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Identification of Genes Responsible for Cell Migration by a Library of Randomized Ribozymes

Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Hongo, Tokyo 113-8656 [E. S., H. K., K. T.]; Gene Function Research Laboratory, National Institute of Advanced Industrial Science and Technology, Tsukuba Science City, Ibaraki 305-8562 [E. S., H. K., K. T.]; Tsukuba Research Institute, Novartis Pharma, Tsukuba Science City, Ibaraki 300-2611 [T. K.], Japan

Several genes appear to be associated with metastasis, but the underlying mechanisms of metastasis still remain unclear. In this study, we used a library of randomized ribozymes to identify, by inactivation of transcripts, genes involved in cell migration that is an essential aspect of metastasis. Using a chemotaxis assay, the ribozymes that inhibited cell migration were selected from the library. Among such ribozymes, we found two ribozymes that targeted and cleaved ROCK1 mRNA at independent sites. ROCK1 and ROCK2 are Rho kinases, and it has been demonstrated that they regulate the organization of the actin cytoskeleton and are responsible for cell motility and cytokinesis. The two ribozymes that specifically cleaved ROCK1 mRNA inhibited both the migration and invasion of invasive HT1080 fibrosarcoma, but neither had any effect on cell proliferation. Our analysis indicates that the ribozymes toward ROCK1 can block invasive activity but not the proliferation of HT1080 cells without having any effect on expression of ROCK2. Ribozymes identified in this study, including the ribozymes against ROCK1, might be useful in understanding the mechanisms of cell migration and metastasis.

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