Melanocyte expression of survivin promotes development and metastasis of UV-induced melanoma in HGF-transgenic mice.
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.
Thomas
Joshua
J
Huntsman Cancer Institute, Melanoma Program, University of Utah Health Science Center, Salt Lake City, Utah 84112, USA.
Liu
Tong
T
Cotter
Murray A
MA
Florell
Scott R
SR
Robinette
Kyle
K
Hanks
Adrianne N
AN
Grossman
Douglas
D
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D009508:Nevus, Pigmented / Q000139:chemically induced / Q000378:metabolism; D012097:Repressor Proteins; D012880:Skin Pigmentation; D000077022:Survivin; D013755:Tetradecanoylphorbol Acetate; D014466:Ultraviolet Rays
C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D000077022:Survivin; D015127:9,10-Dimethyl-1,2-benzanthracene; D017228:Hepatocyte Growth Factor; D013755:Tetradecanoylphorbol Acetate