Baldi Alfonso, Lombardi Daniela, Russo Patrizia, Palescandolo Emanuele, De Luca Antonio, Santini Daniele, Baldi Feliciano, Rossiello Luigi, Dell'Anna Maria Lucia, Mastrofrancesco Arianna, Maresca Vittoria, Flori Enrica, Natali Pier Giorgio, Picardo Mauro, Paggi Marco G
Laboratory "C," Department for the Development of Therapeutic Programs, Center for Experimental Research, Regina Elena Cancer Institute, Rome, Italy.
Clin Cancer Res. 2005 May 1;11(9):3175-83. doi: 10.1158/1078-0432.CCR-04-0631.
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.
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.
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.
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.
利用人黑色素瘤进展的体外模型系统，我们之前报道了铁蛋白轻链（L-铁蛋白）基因在转移表型中的过表达。在此，我们试图阐明铁蛋白在人黑色素瘤生物学及该疾病进展中的作用。
从LM人转移性黑色素瘤细胞系开始，我们构建了细胞克隆，其中L-铁蛋白基因表达通过特定反义构建体的稳定表达而下调。然后对这些细胞的生长能力、化学侵袭特性及对氧化应激的敏感性进行检测。此外，通过免疫组织化学测定原发性和转移性人黑色素瘤中铁蛋白的蛋白含量。
LM细胞中人工下调L-铁蛋白强烈抑制体外增殖和化学侵袭以及体内细胞生长。此外，L-铁蛋白下调的细胞对氧化应激和凋亡表现出更高的敏感性。同时，对人黑色素瘤组织芯片的免疫组织化学分析显示，转移病灶中铁蛋白表达水平显著高于原发性黑色素瘤（P < 0.0001）。此外，在11例患者队列中，与各自的原发性肿瘤相比，自体淋巴结黑色素瘤转移灶中铁蛋白表达持续上调。
这些数据表明，高铁蛋白表达可通过干扰细胞抗氧化系统来增强转移性黑色素瘤细胞的生长并提高其对氧化应激的抗性。这些发现的潜在意义值得在临床环境中进行验证。
