A novel role of HLA class I in the pathology of medulloblastoma.
BACKGROUND
MHC class I expression by cancer cells enables specific antigen recognition by the immune system and protection of the host. However, in some cancer types MHC class I expression is associated with an unfavorable outcome. We explored the basis of MHC class I association with unfavorable prognostic marker expression in the case of medulloblastoma.


METHODS
We investigated expression of four essential components of MHC class I (heavy chain, beta2m, TAP1 and TAP2) in 10 medulloblastoma mRNA samples, a tissue microarray containing 139 medulloblastoma tissues and 3 medulloblastoma cell lines. Further, in medulloblastoma cell lines we evaluated the effects of HLA class I engagement on activation of ERK1/2 and migration in vitro.


RESULTS
The majority of specimens displayed undetectable or low levels of the heavy chains. Medulloblastomas expressing high levels of HLA class I displayed significantly higher levels of anaplasia and c-myc expression, markers of poor prognosis. Binding of beta2m or a specific antibody to open forms of HLA class I promoted phosphorylation of ERK1/2 in medulloblastoma cell line with high levels, but not in the cell line with low levels of HLA heavy chain. This treatment also promoted ERK1/2 activation dependent migration of medulloblastoma cells.


CONCLUSIONS
MHC class I expression in medulloblastoma is associated with anaplasia and c-myc expression, markers of poor prognosis. Peptide- and/or beta2m-free forms of MHC class I may contribute to a more malignant phenotype of medulloblastoma by modulating activation of signaling molecules such as ERK1/2 that stimulates cell mobility.
Smith
Courtney
C
Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC, USA. smithco@mlhs.org
Santi
Mariarita
M
Rajan
Bhargavi
B
Rushing
Elisabeth J
EJ
Choi
Mi Rim
MR
Rood
Brian R
BR
Cornelison
Robert
R
MacDonald
Tobey J
TJ
Vukmanovic
Stanislav
S
D000708:Anaplasia / Q000473:pathology; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008527:Medulloblastoma / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
D014408:Biomarkers, Tumor; D015395:Histocompatibility Antigens Class I; D016271:Proto-Oncogene Proteins c-myc; D048049:Extracellular Signal-Regulated MAP Kinases; D017493:Leukocyte Common Antigens