The Role of B-RAF Mutations in Melanoma and the Induction of EMT via Dysregulation of the NF- B/Snail/RKIP/PTEN Circuit

Abstract

Melanoma is a highly metastatic cancer, and there are no current therapeutic modalities to treat this deadly malignant disease once it has metastasized. Melanoma cancers exhibit B-RAF mutations in up to 70% of cases. B-RAF mutations are responsible, in large part, for the constitutive hyperactivation of survival/antiapoptotic pathways such as the MAPK, NF-κB, and PI3K/AKT. These hyperactivated pathways regulate the expression of genes targeting the initiation of the metastatic cascade, namely, the epithelial to mesenchymal transition (EMT). EMT is the result of the expression of mesenchymal gene products such as fibronectin, vimentin, and metalloproteinases and the invasion and inhibition of E-cadherin. The above pathways cross-talk and regulate each other’s activities and functions. For instance, the NF-κB pathway directly regulates EMT through the transcription of gene products involved in EMT and indirectly through the transcriptional up-regulation of the metastasis inducer Snail. Snail, in turn, suppresses the expression of the metastasis suppressor gene product Raf kinase inhibitor protein RKIP (inhibits the MAPK and the NF-κB pathways) as well as PTEN (inhibits the PI3K/AKT pathway). The role of B-RAF mutations in melanoma and their direct role in the induction of EMT are not clear. This review discusses the hypothesis that B-RAF mutations are involved in the dysregulation of the NF-κB/Snail/RKIP/PTEN circuit and in both the induction of EMT and metastasis. The therapeutic implications of the dysregulation of the above circuit by B-RAF mutations are such that they offer novel targets for therapeutic interventions in the treatment of EMT and metastasis.

Long Pentraxin-3 Inhibits Epithelial–Mesenchymal Transition in Melanoma Cells

“…Data are the mean AE SEM of 30 tissue fields from 3 different implants per group. E and F, C57BL/6 mice (10 animals per group) were injected subcutaneously with 2. of EMT-driving transcription factors, including Snai1 and Snai2 (6), and downregulation of E-cadherin (7), a potent suppressor of tumor cell invasion and metastasis (4,5). In this work, we provide experimental evidences that the FGF2 antagonist PTX3 (18,23) inhibits EMT in melanoma cells, hampering their tumorigenic and metastatic activity in vitro and in vivo.…”

“…After activation of EMT or EMT-like programs, tumor cells lose their epithelial features, including cell adhesion and polarity, reorganize their cytoskeleton, and acquire a mesenchymal morphology and the ability to migrate (3). EMT is mediated by the upregulation of several transcription repressors, including Snai1/Snail, Snai2/Slug, Twist, and ZEB1, and is characterized by increased expression of the mesenchymal markers Vimentin and N-cadherin and downregulation of the E-cadherin gene, an epithelial marker and potent suppressor of tumor cell invasion and metastasis (4,5). Accordingly, Snai1 and Snai2 drive EMT in melanoma (6) and the transition from the radial growth phase to the vertical growth phase during melanoma progression is associated with a more motile and invasive phenotype characterized by E-cadherin downregulation (7).…”

Qualitative changes in the proteome of extracellular vesicles accompanying cancer cell transition to mesenchymal state

“…In a recent study Peinado et al presented a compelling evidence that a part of this process involves transfer of the activated MET receptor from aggressive melanoma cells (donors) to bone marrow derived regulatory cells (BMDCs), the latter of which then control formation of pre-metastatic niches in distant organs [15]. Interestingly, MET is amongst the most potent effectors of EMT [1,53], the features of which have also been observed in melanoma [54]. Indeed, intercellular trafficking of MET during melanoma metastasis could exemplify wider linkages between processes of EMT and vesiculation.…”

Macrophages in skin melanoma-the key element in melanomagenesis (Review)

“…At the dissemination stage in a majority of cases, the disease is resistant to treatment with cytostatics and radiotherapy (1). Therefore, the identification of novel molecular mechanisms involved in the melanomagenesis process and tumor progression have enabled the production of targeted therapies that yield notable effects (1).…”

“…Melanomas are a rare but aggressive cutaneous type of cancer in humans (1). At the dissemination stage in a majority of cases, the disease is resistant to treatment with cytostatics and radiotherapy (1).…”