Plexin C1 is a type I transmembrane receptor with intrinsic R-
Ras GTPase activity, which regulates cytoskeletal remodeling and adhesion in normal human melanocytes. Melanocytes are pigment-producing cells of the epidermis, precursors for
melanoma, and express high levels of
Plexin C1, which is lost in
melanoma in vitro and in vivo. To determine if
Plexin C1 is a
tumor suppressor for
melanoma, we introduced
Plexin C1 into a primary human
melanoma cell line, and phenotypes including migration, apoptosis, proliferation and
tumor growth in mice were analyzed. Complimentary studies in which
Plexin C1 was silenced in human melanocytes were performed.
Plexin C1 significantly inhibited migration and proliferation in
melanoma, whereas in melanocytes, loss of
Plexin C1 increased migration and proliferation. In mouse xenografts,
Plexin C1 delayed
tumor growth of
melanoma at early time points, but
tumors eventually escaped the suppressive effects of
Plexin C1, due to
Plexin C1-dependent activation of the pro-survival
protein Akt. R-Ras activation stimulates
melanoma migration.
Plexin C1 lowered R-Ras activity in
melanoma and melanocytes, consistent with inhibitory effects of
Plexin C1 on migration of melanocytes and
melanoma. To determine if R-Ras is expressed in melanocytic lesions in vivo, staining of tissue microarrays of
nevi and
melanoma were performed. R-Ras expression was highly limited in melanocytic lesions, being essentially confined to primary
melanoma, and almost completely absent in
nevi and metastatic
melanoma. These data suggest that loss of
Plexin C1 in
melanoma may promote early steps in
melanoma progression through suppression of migration and proliferation, but pro-survival effects of
Plexin C1 ultimately abrogate the
tumor suppressive effects of
Plexin C1. In primary
melanoma, loss of
Plexin C1 may function in early steps of
melanoma progression by releasing inhibition of R-Ras activation, and stimulating migration.