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M. Onken, L.A. Worley, J. Harbour; Functional Gene Expression Analysis Of Uveal Melanoma Reveals Epithelial Program . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2227.
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© ARVO (1962-2015); The Authors (2016-present)
Microarray gene expression profiling is a powerful tool for generating molecular cancer classifications. However, elucidating biological insights from these large datasets has been challenging. Previously, we identified a gene expression–based classification of primary uveal melanomas that accurately predicts survival. Class 1 tumors have a low risk and class 2 tumors have a high risk of metastatic death. Here, we searched for functional themes underlying the gene expression classification.
We used genes that discriminate the two tumor classes to identify biological functions associated with the class 2 signature, and then verified these findings in cultured cells and our mouse model of aggressive uveal melanoma.
A search for Gene Ontology categories enriched in our class–discriminating gene list revealed down–regulation of neural crest and melanocyte–specific genes and up–regulation of epithelial genes in class 2 tumors. Correspondingly, class 2 tumors exhibited epithelial features, such as polygonal cell morphology, up–regulation of the epithelial adhesion molecule E–cadherin, co–localization of E–cadherin and ß–catenin to the plasma membrane, and formation of cell–cell adhesions and acinar structures. One of our top class–discriminating genes was the helix–loop–helix inhibitor Id2, which was strongly down–regulated in class 2 tumors. The class 2 phenotype was recapitulated in Id2–depleted, cultured human uveal melanoma cells and in an Id2–/– mouse uveal melanoma model. Id2 appeared to suppress the epithelial–like class 2 phenotype through inhibition of a transcriptional activator of the E–cadherin promoter in melanoma cells. As a result, Id2 loss triggered up–regulation of E–cadherin, which in turn promoted anchorage independent cell growth and formation of acinar structures in 3–dimensional culture, both likely antecedents to metastasis.
These findings reveal new roles for Id2 and E–cadherin in uveal melanoma progression, they potentially explain the underlying biology of morphological features traditionally used as prognostic indicators in uveal melanoma, and they suggest new avenues for research into prognosis and therapy.
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