Clinicopathological significance of major histocompatibility complex class I-related chain a and B expression in thyroid cancer.
BACKGROUND
Major histocompatibility complex class I-related chains A and B (MICA/B) are two stress-inducible ligands for the immunoreceptor NKG2D that is expressed on cytotoxic T cells and natural killer (NK) cells. It is not known whether MICA/B expression is up-regulated in thyroid cancer as a result of oncogene activation.


OBJECTIVE
The objective of the investigation was to study MICA/B expression and regulation in thyroid cancer and its role in mediating the cytotoxicity of NK cells.


METHODS
MICA/B expression in thyroid cancer was analyzed by immunohistochemical staining. Cell surface MICA/B levels in thyroid tumor cell lines and fresh tumor cells were analyzed by flow cytometric analysis. The susceptibility of thyroid tumor cells to NK cell killing was tested by using (51)Cr release assay.


RESULTS
MICA/B was expressed at moderate or high levels in 18 of 39 papillary thyroid carcinomas and four of eight anaplastic thyroid carcinomas. MICA/B expression was confirmed by flow cytometric analysis in three fresh thyroid neoplasms. MICA/B expression was detected in eight of 10 thyroid tumor cell lines and correlated with their sensitivity to killing by the NKG2/D-positive NK-92 cells. Blocking of NKG2D and MICA/B interaction by specific antibodies partially led to the inhibition of NK-92 cell-mediated cytotoxicity. The MAPK inhibitors were able to block MICA/B expression in MRO87 and HeLa cells. Transient transfection of mutant BRAF and RAS oncogenes led to increased MICA/B expression in 293 cells and WRO82 cells.


CONCLUSIONS
MICA/B expression is up-regulated in thyroid cancer, probably due to the activation of the MAPK pathway. MICA/B in thyroid cancer plays an important role in NK-92 cell-mediated cytotoxicity.
Xu
Xiulong
X
Department of General Surgery, Rush University Medical Center, 1653 West Congress Parkway, Chicago, Illinois 60612, USA. xxu@rush.edu
Rao
Geetha
G
Gaffud
Michael J
MJ
Ding
Helen G
HG
Maki
Guitta
G
Klingemann
Hans-G
HG
Groh
Veronika
V
Spies
Thomas
T
Caillat-Zucman
Sophie
S
Gattuso
Paolo
P
Plate
Janet
J
Prinz
Richard A
RA
D000911:Antibodies, Monoclonal; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D011905:Genes, ras / Q000235:genetics; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009154:Mutation; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013964:Thyroid Neoplasms / Q000276:immunology*; D014162:Transfection
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; C527054:KLRC1 protein, human; C527085:KLRK1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases