Abstract. Nuclear factor (NF)-κB is one of the most impor- tant transcription factors that plays a crucial role in the regulation of a wide spectrum of genes involved in modulating the cell cycle, apoptosis, cell growth, angiogenesis, inflam-

Nuclear factor (NF)-κB is one of the most important transcription factors that plays a crucial role in the regulation of a wide spectrum of genes involved in modulating the cell cycle, apoptosis, cell growth, angiogenesis, inflammation and the tissue invasiveness of highly malignant cells. NF-κB activity has been found to be constitutively elevated in a number of human tumors from either a haematological or solid origin, such as melanomas. In several studies, NF-κB activation was shown to be an adverse prognostic factor, and in melanoma it was proposed as an event that promotes tumor progression. This study aimed to evaluate whether NF-κB activation in tumor tissues, assessed by the expression of the NF-κB p65 subunit, has an effect on the survival of melanoma patients. The expression of NF-κB was immunohistochemically investigated, and the correlation with survival was analyzed. Furthermore, the immunostaining for p53 and survivin was evaluated, and the relationship of these apoptotic and anti-apoptotic factors with NF-κB expression was analyzed. Kaplan-Meier analysis showed that patients with low levels of NF-κB in the nuclei of tumor cells had a significantly longer survival compared to those with high levels. Multivariate analysis confirmed the predictive value of nuclear NF-κB, showing that its expression maintains significance after the model was adjusted using clinicopathological factors. The results demonstrate the correlation of NF-κB p65 nuclear staining with the disease-specific 5-year survival of melanoma patients and suggest that nuclear NF-κB p65 may be promising as an early independent prognostic factor in patients with primary cutaneous melanoma. Introduction Nuclear factor (NF)-κB is one of the most important transcription factors that plays an essential role in the regulation of the expression and function of a wide spectrum of genes involved in the modulation of the cell cycle, apoptosis, cell growth, angiogenesis, inflammation and tissue invasiveness of highly malignant cells (1-3). NF-κB is a homodimeric or heterodimeric complex comprising proteins of the Rel-family: p65 (RelA), RelB, c-Rel, p50 (NF-κB1) and p52 (NF-κB2), all of which contain a Rel homology domain in the N-terminal region that mediates dimerization and DNA binding (4). The most commonly detected dimers are p65/p50, p65/p65 and p50/p50. Due to the presence of a strong transcriptional activation domain, p65 is responsible for the majority of NF-κB transcriptional activity (5). Moreover, the p65/p50 heterodimer comprises the major activated form of NF-κB in numerous cell types (4). NF-κB proteins are expressed in most cells, but are normally sequestered in the cytoplasm through binding with the inhibitors of NF-κBs (IκBs) (6). A number of pathways of cell stimulation, such as pro-inflammatory, mutagenic and pro-apoptotic stimuli, lead to the activation of the IκB kinase complex which phosphorylates the IκBs, targeting them for ubiquitination and degradation by the 26S proteosome according to the canonical NF-κB signal transduction pathway (7,8). The released and activated NF-κB complexes are then free to translocate into the nucleus and engage transcriptional programs, binding to the consensus enhancer sequence on the promoters of target genes. The activation of NF-κB, usually assessed by the presence of nuclear p65, has been observed in a number of human tumors from either a haematological or solid origin, such as melanomas (1). Enhanced nuclear translocation of p65/p50 was found in melanoma cell lines in comparison to normal melanocytes (2). Moreover, other in vitro and in vivo studies have shown that NF-κB activity is up-regulated in dysplastic nevi and lesions of human melanoma when compared to human nevi or melanocytes in normal skin (9-11). Largely due to the central role that NF-κB plays in suppressing apoptosis (7), NF-κB activation appears to promote melanoma progression (12-14). The anti-apoptotic mechanisms are essentially based on the ability of NF-κB to activate the transcription of Nuclear factor-κB expression is predictive of overall survival in patients with cutaneous melanoma DANIELA MuRTAS1, FRANCA PIRAS1, LuIGI MINERBA2, JORGE uGALDE1,4, MIChELA PIGA3, CRISTINA MAxIA1, MARIA TERESA PERRA1 and PAOLA SIRIGu1,4 1Department of Cytomorphology, university of Cagliari, 09042 Monserrato (CA); 2Department of Public health, university of Cagliari, 09124 Cagliari; 3Department of Pathology, ‘SS. Trinità’ hospital, 09121 Cagliari, Italy; 4Department of Pathology, Cancer Institute, Cuenca, Ecuador Received March 19, 2010; Accepted May 18, 2010 DOI: 10.3892/ol_00000112 Correspondence to: Professor Paola Sirigu, Department of Cytomorphology, university of Cagliari, Cittadella universitaria, 09042 Monserrato (CA), Italy E-mail: psirigu@unica.it