Ferritin contributes to melanoma progression by modulating cell growth and sensitivity to oxidative stress.
OBJECTIVE
Employing an in vitro model system of human melanoma progression, we previously reported ferritin light chain (L-ferritin) gene overexpression in the metastatic phenotype. Here, we attempted to characterize the role of ferritin in the biology of human melanoma and in the progression of this disease.


METHODS
Starting from the LM human metastatic melanoma cell line, we engineered cell clones in which L-ferritin gene expression was down-regulated by the stable expression of a specific antisense construct. These cells were then assayed for their growth capabilities, chemoinvasive properties, and sensitivity to oxidative stress. Additionally, ferritin protein content in primary and metastatic human melanomas was determined by immunohistochemistry.


RESULTS
Artificial L-ferritin down-regulation in the LM cells strongly inhibited proliferation and chemoinvasion in vitro and cell growth in vivo. In addition, L-ferritin down-regulated cells displayed enhanced sensitivity to oxidative stress and to apoptosis. Concurrently, immunohistochemical analysis of a human melanoma tissue array revealed that ferritin expression level in metastatic lesions was significantly higher (P < 0.0001) than in primary melanomas. Furthermore, ferritin expression was constantly up-regulated in autologous lymph node melanoma metastases when compared with the respective primary tumors in a cohort of 11 patients.


CONCLUSIONS
These data suggest that high ferritin expression can enhance cell growth and improve resistance to oxidative stress in metastatic melanoma cells by interfering with their cellular antioxidant system. The potential significance of these findings deserves to be validated in a clinical setting.
Baldi
Alfonso
A
Laboratory "C," Department for the Development of Therapeutic Programs, Center for Experimental Research, Regina Elena Cancer Institute, Rome, Italy.
Lombardi
Daniela
D
Russo
Patrizia
P
Palescandolo
Emanuele
E
De Luca
Antonio
A
Santini
Daniele
D
Baldi
Feliciano
F
Rossiello
Luigi
L
Dell'Anna
Maria Lucia
ML
Mastrofrancesco
Arianna
A
Maresca
Vittoria
V
Flori
Enrica
E
Natali
Pier Giorgio
PG
Picardo
Mauro
M
Paggi
Marco G
MG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016373:DNA, Antisense / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005293:Ferritins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide; D007150:Immunohistochemistry; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D015854:Up-Regulation; D014810:Vitamin E / Q000378:metabolism
D016373:DNA, Antisense; D018076:DNA, Complementary; D005231:Fatty Acids, Unsaturated; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D014810:Vitamin E; D005293:Ferritins; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase