Regulation and function of osteopontin in ras-transformed cells.

Transformation of nontumorigenic NIH 3T3 fibroblasts with an activated ras oncogene produces malignant cells that can metastasize. This induction of malignant behavior is due to changes in gene expression induced by Ras-mediated signal transduction. Osteopontin expression is induced in response to Ras, due to increased osteopontin transcription mediated by Ras-responsive regions in the osteopontin gene promoter. The increased expression of osteopontin contributes functionally to the malignant ability of the cells. Ras-transformed cells that express antisense osteopontin RNA show markedly reduced ability to form tumors and to metastasize in experimental animals. Increased osteopontin expression in human tumors thus may also contribute to increased malignancy. Site-directed mutagenesis of recombinant osteopontin protein indicates that an intact RGD sequence is required for cell adhesion and induction of chemotaxis, consistent with the idea that integrin-mediated signal transduction is a consequence of osteopontin binding to cells. Osteopontin may contribute to malignancy by inducing responses in host and/or tumor cells.