inhibition of the hyaluronan-CD44 interaction by merlin contributes to the tumor-suppressor activity of merlin

“…Overproduction of HA promotes anchorageindependent growth of the CD44-expressing breast epithelial cells by inducing an epithelial-mesenchymal transition (Zoltan-Jones et al, 2003) and increasing evidence suggests that ezrin is a key regulator of tumor metastasis Yu et al, 2004). We show in the present study that increased expression of merlin inhibits the CD44-mediated cell binding to HA and reduces the interaction between CD44 and ezrin, and as well as between CD44 and the actin cytoskeleton.…”

“…CD44 and ezrin play important roles in promoting tumor metastasis (Yu et al, 1997;Stamenkovic 1999, 2000;Yu et al, 2004;Khanna et al, 2001Khanna et al, , 2004, whereas merlin acts as a tumor suppressor (Rouleau et al, 1993;Trofatter et al, 1993;Lutchman and Rouleau, 1995;Sherman et al, 1997;McClatchey et al, 1998;Giovannini et al, 1999Giovannini et al, , 2000. Thus far, the functional relationship between CD44 and merlin and the manner in which CD44 affects the tumor-suppressing activity of merlin have not been established.…”

Phosphorylated ezrin is located in the nucleus of the osteosarcoma cell

“…19 Transfection of full-length Vil2 constructs in lowmetastatic cell lines dramatically increase the ability of these cell lines to form macroscopic pulmonary lesions in experimental metastasis assays, demonstrating that ezrin overexpression is sufficient to confer metastatic capacity. 20 In a mouse model of osteosarcoma, ezrin was necessary for metastasis, and in dog tumors, a high expression of ezrin was associated with the early development of metastasis. 8 A relationship was also shown between high expressions of ezrin and poor outcome in 19 pediatric osteosarcoma patients.…”

“…8 Suppression of ezrin protein expression in osteosarcomas by antisense transfection or stable expression of short hairpin RNA, or the disruption of ezrin function by transfection of a dominant-negative ezrin significantly reduced the metastatic behavior in both mouse models and was associated with decreased Akt and mitogen-activated protein kinase (MAPK) activity. 20 The mechanisms of ezrin-related metastatic behavior are linked to an Akt-dependent mammalian target of rapamycin (mTOR). 21 However, the specific mechanism or mechanisms by which ezrin mediates the metastatic process remain to be clarified.…”

Redéploiement des gènes Six au cours de l’évolution

“…La conservation de ces gènes suggère qu'ils participent à des mécanismes essentiels à la survie des organismes. En outre, des résultats récents indiquent qu'un dérègle-ment du gène Six1 est associé à certains types de cancers métastatiques (cancer du sein, tumeur de Wilms et rhabdomyosarcome) [2][3][4]. Ce gène pourrait donc non seulement contrôler la prolifération cellulaire, mais aussi participer à l'acquisition des propriétés invasives des cellules cancéreuses.…”