Transcriptional regulation of osteopontin and the metastatic phenotype: evidence for a Ras-activated enhancer in the human OPN promoter.

Elevated osteopontin (OPN) transcription often correlates with increased metastatic potential of transformed cells, and in several model systems OPN--whether produced by the tumor cells or by stromal cells - has been shown to enhance metastatic ability. Sequence elements in the OPN promoter have been identified on the basis of their ability to interact with protein factors associated with the tumorigenic process in one or more cell lineages. One of these is a Ras-activated enhancer (RAE) that binds a protein, the Ras-response factor (RRF), whose ability to form a complex with the RAE is stimulated by Ras signaling in fibroblasts and epithelial cells. Another is the T cell factor-4 binding site, which in the OPN promoter can retard OPN transcription when bound by the Tcf-4 protein. In Rama 37 rat mammary epithelial cells Tcf-4 suppresses OPN transcription and the metastatic phenotype. A third promoter segment consists of two sequences in the -94 to -24 region of the human OPN promoter able to bind several known transcription factors, including Sp1, Myc and Oct-1, which may act synergistically to stimulate OPN transcription in malignant astrocytic cells. Although expression of other genes may also be regulated by these transcription factors, evidence suggests that often OPN alone can stimulate metastasis. In this communication we address two issues: (1) How does OPN facilitate the metastatic phenotype? (2) What mechanisms are responsible for the increase in OPN transcription in metastatic cells?