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Progranulin (PC-Cell-derived Growth Factor/Acrogranin) Regulates Invasion and Cell Survival¹

Endocrine Research Laboratory, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada H3A 1A1

Progranulin (pgrn; PC-cell-derived growth factor, epithelin precursor, or acrogranin) has been identified recently as an autocrine regulator of tumorigenesis in several cancer cells including SW-13 adrenal carcinomas and some breast cancers, but how pgrn promotes tumor progression is not well understood. SW-13 cells do not form tumors in nude mice but become highly tumorigenic when their pgrn expression is elevated, and this provides a useful model in which to investigate the role of pgrn in tumorigenesis. Here we show that, in SW-13 cells, the level of pgrn expression is a major determinant of the intrinsic activity of the mitogen-activated protein kinase, phosphatidylinositol 3'-kinase, and focal adhesion kinase signaling pathways. Pgrn stimulates the invasion of SW-13 cells across Matrigel-coated filters, increases the expression of matrix metalloproteinase 13 and 17, protects against anoikis, and overcomes the inhibition of cell growth imposed on SW-13 cells by interstitial type-I collagen. Inhibition of the mitogen-activated protein kinase and phosphatidylinositol 3'-kinase signaling pathways impairs each of the pgrn-dependent biological responses tested, but to different extents. The ability of pgrn to stimulate cell division, invasion, and survival demonstrates that pgrn regulates multiple steps in carcinomal progression, and suggests that the pgrn system may be a possible future therapeutic target.