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RhoGDI2 Is an Invasion and Metastasis Suppressor Gene in Human Cancer¹

Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908 [J. J. G., M. J. S., G. O., M. A. H., D. T.]; Genomics Institute of the Novartis Research Foundation, San Diego, California 92121 [G. M. H.]; and Departments of Pathology [C. A. M., H. F. F.] and Health Evaluation Sciences (Biostatistics) [M. R. C.], University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

To discover novel metastasis suppressor genes that are clinically relevant in common human cancers, we used isogenic human bladder cancer cell lines and used DNA microarray technology to identify genes whose expression diminishes as a function of invasive and metastatic competence. We then evaluated the expression profile of such genes in 105 pathologically characterized tumors from seven common organ sites, and we identified one gene, RhoGDI2, whose expression was diminished as a function of primary tumor stage and grade. When RhoGDI2 was transferred back into cells with metastatic ability that lacked its expression, it suppressed experimental lung metastasis but did not affect in vitro growth, colony formation, or in vivo tumorigenicity. In addition, RhoGDI2 reconstitution in these cells blocked invasion in an organotypic assay and led to a reduction of in vitro motility. These results indicate that RhoGDI2 is a metastasis suppressor gene, a marker of aggressive human cancer, and a promising target for therapy.

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