Nuclear factor-κB expression is predictive of overall survival in patients with cutaneous melanoma

Abstract

Abstract. 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. IntroductionNuclear 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 ...

Abl and Arg mediate cysteine cathepsin secretion to facilitate melanoma invasion and metastasis

“…Thus, Abl/Arg not only affect expression, nuclear translocation, and/or activity of the transcription factors but also markedly promote their binding to cathepsin gene promoters. These data are a critical addition to understanding precisely how these transcription factors promote melanoma development, progression, and therapeutic resistance (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Finally, analysis of Oncomine and TCGA data sets revealed that the expression of Abl/Arg and SP1 or ETS1 mRNAs correlated in primary melanomas (Fig.…”

“…Here, we found that Abl/Arg activation-induced secretion of cathepsins B and L plays a critical role in driving Abl/Arg-dependent melanoma invasion and metastasis. Moreover, our data reveal that Abl/Arg induce mRNA expression, promoter activity, and subsequent secretion of cathepsins by activating transcription factors [namely, Ets1, Sp1, and nuclear factor B (NF-B)/p65] that have well-known roles in epithelialmesenchymal transition (EMT), invasion, and therapeutic resistance (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). These data not only uncover new sig naling pathways mediated by Abl kinases, which are likely applicable to other cancers, but also support a new strategy for inhibiting secretion of cathepsins and consequently metastatic progression.…”

Inhibition of SOX4 induces melanoma cell apoptosis via downregulation of NF-κB p65 signaling

“…NF-κB is one of the most important transcription factors that play a crucial role in the suppression of apoptosis, as well as the induction of cell proliferation and inflammation, which is closely associated with cancer development (21)(22)(23)(24). NF-κB activation is involved in the inhibition of apoptosis by upregulating the expression of anti-apoptotic proteins, including Bcl-2, Mcl-1 and survivin (25).…”

Anti-Inflammatory Activity and Mechanism of Cryptochlorogenic Acid from Ageratina adenophora

“…Inflammation is linked with the NF-κB pathway. NF-κB is a nuclear transcriptional factor that is linked to both pro-and anti-inflammatory activities [28]. In dormant cells, the NF-κB dimers are joined by inhibitory molecules, such as IκB, to keep them stable in the cytoplasm.…”