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

Nature Medicine volume 10, pages 175–181 (2004)Cite this article

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.

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Figure 1: cDNA microarray analysis of highly and poorly metastatic RMS cell lines.
Figure 2: Validation of genes identified by cDNA microarray analysis as significantly overexpressed in highly and poorly metastatic cells.
Figure 3: Analysis of expression of VIL2 and SIX1 in staged human RMS tissue.
Figure 4: Phenotypic consequences of altered Ezrin function.
Figure 5: Phenotypic consequences of altered Six-1 expression.

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Acknowledgements

The authors thank P. Maire for the full-length mouse Six1 expression plasmid, R. Lamb for the full-length human VIL2 construct, and H. Takayama and R. Herring for assistance with the RMS cell lines. This work was supported in part by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute.

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Author notes

  1. Yanlin Yu and Javed Khan: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Yanlin Yu & Glenn Merlino

  2. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Javed Khan, Chand Khanna & Lee Helman

  3. Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Paul S Meltzer

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  1. Yanlin Yu
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Correspondence to Glenn Merlino.

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Yu, Y., Khan, J., Khanna, C. et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med 10, 175–181 (2004). https://doi.org/10.1038/nm966

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