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M. Onken, J.P. Ehlers, L. Worley, J.W. Harbour; The helix–loop–helix inhibitor Id2 functions as a tumor suppressor in uveal melanoma . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1193.
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Purpose: Id2 is a dominant–negative inhibitor of basic helix–loop–helix (bHLH) transcription factors that is thought to inhibit cell differentiation, and promote cell proliferation and immortalization. Previous work implicating Id2 as a potential proto–oncogene has shown that it inhibits the Rb tumor suppressor protein, acts as a downstream effector of the Myc proto–oncogene family, and is up–regulated in some cancers. Here we demonstrate a role for Id2 in uveal melanoma. Methods: We used DNA microarray and qPCR to determine levels of Id2 gene expression in human uveal melanoma tumor samples. We used an antisense Id2 expression construct to deplete Id2 in cultured human primary uveal melanoma cells. We then crossed Id2 knockout mice with mice that develop small, spindle–like melanotic eye tumors to determine a role for Id2 in these tumors. Results: We found by gene expression profiling that Id2 mRNA was present in spindle melanomas and absent in epithelioid melanomas. Levels progressively decreased from normal uveal melanocytes to low–grade melanomas to high–grade melanomas, and that low Id2 mRNA expression in tumors predicted metastatic death in patients. We also found that loss of Id2 transformed well–differentiated, spindle melanoma cells in culture into poorly–differentiated, epithelioid cells with enhanced anchorage–independent survival and growth. In our mice, deletion of Id2 resulted in large uveal tumors with a vertical growth phase and cellular morphology resembling epithelioid melanomas in humans. Conclusions: It has been shown that Id2 overexpression can drive the transition of epithelium into melanocyte precursor cells during development, suggesting that Id2 may suppress tumor progression in melanoma by maintaining a more differentiated phenotype. Furthermore, methylation–specific PCR comparing the extent of promoter methylation between human epithelioid and spindle–cell melanomas showed a direct correlation between Id2 mRNA expression levels and promoter methylation. This suggests that the same mechanism that regulates Id2 developmentally is used to select against Id2 during tumor progression in uveal melanoma.
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