Malignant gliomas are the most common primary intracranial neoplasms in adults and are largely refractory to post-surgical therapy despite intensive therapeutic efforts. Using a number of different brain tumor-derived cell lines we have demonstrated that the mRNA for osteopontin (OPN), which is substantially over-expressed by some tumors in comparison with normal tissues, is preferentially expressed in high grade and metastatic brain tumors compared to low grade brain tumors. One glioma-derived cell line, U105MG, which does not express significant amounts of OPN mRNA, could be induced dose-dependently by the tumor-promoting and PKC-activating phorbol ester, TPA, to over-express OPN mRNA in a PKC-dependent manner. Unexpectedly, treatment of U105MG cells with Ca2+ antagonist TMB-8 had no significant effect. Elucidation of regulatory mechanisms for OPN induction in glioma cells should facilitate rational design of novel therapeutics for human malignant gliomas.