Distinct MHC gene expression patterns during progression of melanoma |
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| Authors: | Yan Degenhardt Galene Horiates Katherine Nathanson Xiaolu Yang Meenhard Herlyn Barbara Weber |
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| Affiliation: | 1. Cancer Metabolism DPU, Oncology, GlaxoSmithKline, King of Prussia, PAYan Degenhardt, Jia Huang and Joel Greshock contributed equally to this work.;2. Cancer Metabolism DPU, Oncology, GlaxoSmithKline, King of Prussia, PA;3. Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA;4. The Wistar Institute, Philadelphia, PA;5. Novartis Institutes for Biomedical Research, Boston, MA |
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| Abstract: | Abnormal expression of major histocompatibility complex (MHC) molecules in melanoma has been reported previously. However, the MHC molecule expression patterns in different growth phases of melanoma and the underlying mechanisms are not well understood. Here, we demonstrate that in vertical growth phase (VGP) melanomas, MHC genes are subject to increased rates of DNA copy number gains, accompanied by increased expression, in comparison to normal melanocytes. In contrast, MHC expression in metastatic melanomas drastically decreased compared to VGP melanomas, despite still prevalent DNA copy number gains. Subsequent investigations found that the master transactivator of MHC genes, CIITA, was also significantly downregulated in metastatic melanomas when compared to VGP melanomas. This could be one of the mechanisms accounting for the discrepancy between DNA copy number and expression level in metastatic melanomas, a potentially separate mechanism of gene regulation. These results infer a dynamic role of MHC function in melanoma progression. We propose potential mechanisms for the overexpression of MHC molecules in earlier stages of melanoma as well as for its downregulation in metastatic melanomas. © 2009 Wiley‐Liss, Inc. |
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