Lack of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Shows a New Type of Melanoma

Abstract

The majority of human melanomas harbor activating mutations of either N-RAS or its downstream effector B-RAF, which cause activation of mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) kinase and the ERK MAPK cascade. The melanoma-relevant effectors of ERK activation, however, are largely unknown. In this work, we show that increased ERK activation correlates strongly with mutational status of N-RAS or B-RAF in 21 melanoma cell lines. Melanoma lines that were wild-type for RAS/RAF showed low levels of ERK activation comparable with primary human melanocytes. Through supervised analysis of RNA expression profiles, we identified 82 genes, including TWIST1, HIF1a, and IL-8, which correlated with ERK activation across the panel of cell lines and which decreased with pharmacologic inhibition of ERK activity, suggesting that they are ERK transcriptional targets in melanoma. Additionally, lines lacking mutations of N-RAS and B-RAF were molecularly distinct and characterized by p53 inactivation, reduced ERK activity, and increased expression of epithelial markers. Analysis of primary human melanomas by tissue microarray confirmed a high correlation among expression of these epithelial markers in a heterogeneous sample of 570 primary human tumors, suggesting that a significant frequency of primary melanomas is of this ''epithelial-like'' subtype. These results show a molecularly distinct melanoma subtype that does not require ERK activation or epithelial-mesenchymal transformation for progression. [Cancer Res 2007;67(4):1502-12]

Prognostic Significance of Cadherin-Based Adhesion Molecules in Cutaneous Malignant Melanoma

“…Consistent with the expected phenotype following a successful EMT, cluster 2 corroborates the recent publications by two groups describing worse outcomes among the subset of melanomas who successfully completed an EMT as evidenced by the simultaneous down-regulation of proteins promoting keratinocyte adhesion (e.g., E-cadherin and P-cadherin) and upregulation of proteins that facilitate interactions with and invasion through stroma (e.g., N-cadherin and osteonectin/SPARC; refs. 18,39). Furthermore, the high h-catenin in the setting of low E-cadherin may promote preferential activity of the Wnt signaling cascade (12), another marker associated previously with poor outcome in melanoma (21,22).…”

Tumor necrosis factor α drives cadherin 11 expression in rheumatoid inflammation

“…During this process, which takes place during embryogenesis (45), malignant transformation (46), and chronic inflammatory fibrotic diseases (46), epithelial cells lose the expression of E-cadherin and acquire a mesenchymal phenotype, which is characterized by the expression of mesenchymal cadherins, such as N-cadherin and cadherin 11 (45)(46)(47). Interestingly, several transcriptional repressors of E-cadherin, including Snail, ZEB, and Twist proteins, are driven by inflammatory signaling pathways mediated by NF-B (48-50) and MAPK (51). Moreover, it was recently demonstrated that proteins such as Twist 1 can simultaneously act as transcriptional activators of mesenchymal cadherins such as N-cadherin (52).…”

Growth Factors and Oncogenes as Targets in Melanoma: Lost in Translation?

“…In fact, a microarray analysis of cell lines with and without CDKN2A deletions, coupled with confirmatory RT-PCR on 14 cell lines, identified eight genes consistently differing in expression between the two classes 191 . Conversely, although two studies supported an expression profile difference between NRAS and BRAF mutant tumors 192, 193 , others employing stricter statistical parameters did not 188,194 . Overall, genomewide profiling may provide more specific classification than single-gene sequencing.…”