Signaling networks in cutaneous melanoma metastasis identified by complementary DNA microarrays

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. Melanoma and human cancers in general undergo a continuous development from benign to malignant states, as most thoroughly documented in the multistep mole-to-melanoma transition.

To examine how high-throughput microarrays are being used in expression profiling to identify regulated genes, patterns, and pathways that may lead to functional characterization and tumor subclassification.

Ten melanoma metastases were analyzed by DNA array technology for important regulated candidate genes, with subsequent confirmation by real-time reverse transcription polymerase chain reaction.

Hepatocyte growth factor receptor c-met, growth factor receptor-bound protein 10, B-raf proto-oncogene, and several mitogen-activated protein kinase kinase genes were significantly up-regulated in melanoma metastases and several melanoma cell lines relative to normal human melanocytes (P = .03). Among the up-regulated genes, phosphorylated growth factor receptor-bound protein 10 is known to serve a molecular switch turning on the mitogen-activated protein kinase pathway in response to hepatocyte growth factor receptor binding.

As suggested by the DNA arrays, we found the mitogen-activated protein kinase kinase/extracellular-regulated kinase pathway to be activated in most of the cutaneous melanoma metastasis specimens. These findings are in the context of the current microarray technology in melanoma research. Additional steps are needed to gain insights into the pluralistic signaling milieu of this malignancy as we enter the postgenomic era.