Unraveling the genetics behind melanoma and colon cancer

August 14, 2002

Dr. Avri Ben-Ze'ev and colleagues have discovered that when a gene called Nr-CAM, which normally encodes a cell adhesion molecule in neuronal cells, is expressed at high levels in other cell types, it can help drive cancer progression.

As published in Genes & Development, Dr. Ben-Ze'ev and colleagues found that Nr-CAM expression can be induced by two proteins called b-catenin and g-catenin. b-catenin and g-catenin (also known as plakoglobin) are both members of the armadillo protein family which mediate cell-to-cell adhesion. But in addition to its role in cell adhesion, b-catenin also functions in the Wnt intracellular signal transduction cascade, where it activates transcription of a number of genes, including those that promote cell proliferation.

In normal cells, b-catenin is carefully regulated by rapid proteolytic degradation. However, in a variety of tumor types, the b-catenin degradation pathway is disrupted, leading to the aberrant accumulation of b-catenin and, in turn, the deregulation of cell growth. Unlike b-catenin, the role of g-catenin in Wnt signaling and tumorigenesis is less well established.

To uncover novel genes that are activated in response to b- and g-catenin expression, Dr. Ben-Ze'ev and colleagues preformed a DNA microarray analysis of human renal carcinoma cells expressing b-catenin and/or g-catenin. Of 10,000 genes analyzed, Nr-CAM was the most extensively induced by both catenins.

The researchers went on to show that Nr-CAM expression in mouse fibroblast cells causes rapid proliferation in cell culture, and that these cells are capable of forming tumors when injected into live, immunocompromised mice. Dr. Ben-Ze'ev and colleagues also found that Nr-CAM is highly expressed in human melanoma cells and colon cancer tissue. These multiple lines of evidence strongly suggest that Nr-CAM is a novel b- and g-catenin target gene whose expression contributes to tumorigenesis.

Further research will be aimed at elucidating the mechanism of Nr-CAM action in the development of these prevalent cancer types. Since Nr-CAM is expressed on the outer surface of cells, the researchers anticipate that anti-cancer therapies based on Nr-CAM targeting will be easier than with molecules expressed inside the cell.

Cold Spring Harbor Laboratory

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