In searching for genes that suppress the viral transformation of primary cells, we have isolated a number of TRIF (transcript reduced in F2408) genes that are expressed well in primary rat embryo fibroblasts (REFs) but poorly in spontaneously immortalized rat fibroblast cell lines derived from REFs. One of these genes, TRIF52, is a rat homologue of the mouse protein periostin, which is suspected of being involved in oncogenesis. We found here that periostin mRNA expression is markedly downregulated in a variety of human cancer cell lines and human lung cancer tissues. Human cancer cell lines with reduced endogenous periostin gene expression that were infected with a recombinant retrovirus containing the periostin gene had reduced anchorage-independent growth. Mutational analysis revealed that the C-terminal region of periostin is sufficient to convey the anchorage-independent growth-suppressive activity of the protein. These observations together suggest that periostin may serve to inhibit the development of human cancers by acting as a tumor suppressor.