DOI: 10.1097/01.cji.0000190997.94115.55
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Issn Print: 1524-9557
Publication Date: 2005/11/01
Signaling Networks in Cutaneous Melanoma Metastasis Identified by cDNA Microarrays
Sandeep Nambiar; Alireza Mirmohammadsadegh; Roya Doroudi; Mohamad Hassan; Annett Gustrau; Alessandra Marini; Helger Stege; Gernot Roeder; Thomas Ruzicka; Ulrich R Hengge
+ Author Information
Author Information: Dept. of Dermatology, Heinrich-Heine-University, Duesseldorf, Germany;
Excerpt
Melanoma is a complex multigenic disease, susceptibility to which is determined by several parallel and stepwise progressive pathways affecting growth control, differentiation, cell adhesion and survival. High-throughput microarrays are being used in expression profiling with the objectives of identifying regulated genes, patterns and pathways, leading to functional characterization and tumor subclassification. Towards a molecular profile of melanoma, we analyzed 10 melanoma metastases by DNA array technology and identified several important regulated candidate genes, which were subsequently confirmed by Real-time RT-PCR. We identified hepatocyte growth factor (HGF) receptor (c-Met), growth factor receptor-bound protein (Grb)-10, B-RAF and several MAP kinase kinases (MAPKK) as being significantly upregulated in melanoma metastases and several melanoma cell lines relative to normal human melanocytes (p = 0.03). Among the upregulated genes, phosphorylated Grb10 is known to serve as a molecular switch turning on the MAPK pathway in response to HGF receptor binding. Our data suggest that the transcriptional activation of c-Met is correlated with phosphorylated Grb-10 in melanoma metastasis and subsequent activation of the Raf/MEK/ERK pathway as evidenced from elevated phosphorylation of ERK1/2 proteins. Although phosphorylated Grb-10 was associated with increased signaling through the MEK/ERK pathway, it is known to inhibit IGF receptor signaling. Therefore the HGF/c-Met/Grb10/Raf/MEK/ERK pathway seems important in eliciting cell cycle progression, proliferation and migration in cutaneous melanoma metastasis, with phosphorylation of Grb-10 serving as a critical regulatory event.
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