We previously found the apoptosis inhibitor
Survivin to be expressed in
melanocytic nevi and
melanoma but not in normal melanocytes. To investigate the role of
Survivin in
melanoma development and progression, we examined the consequences of forced
Survivin expression in melanocytes in vivo. Transgenic (Tg) mouse lines (Dct-
Survivin) were generated with melanocyte-specific expression of
Survivin, and melanocytes grown from Dct-
Survivin mice expressed
Survivin. Dct-
Survivin melanocytes exhibited decreased susceptibility to UV-induced apoptosis but no difference in proliferative capacity compared with melanocytes derived from non-Tg littermates. Induction of
nevi in Dct-
Survivin and non-Tg mice by topical application of
7,12-dimethylbenz(a)anthracene did not reveal significant differences in lesion onset (median, 10 weeks) or density (4 lesions per mouse after 15 weeks). Dct-
Survivin mice were bred with
melanoma-prone MH19/HGF-B6 Tg mice, and all progeny expressing either individual, neither, or both (
Survivin/HGF) transgenes were UV-treated as neonates and then monitored for 43 weeks. Melanocytes in neonatal
Survivin+/HGF+ mouse skin were less susceptible to UV-induced apoptosis than those from
Survivin-/HGF+ mice. Onset of melanocytic
tumors was earlier (median, 18 versus 24 weeks; P = 0.01, log-rank test), and overall
tumor density was greater (7.7 versus 5.2
tumors per mouse; P = 0.04) in
Survivin+/HGF+ compared with
Survivin-/HGF+ mice. Strikingly,
melanomas arising in
Survivin+/HGF+ mice showed a greater tendency for lymph node (35% versus 0%; P = 0.04) and lung (53% versus 22%)
metastasis and lower rates of spontaneous apoptosis than those in
Survivin-/HGF+ mice. These studies show a role for
Survivin in promoting both early and late events of UV-induced
melanoma development in vivo.