Distinct MHC gene expression patterns during progression of melanoma.
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.
Degenhardt
Yan
Y
Cancer Metabolism DPU, Oncology, GlaxoSmithKline, King of Prussia, PA 19406, USA. yan.y.degenhardt@gsk.com
Huang
Jia
J
Greshock
Joel
J
Horiates
Galene
G
Nathanson
Katherine
K
Yang
Xiaolu
X
Herlyn
Meenhard
M
Weber
Barbara
B
D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D015153:Blotting, Western; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D015536:Down-Regulation; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008544:Melanocytes / Q000166:cytology / Q000276:immunology; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012016:Reference Values; D014158:Transcription, Genetic
D000944:Antigens, Differentiation, B-Lymphocyte; D017931:DNA Primers; D000949:Histocompatibility Antigens Class II; C045084:invariant chain