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Ferritin Contributes to Melanoma Progression by Modulating Cell Growth and Sensitivity to Oxidative Stress

Authors' Affiliations: ¹ Laboratory "C," Department for the Development of Therapeutic Programs and ² Laboratory of Immunology, Center for Experimental Research, Regina Elena Cancer Institute; ³ Service of Oncology, Campus BioMedico University; ⁴ San Gallicano Dermatological Institute, Rome, Italy; ⁵ Deparment of Biochemistry and Biophysics "F. Cedrangolo," Section of Anatomic Pathology, Second University of Naples, Naples, Italy; and ⁶ Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy

Requests for reprints: Marco G. Paggi, Laboratory "C," Department for the Development of Therapeutic Programs, Regina Elena Cancer Institute, Center for Experimental Research, Via E. Chianesi 53, 00128 Rome, Italy. Phone: 39-06-5266-2550; Fax: 39-06-5266-2572; E-mail: paggi{at}ccd.inemm.cnr.it.

Purpose: 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.

Experimental Design: 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.

Key Words: chemoinvasion • metastasis • apoptosis • lipid peroxidation