MHC class I molecules act as tumor suppressor genes regulating the cell cycle gene expression, invasion and intrinsic tumorigenicity of melanoma cells.
The alteration of MHC class I (MHC-I) expression is a frequent event during cancer progression, allowing tumor cells to evade the immune system. We report that the loss of one major histocompatibility complex haplotype in human melanoma cells not only allowed them to evade immunosurveillance but also increased their intrinsic oncogenic potential. A second successive defect in MHC-I expression, MHC-I total downregulation, gave rise to melanoma cells that were more oncogenic per se in vivo and showed a higher proliferation rate and greater migratory and invasive potential in vitro. All these processes were reversed by restoring MHC-I expression via human leukocite antigen-A2 gene transfection. MHC-I cell surface expression was inversely correlated with intrinsic oncogenic potential. Modifications in the expression of various cell cycle genes were correlated with changes in MHC-I expression; the most important differences among the melanoma cell lines were in the transcriptional level of AP2-alpha, cyclin A1 and p21WAF1/CIP1. According to these results, altered MHC-I expression in malignant cells can directly increase their intrinsic oncogenic and invasive potential and modulate the expression of cell cycle genes. These findings suggest that human leukocite antigen class I molecules may act directly as tumor suppressor genes in melanoma.
Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, 18012 Granada, Spain.
Cristina
C
Garrido
Laura
L
Paco
Irene
I
Romero
Enrique
E
Berruguilla
Julia
J
Stefansky
Antonia
A
Collado
Ignacio
I
Algarra
Federico
F
Garrido
Angel M
AM
Garcia-Lora
D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D056750:Cyclin A1 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050556:Fatty Acid-Binding Proteins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D005805:Genes, MHC Class I; D016147:Genes, Tumor Suppressor; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness
C503745:CCNA1 protein, human; C493956:CDKN1A protein, human; D056750:Cyclin A1; D050759:Cyclin-Dependent Kinase Inhibitor p21; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D015395:Histocompatibility Antigens Class I